Acidic nano-emulsion preparation

Abstract

The invention provides an acidic nano-emulsion preparation which is an oil-in-water emulsion and comprises the following active ingredients: 0.01-3wt% of a fat-soluble active ingredient, 0.01-3wt% of an emulsifier, 0.01-3wt% of an emulsifier and the balance of water. 0.8%-6 wt% of liquid modified soybean phospholipid; 0.1 wt% to 0.45 wt% of an acidity regulator; wherein the iodine value of the liquid modified soybean phospholipid is 85-88 g / 100 g, the content of an acetone insoluble substance in the liquid modified soybean phospholipid is 55-65%, and the content of an n-hexane insoluble substance in the liquid modified soybean phospholipid is 0.15-0.3%. The acidic nano-emulsion preparation provided by the invention also has excellent stability under an acidic condition, and also has good bioavailability.

Description

Technical Field

[0001] The invention relates to an emulsion preparation, in particular to a nanoemulsion preparation. Background Art

[0002] Emulsions are usually composed of two immiscible liquids (oil phase and water phase) and emulsifiers (surfactants and cosurfactants) to form a single-phase thermodynamically stable colloidal dispersion system. Among them, nanoemulsions are widely used because they can greatly improve the dissolution rate and systemic bioavailability of active ingredients.

[0003] However, the stability of nanoemulsions is a complex issue. Generally, changes in pH affect the stability of emulsions. In some cases, changes in pH can affect the charge state of the emulsifier and thus the stability of the emulsion. Changes in pH can affect the hydrophobicity and surface charge of the particles, thereby changing their adsorption at the oil-water interface and, in turn, affecting the stability of the emulsion. For example, changes in pH can lead to changes in the charge density and interactions of the particles, which can affect their adsorption and alignment at the oil-water interface.

[0004] At present, the pH value range of nanoemulsion is generally 6-8, and it shows good stability in this pH range. However, in some application scenarios, such as as a carrier of food or nutritional active substances, it is more desirable to obtain nanoemulsion under acidic conditions.

[0005] For example, acidic conditions can enhance the ability of emulsions to inhibit bacterial growth, as the growth of many pathogens can be inhibited by an acidic environment, thereby enhancing the preservation of the preparation. This natural preservative effect achieved by lowering the pH value reduces the reliance on high temperature processing and chemical preservatives.

[0006] In addition, acidity conditions not only inhibit bacterial growth, but also act as a flavor adjuvant, forming a distinctive flavor and balancing the flavor of food preparations.

[0007] However, current nanoemulsions cannot maintain satisfactory stability under acidic conditions. Summary of the invention

[0008] The object of the present invention is to provide an acidic nanoemulsion preparation, wherein the oil-in-water nanoemulsion has excellent stability under acidic conditions and good bioavailability.

[0009] In order to achieve the above object, the present invention proposes an acidic nanoemulsion preparation, which is an oil-in-water emulsion, and its effective ingredients include:

[0010] Fat-soluble active ingredients: 0.01% to 3wt%;

[0011] Liquid modified soybean lecithin: 0.8% to 6wt%;

[0012] Acidity regulator: 0.1% to 0.45wt%;

[0013] The iodine value of the liquid modified soybean lecithin is 85-88 g / 100 g, the content of acetone insoluble matter in the liquid modified soybean lecithin is 55-65%, and the content of n-hexane insoluble matter in the liquid modified soybean lecithin is 0.15-0.3%.

[0014] For fat-soluble active ingredients, when preparing liquid preparations, emulsifiers need to be added because two incompatible liquids need to be mixed. Emulsifiers are substances that can improve the surface tension between the various constituent phases in an emulsion to form a uniform dispersion or emulsion. They are usually classified as surfactants, which can significantly reduce the surface tension of liquids, so that two immiscible liquids (such as oil and water) can be evenly mixed to form a stable emulsion. Emulsifiers prevent droplets from agglomerating by reducing the oil-water interfacial tension to form a stable emulsion film. Emulsifier molecules are arranged on the surface of droplets to form a protective film, reduce interfacial free energy, and keep the droplets at a minimum surface area. The structure of the hydrophilic and lipophilic groups of the emulsifier determines its behavior in the emulsion, thereby affecting the stability and properties of the emulsion.

[0015] One of the core improvements of the present invention is to use liquid modified soybean lecithin as an emulsifier. The present invention significantly improves the emulsification and hydrophilicity of the emulsifier by using liquid modified soybean lecithin as an emulsifier. Unlike traditional lecithin, the iodine value, acetone insoluble matter and n-hexane insoluble matter content of the liquid modified soybean lecithin used in the present invention are significantly lower than those of traditional soybean lecithin, so that it can be dispersed in water and dissolved in oil, and has the characteristics of being soluble in both oil and water. This unique amphiphilicity makes it an ideal carrier of fat-soluble substances, which can effectively solve the problems of dissolution and dispersion and improve the stability of the emulsion.

[0016] Moreover, the anti-oxidation and emulsifying properties of the liquid modified soybean lecithin used in the present invention also help to improve the bioavailability and stability of the active ingredients.

[0017] In the present invention, the iodine value of the liquid modified soybean lecithin is controlled to be 85-88 g / 100 g, which helps to reduce the unsaturated fatty acid chains of the lecithin molecules, thereby reducing their fat solubility and enhancing their solubility in water.

[0018] The content of acetone insoluble matter is controlled at 55-65%, which can increase the proportion of hydrophilic group components in the liquid modified soybean lecithin, further optimize the molecular structure of lecithin, ensure the appropriate proportion of polar head groups in lecithin, and thus help to improve its solubility in water. Although the liquid modified soybean lecithin used in the present invention reduces the content of acetone insoluble matter compared to traditional lecithin, this does not mean that the lower the content, the better. For the component system of the present invention, the acetone insoluble matter content of the liquid modified soybean lecithin is not less than 55% to ensure the stability of the emulsion. Since the content of acetone insoluble matter is higher than 55%, the liquid modified soybean lecithin can form a stable emulsified layer in the emulsion, effectively preventing the aggregation and precipitation of oil droplets. The formation of the emulsified layer is the key to the stability of the emulsion, because it can reduce the interaction force between oil droplets, prevent emulsion stratification, and ensure the stability of the emulsion under various conditions.

[0019] The content of n-hexane insoluble matter is controlled at 0.15-0.3%, which helps to reduce the non-polar components in the phospholipids, ensures that the liquid modified soybean lecithin has hydroxyl groups in its structure, and also helps to remove hydrophobic impurities, ensuring the purity and hydrophilicity of the phospholipids. The above factors work together to improve the water solubility of the liquid modified soybean lecithin, so that it exhibits excellent emulsification properties when preparing water-in-oil emulsions.

[0020] Thus, the liquid modified soybean lecithin used in the present invention increases the hydrophilic-lipophilic balance (HLB value) by reducing the iodine value and the content of acetone insoluble matter and n-hexane insoluble matter, thereby improving its hydrophilicity. This modification enables the nanoemulsion to maintain the stability of the nanoemulsion after the addition of an acidity regulator and the nanoemulsion becomes acidic, because the enhanced hydrophilicity helps to resist the influence of acidic conditions. In contrast, ordinary soybean lecithin has a low HLB value and insufficient hydrophilicity, and its emulsification performance decreases in an acidic environment, resulting in the nanoemulsion being easily precipitated after centrifugation, and the stability is reduced.

[0021] In addition, in the present invention, the content of liquid modified soybean lecithin is also closely related to the realization of the technical effect of the present invention. Specifically, when the mass percentage of liquid modified soybean lecithin in the acidic nanoemulsion exceeds 6%, the fluidity of the emulsion will be significantly reduced. This phenomenon may be due to the increase in the content of liquid modified soybean lecithin, which leads to an increase in the viscosity of the emulsion, thereby affecting its fluidity. When the mass percentage of liquid modified soybean lecithin in the acidic nanoemulsion is less than 0.8%, it cannot be guaranteed that the purpose of the present invention can be achieved.

[0022] Furthermore, the composition ratio of the acidic nanoemulsion preparation of the present invention is:

[0023] Fat-soluble active ingredients: 0.01% to 3wt%;

[0024] Liquid modified soybean lecithin: 0.8% to 6wt%;

[0025] Acidity regulator: 0.1% to 0.45wt%;

[0026] The balance is water.

[0027] Furthermore, in the acidic nanoemulsion preparation of the present invention, the fat-soluble active ingredient includes vitamin D3, and the content of vitamin D3 is 0.01% to 0.18wt%.

[0028] Vitamin D3 is an essential nutrient for an organism, but as a fat-soluble vitamin, it has poor solubility in water. Due to its high fat solubility and low water solubility, its absorption during oral administration is limited. This poor solubility limits its application. The present invention ensures its solubility, bioavailability and stability by adding it to the nanoemulsion of the present invention.

[0029] Furthermore, in the acidic nanoemulsion preparation of the present invention, the fat-soluble active ingredient includes coenzyme Q10, and the content of coenzyme Q10 is 0.3% to 3wt%.

[0030] Coenzyme Q10 is also a fat-soluble compound with poor solubility in water. Currently, the solubility of Coenzyme Q10 is improved by adding co-solvents (such as ethanol). Although ethanol can increase the solubility of Coenzyme Q10, there are potential risks. It may cause adverse reactions in people who are sensitive to alcohol and is not suitable for pregnant women, children and patients with liver disease. The addition of ethanol may also affect the taste of the product, increase the complexity of storage and transportation, and as a flammable substance, there are safety hazards. The present invention can solve the above problems and ensure its solubility, bioavailability and stability.

[0031] Furthermore, in the acidic nanoemulsion preparation of the present invention, the mass percentage of the coenzyme Q10 in the total amount of coenzyme Q10 and liquid modified soybean lecithin added is 27-33%.

[0032] The present invention further improves the technical effect that the present invention aims to achieve by controlling the relative addition amounts of coenzyme Q10 and liquid modified soybean lecithin.

[0033] Furthermore, in the acidic nanoemulsion preparation of the present invention, the mass percentage of the fat-soluble active ingredient in the total amount of the fat-soluble active ingredient and the liquid modified soybean lecithin added is 15-33%.

[0034] The present invention further improves the technical effect that the present invention aims to achieve by controlling the relative addition amounts of the fat-soluble active ingredient and the liquid modified soybean lecithin.

[0035] Furthermore, the pH value of the acidic nanoemulsion preparation of the present invention is 4.0-4.6.

[0036] The present invention achieves stability and low acidity of the emulsion by controlling the pH value of the emulsion within the range of 4.0-4.6. This pH value range makes the emulsion close to the category of low-acid food, so that the growth of microorganisms can be effectively inhibited without adding preservatives, thereby extending the shelf life of the product.

[0037] Furthermore, in the acidic nanoemulsion preparation of the present invention, the acidity regulator is citric acid or ascorbic acid.

[0038] Furthermore, in the acidic nanoemulsion preparation of the present invention, the liquid modified soybean lecithin is obtained by modifying soybean lecithin with butyric anhydride, hydrogen peroxide and sodium hydroxide.

[0039] Furthermore, in the acidic nanoemulsion preparation of the present invention, the liquid modified soybean lecithin is prepared based on the following raw materials:

[0040] Soybean lecithin; butyric anhydride, the mass ratio of which to soybean lecithin is 3-5%; sodium hydroxide, the mass ratio of which to soybean lecithin is 0.7-1.2%; hydrogen peroxide, the mass ratio of which to soybean lecithin is 0.3-0.5%.

[0041] Furthermore, in the acidic nanoemulsion preparation of the present invention, the liquid modified soybean lecithin is prepared based on the following steps:

[0042] Heat and stir the soybean lecithin until it is completely melted;

[0043] butyric anhydride is added to the melted soybean lecithin to carry out a butyrylation reaction;

[0044] Add sodium hydroxide to carry out neutralization reaction;

[0045] Dehydration treatment;

[0046] Hydrogen peroxide is added to effect the hydroxylation reaction.

[0047] The acidic nanoemulsion preparation of the present invention can not only provide necessary nutrients through formula design, but also effectively adjust the acidity of the emulsion, thereby inhibiting the growth of bacteria and improving the safety of the preparation. Under this premise, the stability of the nanoemulsion under acidic conditions that cannot be achieved in existing products is achieved.

[0048] The acidic nanoemulsion preparation of the present invention achieves adaptability to a variety of fat-soluble active ingredients by optimizing the ratio of fat-soluble active ingredients to liquid modified soybean lecithin. This ratio adjustment ensures the stability of the nanoemulsion and the adaptability to different active ingredients, and while ensuring the stability of the emulsion, it also ensures the high bioavailability of the active ingredients. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 The graph shows the changes in the concentration of coenzyme Q10 in rats after intragastric administration of Example 1 and Comparative Example 3 over time. DETAILED DESCRIPTION

[0050] The acidic nanoemulsion preparation of the present invention will be further explained and illustrated below in conjunction with specific embodiments and the accompanying drawings of the specification. However, such explanation and illustration do not constitute an improper limitation on the technical solution of the present invention.

[0051] Examples 1-6 and Comparative Examples 1-2

[0052] In various embodiments of the present invention, the acidic nanoemulsion preparations of Examples 1-6 and Comparative Examples 1-2 were prepared based on the following steps:

[0053] (1) Soybean lecithin is modified to obtain liquid modified soybean lecithin, wherein the iodine value of the liquid modified soybean lecithin is 85-88 g / 100 g, the content of acetone insoluble matter is 55-65%, and the content of n-hexane insoluble matter is 0.15-0.3%.

[0054] In some embodiments, the soybean lecithin used is 100 g of high-purity soybean lecithin, with an iodine value of 100-110 g / 100 g, an acetone insoluble matter content of 85-90%, and a n-hexane insoluble matter content of 0.3-0.4%.

[0055] In some embodiments, the liquid modified soybean lecithin can be prepared by the following steps:

[0056] 101 Pretreatment: Heat the soybean lecithin to 50-55°C and stir until it is completely melted.

[0057] 102 Butyrylation reaction: add butyric anhydride in a mass ratio of 3-5% to soybean lecithin to the melted soybean lecithin, and carry out butyrylation reaction at a temperature of 62-68° C. for 1.5-2.5 hours.

[0058] 103 Neutralization: Slowly add sodium hydroxide in a mass ratio of 0.7-1.2% to soybean lecithin to carry out neutralization reaction, adjust the pH value to 7.1-7.3, and continue the reaction for 45-60 minutes.

[0059] 104 Dehydration treatment: Dehydration treatment is carried out at 60-68° C. until the moisture content is less than 0.5%.

[0060] 105 Hydroxylation reaction: adding hydrogen peroxide in an amount of 0.3-0.5% by mass of the soybean lecithin, and carrying out a hydroxylation reaction at 82-88° C. for 45-60 minutes.

[0061] 106 Purification treatment: Column chromatography technology is used for purification process, using silica gel as stationary phase and n-hexane as mobile phase to remove unreacted chemicals and by-products.

[0062] 107 Liquidization treatment: The liquid modified soybean lecithin is heated and melted at 80-88°C to adjust the viscosity and fluidity.

[0063] Table 1 lists the raw material ratios and modification processes of the liquid modified soybean lecithin used in Examples 1-6 and Comparative Examples 1-2.

[0064] Table 1.

[0065]

[0066]

[0067]

[0068]

[0069] Table 2 lists the composition characteristics of the liquid modified soybean lecithin used in Examples 1-6 and Comparative Examples 1-2.

[0070] Table 2.

[0071]

[0072] (2) Preparation of nanoemulsion preparations based on liquid modified soybean lecithin:

[0073] The liquid modified soybean lecithin is heated and stirred at 35-45°C for 10-25 minutes until a liquid solution is formed, and then the fat-soluble active ingredient is quickly added and continued to be stirred for 8-30 minutes to achieve uniform dispersion of the fat-soluble active ingredient. At the same time, the acidity regulator is mixed with pure water at 40-49°C and stirred until the acidity regulator is completely dissolved. Subsequently, the mixed solution of the liquid modified soybean lecithin and the fat-soluble active ingredient is combined with the acidity regulator solution, and heated and stirred at 40-60°C and 400-900 rpm to ensure sufficient mixing of the two solutions and the formation of colostrum.

[0074] The colostrum is passed through a high-speed shear emulsification process at 5000-12000 rpm to refine the droplets and form a uniform colostrum emulsion. Subsequently, the emulsion is homogenized by a high-pressure homogenizer at 12000-14100 psi to ensure that the droplets in the emulsion are smaller and evenly distributed.

[0075] Table 3 lists the contents of the ingredients in the acidic nanoemulsion preparations of Examples 1-6 and Comparative Examples 1-2.

[0076] Table 3. (The balance is pure water)

[0077]

[0078] Table 4 lists the preparation process parameters of the acidic nanoemulsion preparations of Examples 1-6 and Comparative Examples 1-2.

[0079] Table 4.

[0080]

[0081]

[0082] In order to verify the stability of the acidic nanoemulsion preparation of the present invention, centrifugal stability evaluation and acidic stability evaluation were performed on it, wherein:

[0083] (1) Centrifugal stability evaluation

[0084] Take each example and comparative example, centrifuge at 8000rpm for 30 minutes, and observe the severity of precipitation or stratification. The result of the evaluation immediately after preparation is the "centrifugal stability" evaluation, and the result of the evaluation after accelerated storage for 3 days after preparation is the "centrifugal stability after accelerated storage (accelerated 3d)".

[0085] (2) Acid stability evaluation:

[0086] Each example and comparative example was allowed to stand at 37° C. for 2 hours. The stability of the preparation was evaluated by observing the appearance changes of the preparation under acidic conditions, such as precipitation, stratification, color change or transparency change. The stability was further determined by centrifugation test (8000 rpm, 30 minutes).

[0087] Table 5 lists the stability of the nanoemulsion formulations of Examples 1-6 and Comparative Examples 1-2.

[0088] Table 5.

[0089]

[0090] Note: “###” indicates obvious water precipitation or stratification after centrifugation; “##” indicates relatively obvious water precipitation or stratification after centrifugation; “#” indicates a small amount of water precipitation or stratification after centrifugation; “-” indicates stability and no obvious change after centrifugation.

[0091] It can be seen from Table 5 that the nanoemulsions of the present invention all exhibit excellent stability, while the stability of Comparative Examples 1 and 2 is inferior to that of the present invention.

[0092] Comparative Example 3 is a coenzyme Q10 soft capsule without adding liquid modified soybean lecithin, and its raw materials are: coenzyme Q10 2.9wt%, microcrystalline cellulose 60wt%, dextrin 25wt%, silicon dioxide 0.5wt%, magnesium stearate 0.1wt%, pure water 74.4wt%. Coenzyme Q10, microcrystalline cellulose, dextrin, silicon dioxide, magnesium stearate and pure water are added to a grinder for grinding for 30mins, and then passed through an 80-mesh sieve to obtain a uniform mixture. The ground mixture is added to a three-dimensional mixer for mixing and stirring, and the stirring rate is set to 100r / min and the stirring time is 30mins. In addition, the temperature is maintained at 25°C. The mixed materials are filled into capsules to obtain coenzyme Q10 soft capsules.

[0093] In order to further prove that the acidic nanoemulsion preparation of the present invention has good bioavailability, the present invention uses Example 1 and Comparative Example 3 to conduct animal comparative absorption experiments. The animal comparative absorption experiment uses the following means:

[0094] All rats were randomly divided into 2 groups: experimental group and control group, with 6 rats in each group.

[0095] The experimental group was orally gavaged with 0.084 mL / kg of the sample of Example 1 every day; the control group was orally gavaged with the sample of Comparative Example 3 every day, and the gavage dose was required to keep the effective ingredient of coenzyme Q10 consistent with that of the experimental group, which was calculated to be 2.5 mg / kg. Both groups of rats were gavaged once in the morning and evening for the first 4 days, and once in the morning on the 5th day, for a total of 9 times. After gavage on the 4th day, the rats in each group were fasted but not watered overnight.

[0096] The timing started after the last intragastric administration on the 5th day. Blood was collected from the two groups of rats at 7 time points, namely 0, 1, 2, 4, 8, 12, and 24 hours after the last intragastric administration. Plasma was obtained by centrifugation and the concentration of coenzyme Q10 in the plasma was tested.

[0097] Table 6 lists the blood drug concentration test results of coenzyme Q10 components in rats after intragastric administration of the two products of Example 1 and Comparative Example 3.

[0098] Table 6.

[0099]

[0100]

[0101] As can be seen from Table 6, the blood concentration of the coenzyme Q10 component in the rats administered with the present invention is significantly higher than that in the control group.

[0102] in addition, Figure 1 The graph shows the changes in the concentration of coenzyme Q10 in rats after intragastric administration of Example 1 and Comparative Example 3 over time.

[0103] like Figure 1 As shown, the concentration of coenzyme Q10 in Example 1 (experimental group) of the present invention is significantly higher than that in Comparative Example 3 (control group).

[0104] It can be concluded that, compared with Comparative Example 3, after using the coenzyme Q10 emulsion of Example 1 of the present invention, the concentration of coenzyme Q10 in the plasma of rats is significantly higher, the average relative bioavailability of its active ingredient coenzyme Q10 reaches 209%, the maximum relative bioavailability reaches 243.5%, and the maximum absorption rate difference can reach 361.9%. This fully demonstrates that the acidic coenzyme Q10 nanoemulsion of the present invention has higher bioavailability.

[0105] It should be noted that the combination of the various technical features in this case is not limited to the combination described in the claims of this case or the combination described in the specific embodiments. All technical features recorded in this case can be freely combined or combined in any way unless there is a contradiction between them.

[0106] It should also be noted that the above-listed embodiments are only specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and similar changes or modifications made therewith can be directly derived or easily associated with the contents disclosed by those skilled in the art from the present invention, and all should belong to the protection scope of the present invention.

Claims

1. An acidic nanoemulsion preparation, which is an oil-in-water emulsion, characterized in that: Its active ingredients include: Fat-soluble active ingredients: 0.01% to 3wt%; Liquid modified soybean lecithin: 0.8% to 6wt%; Acidity regulator: 0.1% to 0.45wt%; The iodine value of the liquid modified soybean lecithin is 85-88 g / 100 g, the content of acetone insoluble matter in the liquid modified soybean lecithin is 55-65%, and the content of n-hexane insoluble matter in the liquid modified soybean lecithin is 0.15-0.3%.

2. The acidic nanoemulsion preparation according to claim 1, characterized in that Its composition ratio is: Fat-soluble active ingredients: 0.01% to 3wt%; Liquid modified soybean lecithin: 0.8% to 6wt%; Acidity regulator: 0.1% to 0.45wt%; The balance is water.

3. The acidic nanoemulsion preparation according to claim 1 or 2, characterized in that The fat-soluble active ingredient includes vitamin D3, and the content of vitamin D3 is 0.01% to 0.18wt%.

4. The acidic nanoemulsion preparation according to claim 1 or 2, characterized in that The fat-soluble active ingredient includes coenzyme Q10, and the content of coenzyme Q10 is 0.3% to 3wt%.

5. The acidic nanoemulsion preparation according to claim 4, characterized in that The mass percentage of the coenzyme Q10 in the total amount of coenzyme Q10 and liquid modified soybean lecithin added is 27-33%.

6. The acidic nanoemulsion preparation according to claim 1 or 2, characterized in that, The mass percentage of the fat-soluble active ingredient in the total amount of the fat-soluble active ingredient and the liquid modified soybean lecithin added is 15-33%.

7. The acidic nanoemulsion preparation according to claim 1 or 2, characterized in that, Its pH value is 4.0-4.

6.

8. The acidic nanoemulsion preparation according to claim 1 or 2, characterized in that, The acidity regulator is citric acid or ascorbic acid.

9. The acidic nanoemulsion preparation according to claim 1 or 2, characterized in that: The liquid modified soybean lecithin is obtained by modifying soybean lecithin with butyric anhydride, hydrogen peroxide and sodium hydroxide.

10. The acidic nanoemulsion preparation according to claim 9, characterized in that The liquid modified soybean lecithin is prepared based on the following raw materials: Soybean lecithin; butyric anhydride, the mass ratio of which to soybean lecithin is 3-5%; sodium hydroxide, the mass ratio of which to soybean lecithin is 0.7-1.2%; hydrogen peroxide, the mass ratio of which to soybean lecithin is 0.3-0.5%.

11. The acidic nanoemulsion preparation according to claim 9 or 10, characterized in that The liquid modified soybean lecithin is prepared based on the following steps: Heat and stir the soybean lecithin until it is completely melted; butyric anhydride is added to the melted soybean lecithin to carry out a butyrylation reaction; Add sodium hydroxide to carry out neutralization reaction; Dehydration treatment; Hydrogen peroxide is added to effect the hydroxylation reaction.

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