High-purity alkaline compound vitamin C composition as well as liposome soft capsule and preparation method thereof

Abstract

The invention belongs to the technical field of health care products or medicines, and discloses a high-purity alkaline compound vitamin C composition, and a liposome soft capsule and a preparation method thereof. The invention firstly provides a composition composed of sodium ascorbate, sodium erythorbate and the like, and the sodium erythorbate and trisodium citrate are utilized to synergistically construct a chemical dual-stability barrier. On the basis, the composition is further encapsulated through a low-temperature oxygen-free liposome preparation process to form a physical protection barrier capable of improving bioavailability, and the composition is prepared into a soft capsule dosage form. According to the preparation method disclosed by the invention, low-temperature and inert gas protection measures run through all the time, and the preparation method not only comprises superfine grinding and mixing of the core composition, but also comprises low-temperature and high-pressure homogenization and subsequent filling processes of the lipidosome. The final product is alkalescent and good in stability, and the absorption rate of active ingredients is remarkably improved through a liposome delivery system.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of health products or pharmaceuticals, and particularly relates to a high-purity alkaline compound vitamin C composition, a liposome soft capsule thereof and a preparation method. BACKGROUND

[0002] Vitamin C, also known as ascorbic acid, is one of the core nutrients necessary for maintaining normal physiological functions of the human body. Research has found that existing vitamin C products on the market generally have the following problems: 1. Acid irritation problem: Traditional vitamin C products mainly exist in the form of ascorbic acid, and its aqueous solution is significantly acidic (pH value is usually between 2-3). Although this acidity is safe for most people, for people who need to supplement vitamin C for a long time and in large doses, or for consumers with a more sensitive gastrointestinal tract (such as those with gastritis or gastric ulcers), continuous acid intake can irritate the gastric mucosa and cause discomfort, thereby limiting the product's target population and compliance.

[0003] 2. Chemical instability problem: The molecular structure of vitamin C contains an enediol group, which makes it have strong reducing properties and also leads to its highly unstable chemical properties. It is highly sensitive to various environmental factors and can easily be oxidized and decomposed, thus losing its effectiveness. This instability results in a continuous decrease in the content of active ingredients during the production, storage, transportation, and even use by the end consumer, which not only reduces the actual efficacy of the product but also greatly shortens the effective shelf life of the product.

[0004] To solve the above problems, existing technologies have made some attempts, but all have deficiencies. For example, some products add alkaline substances such as sodium bicarbonate to neutralize the acidity, but this can cause gas (burping) when taken and introduce too much sodium ion; some products add a single antioxidant (such as sulfite), but this can pose a safety hazard and has limited protective effect; some complex formulations are simply a simple superposition of multiple nutrients without considering the synergistic effect between components, and may even have an antagonistic effect. In terms of preparation process, traditional mixing and drying methods often have long processes, high energy consumption, and it is difficult to precisely control key factors such as temperature and oxygen, resulting in a considerable loss of active ingredients during the production process. In addition, even if the stability and taste of traditional vitamin C products are improved, their bioavailability after oral administration still has room for improvement. Some of the active ingredients may be destroyed before reaching the absorption site when ordinary powders or tablets pass through the gastrointestinal tract.

[0005] In summary, there is an urgent need in the market for a vitamin C product that can simultaneously solve the problems of acid irritation, chemical instability, and poor physical properties, and a preparation method that can ensure its high quality and be scaled up for production. SUMMARY

[0006] The present application aims to overcome the deficiencies of the prior art, and provides a high-purity alkaline compound vitamin C composition which is scientifically formulated, stable in properties, high in purity, good in bioavailability, and mild and non-irritating to the human body, and a preparation method thereof.

[0007] The above technical objective of the present application is achieved by the following technical solution: a high-purity alkaline compound vitamin C composition, comprising the following components: sodium ascorbate; sodium erythorbate; sodium selenite or a premix thereof; erythritol; trisodium citrate; and nano-silicon dioxide.

[0008] Further, the components constitute the following by weight: sodium ascorbate: 60-80 parts; sodium erythorbate: 15-25 parts; sodium selenite premix (1% sodium selenite content): 0.01-0.1 parts; erythritol: 1-10 parts; trisodium citrate: 0.5-2 parts; nano-silicon dioxide: 0.1-0.5 parts.

[0009] Further, the pH value of the aqueous solution of the composition after being dissolved in pure water is 7.2 to 7.8.

[0010] A preparation method of a high-purity alkaline compound vitamin C composition, comprising the following steps: a) ultrafine grinding pretreatment: sodium ascorbate and sodium erythorbate are ultrafine ground at a low temperature below 5°C and in an inert gas protection environment to obtain a main material powder; b) gradient dry mixing: the main material powder is mixed with a supplementary material premix in stages in a gradient manner in an oxygen-free environment, the supplementary material premix comprising sodium selenite, trisodium citrate, nano-silicon dioxide, and erythritol which are premixed uniformly; c) low-temperature oxygen-free drying: the uniformly mixed material in step b) is dried in an environment protected by inert gas at -5°C to 5°C.

[0011] Further, in step a), the ultrafine grinding grinds the raw material to a particle size D90 of less than 50 microns.

[0012] Further, in step b), the gradient mixing includes adding the auxiliary material premix into the main material powder for mixing at least twice.

[0013] Further, the inert gas in step a) or step c) is nitrogen.

[0014] Further, all steps of the preparation method are performed in an environment with a relative humidity of less than 40%.

[0015] A liposome soft capsule, the content of which is a liposome suspension containing a high-purity alkaline complex vitamin C composition, the composition comprising sodium ascorbate, sodium erythorbate, sodium selenite or a premix thereof, erythritol, trisodium citrate and nanometer silicon dioxide.

[0016] Further, the liposome suspension comprises the following components: the aforementioned composition as the core active substance; and pharmaceutically acceptable auxiliary materials such as phospholipids and cholesterol. Preferably, the phospholipids are soybean phospholipids or egg yolk lecithin.

[0017] A preparation method of a liposome soft capsule, characterized in that the method comprises encapsulating the aforementioned high-purity alkaline complex vitamin C composition in phospholipid vesicles through a liposome preparation process under low temperature and inert gas protection, and performing soft capsule filling; the liposome preparation process comprises a low-temperature high-pressure homogenization step.

[0018] Further, in the liposome preparation process, the pressure of the low-temperature high-pressure homogenization is 100-150 MPa, the cycle number is 3-5 times, and the temperature of the material is controlled to be below 10°C throughout the process through jacket cooling.

[0019] Compared with the prior art, the present application has the following beneficial effects: 1. The present application constructs a dual protection mechanism of antioxidant and chelation of metal ions through the synergistic effect of sodium erythorbate and trisodium citrate. Figure 3 According to, sodium erythorbate as a reducing agent preferentially consumes oxygen in the system, while trisodium citrate removes trace metal ions that can catalyze oxidation reactions through chelation. This multi-path protection method, combined with the whole-process low-temperature oxygen-free preparation process, effectively inhibits the degradation of vitamin C. After being placed in the accelerated stability test (40°C, relative humidity 75%) for 6 months, the vitamin C content retention rate of the product of the present application can reach 98.5% or more, compared with the comparative sample using the traditional formula and process (the content retention rate is usually less than 85%), the stability is greatly improved, which helps to prolong the effective shelf life of the product.

[0020] 2、The buffer system constructed by the trisodium citrate can stably maintain the pH value of the aqueous solution of the composition in the weak alkaline range of 7.2 to 7.8. The pH range is close to the human body environment, avoiding the irritation of the traditional ascorbic acid product to the gastrointestinal tract of some users due to its inherent acidity. This makes the product more suitable for people who need long-term or large-dose vitamin C supplementation, improving the applicability and use compliance of the product.

[0021] 3、The application introduces nanosilica as a functional excipient, which effectively solves the problem of moisture absorption and caking of vitamin C powder raw materials due to its excellent anti-adhesion and flowability. Synergistic effect with erythritol enables the final product to maintain good loose state and dispersibility under long-term storage conditions. Excellent powder flowability also provides convenience for subsequent automated production (such as high-speed capsule filling or tabletting), which helps to ensure dose uniformity.

[0022] 4、The application further prepares the core composition into a liposome soft capsule, which utilizes the phospholipid bilayer structure to form physical protection for the active ingredients, so as to prevent them from being destroyed in the digestive environment and promote their efficient absorption in the intestinal tract, so that the bioavailability of the liposome dosage form of the application is much higher than that of ordinary powder preparations, ensuring that the nutritional ingredients can more effectively act on the human body and exert their physiological effects. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The structural composition diagram of the high-purity basic compound vitamin C composition of the application; Figure 2 The overall preparation process flow chart of the composition of the application; Figure 3 The mechanism diagram of the synergistic stabilizing effect of the composition of the application; Figure 4 The drug-time curve comparison diagram of the composition (control group) and the liposome preparation (experimental group) of the application. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical scheme and advantages of the application more clear, the following will combine the drawings, multiple examples and comparative examples to further describe the application in detail. It should be understood that the specific examples and comparative examples described herein are only used to explain the application, and are not used to limit the protection scope of the application.

[0025] Example 1 The embodiment provides a high-purity alkaline vitamin C composition, the components of which are as claimed in claim 2, and specifically, in parts by weight: 70 parts of sodium ascorbate, 20 parts of sodium erythorbate, 0.05 parts of sodium selenite premix (sodium selenite content 1%), 5 parts of erythritol, 1 part of trisodium citrate, and 0.2 parts of nano-silicon dioxide. The functional positioning and hierarchical relationship of the components can be referred to the structure block diagram shown in Figure 1

[0026] The preparation method refers to the overall process shown in Figure 2 , and the specific steps are as follows: Step a) ultrafine grinding pretreatment (corresponding to the second block in Figure 2 ): 70 kg of sodium ascorbate and 20 kg of sodium erythorbate are put into a jacketed low-temperature pulverizer, the temperature in the bin is controlled at 0°C±2°C through jacket cooling, and nitrogen is filled to make the oxygen content lower than 0.5%. The device is started to perform ultrafine grinding, and the particle size D90 of the discharged powder is controlled to be 45μm.

[0027] Step b) gradient dry mixing (corresponding to the fifth block in Figure 2 ): first, 0.05 kg of sodium selenite premix, 1 kg of trisodium citrate, 0.2 kg of nano-silicon dioxide and 1 kg of erythritol are premixed for 25 minutes to prepare “auxiliary premix A” (corresponding to the fourth block in Figure 2 ): then, the main material powder obtained in step a) is premixed with the remaining 4 kg of erythritol at low speed for 15 minutes in an oxygen-free environment (corresponding to the third block in Figure 2 ): then, “auxiliary premix A” is added in three times with an interval of 10 minutes. This gradient addition mode is designed to ensure uniform dispersion of trace auxiliary materials in a large amount of main materials. After the addition is completed, the mixing is continued for 30 minutes.

[0028] Step c) low-temperature oxygen-free drying (corresponding to the sixth block in Figure 2 ): the final mixture obtained in step b) is maintained in an oxygen-free environment in the mixer, and the material temperature is controlled at 0°C±2°C, and vacuum drying is performed for 4 hours to remove trace moisture.

[0029] The entire preparation process is carried out in an environment with a temperature of 20°C and a relative humidity of less than 40%. Finally, a powder-shaped composition with good fluidity is obtained, and product packaging is performed (corresponding to the seventh block in Figure 2 ): the pH value of the aqueous solution is measured to be 7.5 after sampling and dissolving in pure water.

[0030] Example 2 ​A composition comprising the following components in the following proportions: sodium ascorbate 60 parts, sodium erythorbate 25 parts, sodium selenite premix (1%) 0.01 parts, erythritol 8 parts, trisodium citrate 0.5 parts, nano-silica 0.1 parts. The preparation method is the same as in Example 1, except that in step b) the "excipient premix A" is added in two portions. The pH of the final product is 7.3.

[0031] Example 3 A composition comprising the following components in the following proportions: sodium ascorbate 80 parts, sodium erythorbate 15 parts, sodium selenite premix (1%) 0.1 parts, erythritol 1 part, trisodium citrate 2 parts, nano-silica 0.5 parts. The preparation method is the same as in Example 1. The pH of the final product is 7.8.

[0032] Example 4 This example provides a liposome soft capsule prepared based on the composition described in Example 1.

[0033] 1. Liposome preparation: accurately weigh 30 kg of soybean phospholipid and 3 kg of cholesterol, dissolve in an appropriate amount of anhydrous ethanol. Disperse 10 kg of the composition powder prepared in Example 1 in 67 kg of purified water in a nitrogen-protected low-temperature jacketed tank, maintaining the temperature at 5°C to obtain an aqueous suspension. Using a high-pressure homogenization method, the above phospholipid ethanol solution and aqueous suspension are pre-mixed at 5°C under nitrogen protection, and then homogenized at a pressure of 120 MPa for 4 cycles, with the outlet material temperature being ensured not to exceed 8°C by circulating cooling water throughout the process.

[0034] Finally, a liposome suspension encapsulating the composition is obtained. In the suspension, the composition as the core active substance is encapsulated inside a near-spherical closed vesicular structure composed of a phospholipid bilayer. Through detection, the average particle size of the obtained liposome is 150 nm.

[0035] 2. Soft capsule preparation and filling: transfer the above liposome suspension to a nitrogen-protected low-temperature tank, use a soft capsule press to fill under the following conditions: 18°C, relative humidity 35%, and throughout the process in a light-protected environment, with each capsule containing 500 mg of content, to obtain high-purity basic complex vitamin C liposome soft capsule finished products.

[0036] Comparative Example 1 A conventional vitamin C composition containing only ascorbic acid 100 parts. Mix at room temperature in an air environment for 30 minutes.

[0037] Comparative Example 2 A composition not containing trisodium citrate, with the remaining components and preparation method being the same as in Example 1.

[0038] Comparative Example 3 The composition without sodium erythorbate, the rest of the components and the preparation method are the same as those in Example 1.

[0039] Comparative Example 4 The composition prepared by the traditional process, the components are the same as those in Example 1, but the preparation method is: all components are added to a V-type mixer at one time, and mixed at room temperature in an air environment for 30 minutes.

[0040] Effect verification test In order to verify the beneficial effects of the present application, the samples prepared in Examples 1-3 and Comparative Examples 1-4 above were subjected to the following tests: 1. Accelerated stability test: each sample was placed in a condition of 40°C and relative humidity of 75%, and samples were taken at 0, 1, 3 and 6 months, respectively, and the content of sodium ascorbate (or ascorbic acid) was determined by high performance liquid chromatography, and the content retention rate was calculated. Each group of samples was subjected to 3 parallel tests.

[0041] 2. pH value and physical property test: the sample was prepared into a 1% aqueous solution, and a precision pH meter was used to determine the pH value. Another sample was placed in an environment with a relative humidity of 75% for 24 hours, and its physical properties were observed.

[0042] Test results The following table summarizes the key test data of each group of samples:

[0043] 2. Bioavailability comparison test In order to verify the beneficial effects of the liposome soft capsules of the present application, the powder composition prepared in Example 1 (control group) and the liposome soft capsule content prepared in Example 4 (experimental group) were selected for pharmacokinetic comparison test of Wistar rats by gavage.

[0044] Test method: the rats were randomly divided into two groups, and after fasting for 12 hours, the two groups were given gavage, and the dosage was 100 mg / kg of vitamin C. At different time points after administration, the blood samples of rats were collected, treated and then the concentration of vitamin C in plasma was determined by high performance liquid chromatography, and the main pharmacokinetic parameters were calculated. The following table is the bioavailability comparison test data.

[0045]

[0046] Result analysis: first, comparing Examples 1-3 with Comparative Example 1, the pH values of the former are all stable in the weak alkaline range of 7.2-7.8, while the latter is strongly acidic, which proves that the present application effectively solves the problem of acid irritation.

[0047] Secondly, in terms of chemical stability of the core, from the complete degradation curve data, it can be seen that the content retention rate of Examples 1-3 always maintained at a very high level during the entire 6-month accelerated test period, and the decay was very slow. In contrast, all the comparative examples showed a faster degradation rate. In particular, comparing Example 1 with Comparative Example 2 (without sodium citrate) and Comparative Example 3 (without sodium erythorbate), it is clear that the stability will be greatly reduced if either of the key stabilizers is missing alone. This directly proves that sodium erythorbate and sodium citrate play a synergistic role in the present application, together building a double protection mechanism as shown in Figure 3 and producing unexpected technical effects. At the same time, comparing Example 1 with Comparative Example 4 (same formula, traditional process), the stability of the former is also significantly better, which proves that the low-temperature, oxygen-free preparation process adopted in the present application is necessary to protect the active ingredients.

[0048] Finally, in terms of physical properties, all the examples containing nanosilica and Comparative Examples 2 and 3 maintained good physical properties in a high-humidity environment, while Comparative Example 1 lacking this component and Comparative Example 4 using a traditional process were severely caked. This proves that the introduction of nanosilica is a key technical feature to solve the physical stability of the product.

[0049] In addition, from the bioavailability test data in Table 2, it can be seen that the peak concentration C max and the area under the concentration-time curve AUC 0-8 of the experimental group (liposomes) were significantly higher than those of the control group (ordinary powder). After calculation, the bioavailability of the experimental group relative to the control group was 253%, which indicates that the liposome delivery system adopted in the present application can effectively protect the core ingredients from the digestive tract and greatly promote their absorption in the body In summary, the test data prove that the present application, through its six-component formula design, combined with the low-temperature, oxygen-free, gradient mixing preparation process, and by further preparing it into a liposome dosage form, synergistically solves the multiple technical problems of existing vitamin C products in terms of chemical stability, mildness to the human body, physical properties, and bioavailability.

[0050] The above merely illustrates the specific embodiments of the present application, but the protection scope of the present application is not limited thereto. Any changes or replacements within the technical scope disclosed by the present application can be easily conceived by those skilled in the art, and should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A high-purity alkaline compound vitamin C composition, characterized in that, The composition comprises the following components: Sodium ascorbate; Sodium isoascorbate; Sodium selenite or its premixes; Erythritol; Trisodium citrate; and Nano-silica.

2. The composition according to claim 1, characterized in that, The components, by weight, are as follows: Sodium ascorbate: 60-80 parts; Sodium isoascorbate: 15-25 parts; Sodium selenite premix (based on 1% sodium selenite content): 0.01-0.1 parts; Erythritol: 1-10 parts; Trisodium citrate: 0.5-2 parts; Nano silica: 0.1-0.5 parts.

3. The composition according to claim 1 or 2, characterized in that, When the composition is dissolved in pure water, the pH of its aqueous solution is 7.2 to 7.

8.

4. A method for preparing the composition according to claim 1, characterized in that, Includes the following steps: a) Ultrafine grinding pretreatment: Sodium ascorbate and sodium isoascorbate are ultrafine ground in a low temperature environment below 5°C and an inert gas protection environment to obtain the main material powder; b) Gradient dry mixing: The main powder and an auxiliary premix are mixed in stages under an anaerobic environment. The auxiliary premix contains sodium selenite, trisodium citrate, nano silica and erythritol that are premixed evenly. c) Low-temperature oxygen-free drying: The material mixed evenly in step b) is dried in an environment of -5°C to 5°C under inert gas protection.

5. The preparation method according to claim 4, characterized in that, In step a), the ultrafine grinding process pulverizes the raw material to a particle size D90 of less than 50 micrometers.

6. The preparation method according to claim 4, characterized in that, In step b), the gradient mixing includes adding the excipient premix to the main ingredient powder at least twice for mixing.

7. The preparation method according to claim 4, characterized in that, The inert gas mentioned in step a) or step c) is nitrogen.

8. The preparation method according to claim 4, characterized in that, All steps of the preparation method are carried out in an environment with a relative humidity of less than 40%.

9. A liposome soft capsule, characterized in that, Its contents are a suspension containing liposomes, the core of which encapsulates a high-purity alkaline complex vitamin C composition as described in any one of claims 1 to 3.

10. The method for preparing liposome soft capsules as described in claim 9, characterized in that, The method includes encapsulating the composition as described in any one of claims 1 to 3 into phospholipid vesicles using a liposome preparation process under low temperature and inert gas protection, and then filling the liposomes into soft capsules; the liposome preparation process includes a low temperature and high pressure homogenization step.

Images