Vitamin B2 injection composition and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to a vitamin B2 injection composition and a preparation method thereof. The invention provides a preparation method of a vitamin B2 injection composition, which comprises the following steps: mixing malic acid, citric acid and propylene glycol, heating to 80-90 DEG C, and continuously stirring until transparent liquid is formed; adding zein and riboflavin sodium phosphate into the transparent liquid under a dark condition, and carrying out heat preservation reaction at 25-30 DEG C for at least 30 seconds to obtain a stock solution; and mixing the stock solution, an auxiliary agent and water to prepare the vitamin B2 injection composition with the pH value of 4.5-6.5. The deep eutectic solvent is prepared from malic acid, citric acid and propylene glycol, the zein and the riboflavin sodium phosphate are uniformly mixed, and the prepared vitamin B2 injection composition has good light stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology and relates to a vitamin B2 injection composition and its preparation method. Background Technology

[0002] Riboflavin, or vitamin B2, is an essential water-soluble vitamin for the human body, playing a crucial role in growth, metabolism, and development. It is a component of coenzymes such as flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), and is widely involved in the redox reactions and energy metabolism of carbohydrates, proteins, and fats. Clinically, vitamin B2 is widely used to prevent and treat riboflavin deficiency, such as angular cheilitis, glossitis, conjunctivitis, and scrotal dermatitis. It is also an important component in many compound vitamin preparations and nutritional infusions. In pharmaceutical preparations, its derivative, riboflavin 5'-monophosphate sodium, is often used as a raw material to enhance water solubility and stability. However, both riboflavin and riboflavin 5'-monophosphate sodium share a highly conjugated chromophore in their molecular structure, a structural characteristic that, while enabling electron transport, also makes them extremely sensitive to light, especially ultraviolet light and the blue-violet region of visible light. Under light, riboflavin molecules are excited to undergo photochemical reactions, which trigger irreversible degradation. The degradation pathway mainly includes photoreduction and photooxidation reactions, generating a series of degradation products such as photoflavin and photopigment. These products not only lose their original vitamin activity, but may also bring potential safety risks.

[0003] The light instability of vitamin B2 injection has long been a serious challenge in its formulation development, production, storage, and clinical use. This problem manifests itself in several ways: First, while partial light protection measures can be taken during production and filling, complete light isolation is difficult, costly, and unreliable. Second, in distribution and storage, insufficient light protection or prolonged exposure to inappropriate light can significantly reduce the effective drug content, affecting efficacy and potentially exceeding the pharmacopoeia's impurity limits due to the accumulation of degradation products. Finally, before clinical use, infusion bags typically need to be exposed to indoor light for preparation and infusion, a process that can last for several hours, potentially causing significant loss of efficacy. To overcome this technical bottleneck, those skilled in the art have explored various strategies. The most common solution is to use brown or amber-colored glass ampoules or bottles for packaging, utilizing the glass's color to block some harmful light. However, this method has several limitations: First, light-blocking glass does not block 100% of certain wavelengths of light (such as some visible light), and there is still a risk of degradation during long-term storage; second, it cannot solve the problem of exposure that can last for several hours from preparation to infusion during clinical use; third, brown glass poses a risk of heavy metal leaching and is not conducive to medical staff observing the clarity of the solution and the presence of sediment. In addition, colored glass is expensive and fragile, making it less than ideal. Another approach is to improve the formulation and process. For example, antioxidants (such as sulfites and ascorbic acid) or chelating agents (such as EDTA-2Na) can be added to the injection formulation to inhibit oxidation. However, the photodegradation mechanism of riboflavin is complex, and a single antioxidant pathway often has limited effectiveness. Some studies have also attempted to improve stability by adjusting the pH value to its most stable range (usually acidic to weakly acidic) or by preparing it as a lyophilized powder for injection. However, powder injections have problems such as the need for reconstitution before use, increased operational steps and contamination risks, and high costs, and they also face the same photostability issues after reconstitution.

[0004] In summary, current technologies for addressing the photostability issue of vitamin B2 injections largely rely on passive light protection or limited excipient addition, lacking a novel stabilization strategy that actively and efficiently protects riboflavin molecules at the molecular level throughout the entire formulation and its lifecycle. Therefore, there is an urgent need to develop a vitamin B2 injection composition and its preparation method that can fundamentally and significantly improve its photochemical stability, ensuring efficacy and safety throughout the entire process from production to clinical use, while also being technologically feasible and cost-effective. Summary of the Invention

[0005] The purpose of this invention is to solve the technical problem of poor photostability in vitamin B2 injection. This invention uses malic acid, citric acid, and propylene glycol to prepare a eutectic solvent, achieving homogeneous mixing of zein and riboflavin sodium phosphate, resulting in a vitamin B2 injection composition with good photostability.

[0006] On one hand, the present invention relates to a method for preparing a vitamin B2 injection composition, comprising: mixing malic acid, citric acid and propylene glycol, heating to 80-90°C and stirring continuously until a transparent liquid is formed; The stock solution is prepared by adding zein and riboflavin sodium phosphate to the transparent liquid under light-protected conditions and reacting at 25-30°C for at least 30 seconds. The stock solution, adjuvants, and water are mixed to prepare a vitamin B2 injection composition with a pH value of 4.5-6.5.

[0007] Furthermore, in the preparation method of the vitamin B2 injection composition provided by the present invention, the weight ratio of malic acid, citric acid and propylene glycol is 1:1.5:2.5~3.5.

[0008] Furthermore, in the preparation method of the vitamin B2 injection composition provided by the present invention, the weight ratio of zein and riboflavin sodium phosphate is 0.1~1:1.

[0009] Furthermore, in the preparation method of the vitamin B2 injection composition provided by the present invention, the weight ratio of the sodium riboflavin phosphate to the transparent liquid is 1:2~4.

[0010] Furthermore, in the preparation method of the vitamin B2 injection composition provided by the present invention, the adjuvant is selected from at least one of a self-solvent, a chelating agent, a polyol, or a pH adjuster.

[0011] Furthermore, in the preparation method of the vitamin B2 injection composition provided by the present invention, the cosolvent is nicotinamide.

[0012] Furthermore, in the preparation method of the vitamin B2 injection composition provided by the present invention, the chelating agent is selected from at least one of sodium edetate, sodium citrate, or sodium succinate.

[0013] Furthermore, in the preparation method of the vitamin B2 injection composition provided by the present invention, the polyol is selected from at least one of propylene glycol, ethylene glycol or glycerol.

[0014] Furthermore, in the preparation method of the vitamin B2 injection composition provided by the present invention, the pH adjuster is selected from hydrochloric acid or sodium hydroxide.

[0015] On the other hand, the present invention relates to a vitamin B2 injection composition, which is prepared by the method described above for preparing the vitamin B2 injection composition.

[0016] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages: This invention utilizes malic acid, citric acid, and propylene glycol to prepare a eutectic solvent, achieving homogeneous mixing of zein and riboflavin sodium phosphate, resulting in a vitamin B2 injection composition with good photostability. This eutectic solvent, as an excellent reaction medium and carrier, can simultaneously and fully dissolve zein and riboflavin sodium phosphate stably and homogeneously, achieving a certain degree of molecular-level complexation. In acidic solutions, zein undergoes a conformational change; pre-mixing and this conformational change are prerequisites for zein to better exert its photoprotective effect. As a natural compound, zein acts as a photostabilizer, protectant, and sacrificial agent. Its molecular structure preferentially absorbs ultraviolet light or quenches reactive oxygen species generated by photoexcitation, effectively shielding or protecting the photosensitive riboflavin sodium phosphate molecules from photochemical degradation. Detailed Implementation

[0017] The technical solution of the present invention will be described below with reference to embodiments; however, the present invention is not limited to the following embodiments. Unless otherwise specified, the experimental and detection methods described in each embodiment are conventional methods; unless otherwise specified, the reagents and materials are commercially available. Unless otherwise specified, all percentages in the following embodiments refer to weight percentages. Unless otherwise specified, all ratios in the following embodiments refer to weight ratios.

[0018] The CAS number of the zein used in the following examples is 9010-66-6, which is a medical excipient.

[0019] Example 1 This embodiment provides a preparation process for a vitamin B2 injection composition.

[0020] Step 1: Place malic acid, citric acid and propylene glycol in a round-bottom flask in a weight ratio of 1:1.5:2.5~3.5, heat in a water bath to 80~90℃ and stir constantly until a transparent liquid is formed.

[0021] Step 2: Maintain a temperature of 25~30℃, and add zein and sodium riboflavin phosphate sequentially to the transparent liquid under light-protected conditions. Keep the reaction at this temperature for at least 30 seconds to obtain the stock solution. The weight ratio of zein to sodium riboflavin phosphate is 0.1~1:1, and the weight ratio of sodium riboflavin phosphate to the transparent liquid is 1:2~4.

[0022] Step 3: Take a new round-bottom flask, add an appropriate amount of water (1 / 2 of the total water volume), add chelating agent, solubilizer and polyol and stir to dissolve, then add the stock solution obtained in step 2 and the remaining water, stir thoroughly and then add pH adjuster to a pH value of 4.5~6.5 to obtain the vitamin B2 injection composition.

[0023] Optionally, the cosolvent is nicotinamide, the chelating agent is selected from at least one of sodium edetate, sodium citrate or sodium succinate, the polyol is selected from at least one of propylene glycol, ethylene glycol or glycerol, the pH adjuster is selected from hydrochloric acid or sodium hydroxide, and the water is deionized water, water for injection or double-distilled water.

[0024] Optionally, nitrogen gas is continuously introduced during the preparation process in step 3.

[0025] Based on the above preparation process, this embodiment provides the following formulation: Table 1 Formulation of Vitamin B2 Injection Composition Comparative Example 1 This comparative example is the same as formulation 1 in Example 1, except that it does not contain zein. Comparative Example 2 This comparative example is the same as formulation 1 in Example 1, except that it does not contain malic acid. Comparative Example 3 This comparative example is the same as formulation 1 in Example 1, except that it does not contain citric acid. Comparative Example 4 This comparative example is the same as formulation 1 in Example 1, except that it does not contain propylene glycol.

[0026] Comparative Example 5 This comparative example is the same as formulation 1 in Example 1, except that the preparation process is as follows: Add an appropriate amount of water (1 / 2 of the total water volume) to a round-bottom flask, add chelating agent, solubilizer and polyol and stir to dissolve. Then add malic acid, citric acid, propylene glycol, zein, riboflavin sodium phosphate and the remaining water. Stir thoroughly and then add pH adjuster to pH 4.5 to obtain the vitamin B2 injection composition.

[0027] Example 2 This embodiment provides the verification process for the vitamin B2 injection composition configured above.

[0028] The prepared vitamin B2 injection solution was divided into two portions. One portion was placed in a 500 mL white volumetric flask and designated as Sample A; the other portion was placed in a 500 mL brown volumetric flask and stored away from light, designated as Sample B. Sample A was placed on a reagent rack in a room where it was exposed to direct sunlight during the day (10 cm from a south-facing window with an area of ​​approximately 3 m²). 2 Let it stand for 7 days.

[0029] Because there is a good linear relationship between the fluorescence emission peak intensity and concentration of vitamin B2 solution at low concentrations, the change in vitamin B2 concentration in the vitamin B2 injection composition after standing for 7 days was measured using a fluorescence method. The resulting calibration curve equation for vitamin B2 was I = 154.78 × C, with a correlation coefficient R of 0.99913. Where I represents the fluorescence emission peak intensity, and C represents the concentration of riboflavin sodium phosphate (%).

[0030] Degradation rate M = [(0.1% - concentration of riboflavin sodium phosphate in the sample after standing for 7 days) / 0.1%] × 100%.

[0031] The experimental results are shown in Table 2.

[0032] Table 2 Degradation rate of vitamin B2 injection composition As shown in Table 2, the vitamin B2 injection composition and its stepwise preparation process provided in Example 1 significantly improve the photostability of the product. Formula 4, with optimized zein content and pH, showed the best performance, with a degradation rate of only 2.18% after 7 days of light exposure. Conversely, the absence of any one of the following components (Comparative Examples 1-4) – zein, malic acid, citric acid, or propylene glycol – led to a sharp increase in degradation rate exceeding 60%. Furthermore, changing the preparation process (Comparative Example 5) increased the degradation rate to 54.69%, far exceeding the 10.57% of Formula 1. This indicates that the use of malic acid, citric acid, and propylene glycol as a eutectic solvent allows for the fusion of zein and riboflavin sodium phosphate, and this extraction and fusion process is beneficial to the photostability of the vitamin B2 injection composition.

[0033] As described above, the basic principles, main features, and advantages of the present invention have been well described. The above embodiments and specifications are merely descriptions of preferred embodiments of the present invention, and the present invention is not limited to the above embodiments. Various changes and improvements made to the technical solutions of the present invention by those skilled in the art without departing from the spirit and scope of the present invention should fall within the protection scope defined by the present invention.

Claims

1. A method for preparing a vitamin B2 injection composition, characterized in that, include: Mix malic acid, citric acid and propylene glycol, heat to 80-90°C and stir constantly until a transparent liquid is formed; The stock solution was prepared by adding zein and riboflavin sodium phosphate to the transparent liquid under light-protected conditions and reacting at 25-30°C for at least 30 seconds. The stock solution, adjuvants, and water are mixed to prepare a vitamin B2 injection composition with a pH value of 4.5-6.

5.

2. The method for preparing the vitamin B2 injection composition according to claim 1, characterized in that, The weight ratio of malic acid, citric acid and propylene glycol is 1:1.5:2.5~3.

5.

3. The method for preparing the vitamin B2 injection composition according to claim 1, characterized in that, The weight ratio of zein to riboflavin sodium phosphate is 0.1 to 1:

1.

4. The method for preparing the vitamin B2 injection composition according to claim 1, characterized in that, The weight ratio of the sodium riboflavin phosphate to the transparent liquid is 1:2~4.

5. The method for preparing the vitamin B2 injection composition according to claim 1, characterized in that, The auxiliary agent is selected from at least one of self-solvent, chelating agent, polyol or pH adjuster.

6. The method for preparing the vitamin B2 injection composition according to claim 5, characterized in that, The co-solvent is nicotinamide.

7. The method for preparing the vitamin B2 injection composition according to claim 5, characterized in that, The chelating agent is selected from at least one of sodium edetate, sodium citrate, or sodium succinate.

8. The method for preparing the vitamin B2 injection composition according to claim 5, characterized in that, The polyol is selected from at least one of propylene glycol, ethylene glycol, or glycerol.

9. The method for preparing the vitamin B2 injection composition according to claim 5, characterized in that, The pH adjuster is selected from hydrochloric acid or sodium hydroxide.

10. A vitamin B2 injection composition, characterized in that, It is prepared by the method of any one of claims 1 to 9 for the preparation of vitamin B2 injection composition.

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