A highly stable oral solution of valine and a method of making the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a high-stability oral solution of five-vitamin lysine and a preparation method thereof. The W1 / O / W2 double emulsion system is applied to the five-vitamin lysine oral solution, the two-boundary three-phase structure is utilized to realize the partitioned encapsulation of water-soluble vitamins and fat-soluble vitamins, and the chemical stability of sensitive components is protected; a multiple antioxidation protection system covering the oil phase, the inner water phase and the outer water phase is established, and the effective period retention rate of vitamin C and vitamin A is significantly improved. Moreover, sucralose is used to replace sucrose, the Maillard reaction is blocked from the source, and the browning in the storage process of the medicine solution is avoided. The preparation method adopts the mature two-step emulsification method and the high-pressure homogenization process, the steps are clear, the conditions are controllable, the used auxiliary materials are all common pharmaceutical or food-grade auxiliary materials, and the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a highly stable five-dimensional lysine oral solution and its preparation method. Background Technology

[0002] Five-vitamin lysine oral solution is a non-prescription compound preparation of vitamins. Each milliliter contains 300 IU of vitamin A, 20 IU of vitamin D2, 5 mg of vitamin C, 0.2 mg of vitamin B6, 2 mg of nicotinamide, and 6 mg of lysine hydrochloride. It is mainly used to prevent and treat diseases caused by multiple vitamin deficiencies in children. However, currently available commercially available five-vitamin lysine oral solutions have the following problems: (1) The five-vitamin lysine oral solution contains both water-soluble vitamins (vitamin C, vitamin B6, nicotinamide) and fat-soluble vitamins (vitamin A, vitamin D2). Existing technology directly dissolves or disperses all components in the same aqueous system, and the components are in contact with each other. Fat-soluble vitamins have poor dispersibility and are easy to aggregate in the aqueous phase, while water-soluble vitamins are directly exposed to degradation factors such as oxygen and metal ions in the aqueous phase.

[0003] (2) Vitamin C is extremely sensitive to light, heat, and oxygen, and is one of the most unstable components; vitamins A and D2 are also highly sensitive to oxidation, acid, and light. Therefore, the stability of the five-vitamin lysine oral solution decreases as pH increases.

[0004] (3) Trace amounts of heavy metal ions such as iron and copper are strong catalysts for vitamin oxidation, and can accelerate degradation several times at the ppm level.

[0005] (4) Sucrose is often used as a flavoring agent in existing formulations. Lysine hydrochloride contains free amino groups, which react with reducing sugars such as sucrose during storage via Maillard reaction, resulting in browning of the drug solution and a decrease in the effectiveness of lysine.

[0006] (5) The five-dimensional lysine oral solution is mainly used for children. The acidic components such as vitamin C can irritate the gastric mucosa and affect medication adherence.

[0007] (6) Existing improvement schemes mostly use cyclodextrin inclusion, which improves vitamin stability to a certain extent, but cannot achieve the separation and protection of water-soluble and fat-soluble components. Moreover, the inclusion rate is limited by the number of cyclodextrin cavities, and excessive cyclodextrin dosage poses a drug safety hazard.

[0008] Therefore, there is an urgent need to provide a five-vitamin lysine oral solution that can achieve partitioned encapsulation and synergistic protection of water-soluble and fat-soluble vitamins. Summary of the Invention

[0009] The purpose of this invention is to provide a highly stable five-dimensional lysine oral solution and its preparation method, thereby solving the technical problems of poor stability, interference between water-soluble and fat-soluble vitamins, and gastrointestinal irritation in existing five-dimensional lysine oral solutions.

[0010] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a highly stable five-dimensional lysine oral solution, which has a W1 / O / W2 dual emulsion structure, where W1 is the inner aqueous phase, O is the oil phase, and W2 is the outer aqueous phase; the pH of the five-dimensional lysine oral solution is 3.4~3.8. The five-dimensional lysine oral solution, per 1000 mL, comprises the following components: The aqueous phase comprises: 5g vitamin C, 0.2g vitamin B6, 2g nicotinamide, 6g lysine hydrochloride, 1-5g hydroxypropyl-β-cyclodextrin, 0.05-0.5g reduced glutathione, and a portion of water; the volume ratio of the aqueous phase to the oil phase is 1:2-3:5. The oil phase comprises: 300,000 units of vitamin A, 20,000 units of vitamin D2, 1-6 g of water-oil interface emulsifier, 0.06-0.6 g of oil phase antioxidant, and 20-100 mL of oil phase solvent; The external aqueous phase comprises: 1-10g of oil-water interface emulsifier, 1-5g of hydroxypropyl-β-cyclodextrin, 0.1-0.3g of metal ion chelating agent, 30-80g of osmotic pressure regulator, 0.2-1g of non-reducing sweetener, 1-5g of colloid, 0.3-0.5g of preservative, 0.5-2g of fruit flavoring, and the balance being water; The water-oil interface emulsifier comprises a mixture of soybean lecithin and glyceryl citrate; the oil phase antioxidant comprises a mixture of tocopherol concentrate and rosemary extract. The oil-water interface emulsifier is a sucrose fatty acid ester.

[0011] Furthermore, in the highly stable five-dimensional lysine oral solution, the mass ratio of soybean lecithin to monoglyceride citrate is 0.5~3:0.5~3; the mass ratio of the tocopherol mixture concentrate to the rosemary extract is 0.05~0.5:0.01~0.1.

[0012] Furthermore, in the aforementioned highly stable pentavalent lysine oral solution, the oil phase solvent comprises medium-chain triglycerides or caprylic / capric triglycerides.

[0013] Furthermore, in the aforementioned highly stable pentadysine oral solution, the metal ion chelating agent is EDTA-2Na; the osmotic pressure regulator includes xylitol or sorbitol; the non-reducing sweetener is sucralose; the colloid is a mixture of pectin and chitosan in a mass ratio of 0.5~2.5:0.5~2.5; the preservative is ethylparaben; and the fruit flavoring includes orange flavoring, peach flavoring, or strawberry flavoring.

[0014] Furthermore, in the aforementioned highly stable pentadimensional lysine oral solution, based on 1000 mL of the pentadimensional lysine oral solution, the external aqueous phase further includes 1-10 g of stabilizer; the stabilizer includes OSA modified starch or pectin.

[0015] Furthermore, in the aforementioned highly stable pentaviridine oral solution, the reagent used to adjust the pH of the pentaviridine oral solution to 3.4-3.8 is a mixture of citric acid and sodium citrate.

[0016] This invention also provides a method for preparing a highly stable five-dimensional lysine oral solution, comprising the following steps: (1) Preparation of internal aqueous phase: Vitamin C, vitamin B6, nicotinamide, lysine hydrochloride, hydroxypropyl-β-cyclodextrin, reduced glutathione and some water are mixed to obtain an internal aqueous phase solution; Preparation of the oil phase: Vitamin A, vitamin D2, water-oil interface emulsifier, oil phase antioxidant and oil phase solvent are mixed to obtain an oil phase solution; Preparation of external aqueous phase: The oil-water interface emulsifier, hydroxypropyl-β-cyclodextrin, metal ion chelating agent, osmotic pressure regulator, non-reducing sweetener, colloid, preservative, fruit flavoring and the balance water are mixed to obtain an external aqueous phase solution; (2) Add the aqueous phase solution to the oil phase solution and perform shear emulsification to obtain W1 / O primary emulsion; (3) Add W1 / O primary emulsion to the external aqueous phase solution and mix and disperse to obtain W1 / O / W2 double emulsion; (4) Homogenize the W1 / O / W2 double emulsion; (5) Adjust the pH of the homogenized W1 / O / W2 double emulsion to 3.4~3.8, fill it under a protective atmosphere; after filling, purge the headspace with nitrogen and seal it to obtain a five-dimensional lysine oral solution. Steps (1) to (5) are carried out in a light-proof and protective atmosphere.

[0017] Furthermore, in the preparation method, the shear rate of the shear emulsification in step (2) is 8000~15000 r / min, and the emulsification time is 10~30 min.

[0018] Furthermore, in the preparation method, the stirring rate of the mixing and dispersion in step (3) is 300~600 r / min, and the dispersion time is 10~20 min.

[0019] Furthermore, in the preparation method, the homogenization pressure of the homogenization process in step (4) is 50~80MPa, and the number of homogenization times is 1~3.

[0020] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects: (1) The present invention applies the W1 / O / W2 dual emulsion system to the five-dimensional lysine oral solution. By utilizing the two-interface three-phase structure, the water-soluble vitamins (vitamin C, vitamin B6, nicotinamide, lysine hydrochloride) and fat-soluble vitamins (vitamin A, vitamin D2) are encapsulated separately, thus protecting the chemical stability of sensitive components.

[0021] (2) This invention establishes a multi-phase antioxidant protection system covering the oil phase, internal aqueous phase, and external aqueous phase. Reduced glutathione is added to the internal aqueous phase, coexisting with vitamin C and vitamin B6, achieving in-situ free radical scavenging; the oil phase provides a physical barrier for reduced glutathione, preventing its oxidative inactivation. In the external aqueous phase, EDTA-2Na chelates metal ions, forming a synergistic antioxidant network of internal scavenging and external chelation. Tocopherol and rosemary extract in the oil phase provide combined antioxidant protection. This triple antioxidant synergistic effect significantly improves the shelf-life retention of vitamin C and vitamin A.

[0022] (3) The present invention stabilizes the dual interface through the W1 / O interface (a combination of soybean lecithin and glyceryl citrate) and the O / W2 interface (a combination of sucrose fatty acid ester and OSA modified starch / pectin), and combines the electrostatic adsorption and network structure formation of pectin-chitosan protective colloid in the external aqueous phase, which significantly improves the physical stability and storage stability of the dual emulsion.

[0023] (4) In this invention, hydroxypropyl-β-cyclodextrin is added to the inner aqueous phase and the outer aqueous phase respectively. In the inner aqueous phase, it provides molecular-level microenvironmental stability protection for vitamin C and vitamin B6, and provides secondary protection for vitamins that may be leaked in the outer aqueous phase. At the same time, it helps to stabilize other components in the outer aqueous phase, forming a multi-level stable system.

[0024] (5) The pectin-chitosan complex in this invention forms a pH-responsive gel protective layer in the stomach, adhering to the gastric mucosa surface and reducing the direct irritation of components such as vitamin C to the stomach wall. This makes it particularly suitable for long-term use by children and other people with sensitive gastrointestinal function. Furthermore, this invention uses non-reducing sweeteners such as sucralose to replace sucrose, blocking the Maillard reaction at its source and avoiding browning problems during drug storage. This invention does not require the addition of chemical antioxidants such as sulfites, avoiding potential safety issues and adverse taste effects.

[0025] (6) The preparation method of the present invention adopts a mature two-step emulsification method and high-pressure homogenization process. The steps are clear and the conditions are controllable. All excipients used are common pharmaceutical or food grade excipients, which are suitable for large-scale industrial production. Detailed Implementation

[0026] This invention provides a highly stable five-dimensional lysine oral solution, which has a W1 / O / W2 dual emulsion structure, where W1 is the inner aqueous phase, O is the oil phase, and W2 is the outer aqueous phase; the pH of the five-dimensional lysine oral solution is 3.4~3.8. The five-dimensional lysine oral solution, per 1000 mL, comprises the following components: The aqueous phase comprises: 5g vitamin C, 0.2g vitamin B6, 2g nicotinamide, 6g lysine hydrochloride, 1-5g hydroxypropyl-β-cyclodextrin, 0.05-0.5g reduced glutathione, and a portion of water; the volume ratio of the aqueous phase to the oil phase is 1:2-3:5. The oil phase comprises: 300,000 units of vitamin A, 20,000 units of vitamin D2, 1-6 g of water-oil interface emulsifier, 0.06-0.6 g of oil phase antioxidant, and 20-100 mL of oil phase solvent; The external aqueous phase comprises: 1-10g of oil-water interface emulsifier, 1-5g of hydroxypropyl-β-cyclodextrin, 0.1-0.3g of metal ion chelating agent, 30-80g of osmotic pressure regulator, 0.2-1g of non-reducing sweetener, 1-5g of colloid, 0.3-0.5g of preservative, 0.5-2g of fruit flavoring, and the balance being water; The water-oil interface emulsifier comprises a mixture of soybean lecithin and glyceryl citrate; the oil phase antioxidant comprises a mixture of tocopherol concentrate and rosemary extract. The oil-water interface emulsifier is a sucrose fatty acid ester.

[0027] In this invention, the pH of the five-dimensional lysine oral solution is preferably 3.4 to 3.6, and more preferably 3.5.

[0028] In this invention, the reagent used to adjust the pH of the pentavirgic lysine oral solution to 3.4-3.8 is preferably a mixture of citric acid and sodium citrate. The preferred mass ratio of citric acid to sodium citrate is 1:1. The amount of reagent used is not limited; adjusting the pH to the desired range is sufficient.

[0029] In this invention, the mass ratio of soybean lecithin to glyceryl monocitrate is preferably 0.5~3:0.5~3, more preferably 1~2:1~2, and even more preferably 1.5:1.5.

[0030] In this invention, the mass ratio of the tocopherol concentrate to the rosemary extract is preferably 0.05~0.5:0.01~0.1, more preferably 0.2~0.4:0.02~0.04, and even more preferably 0.3:0.03.

[0031] In this invention, the oil phase solvent preferably includes medium-chain triglycerides or caprylic / capric triglycerides, and more preferably medium-chain triglycerides.

[0032] In this invention, the metal ion chelating agent is preferably EDTA-2Na.

[0033] In this invention, the osmotic pressure regulator preferably includes xylitol or sorbitol, and more preferably xylitol.

[0034] In this invention, the non-reducing sweetener is preferably sucralose.

[0035] In this invention, the colloid is preferably a mixture of pectin and chitosan in a mass ratio of 0.5~2.5:0.5~2.5, more preferably 1~2:1~2, and even more preferably 1.5:1.5.

[0036] In this invention, the preservative is preferably ethylparaben.

[0037] In this invention, the fruit flavoring preferably includes orange flavoring, peach flavoring, or strawberry flavoring, and more preferably orange flavoring.

[0038] In this invention, taking the five-dimensional lysine oral solution as 1000 mL, the external aqueous phase preferably further includes 1-10 g of stabilizer, more preferably 4-8 g, and even more preferably 5 g.

[0039] In this invention, the stabilizer preferably includes OSA modified starch or pectin, and more preferably OSA modified starch.

[0040] In this invention, the five-dimensional lysine oral solution is taken as 1000 mL: In the aqueous phase, hydroxypropyl-β-cyclodextrin is preferably 2-4g, more preferably 3g; reduced glutathione is preferably 0.1-0.3g, more preferably 0.2g; the volume ratio of the aqueous phase to the oil phase is preferably 2.8:5-3:5; more preferably 3:5. In the oil phase, the water-oil interface emulsifier is preferably 2-4g, more preferably 3g; the oil phase antioxidant is preferably 0.22-0.44g, more preferably 0.33g; and the oil phase solvent is preferably 40-70mL, more preferably 50mL. In the external aqueous phase, the oil-water interface emulsifier is preferably 3-8g, more preferably 5g; hydroxypropyl-β-cyclodextrin is preferably 1-3g, more preferably 2g; the metal ion chelating agent is preferably 0.15-0.25g, more preferably 0.2g; the osmotic pressure regulator is preferably 40-60g, more preferably 50g; the non-reducing sweetener is preferably 0.4-0.8g, more preferably 0.5g; the colloid is preferably 2-4g, more preferably 3g; the preservative is preferably 0.35-0.45g, more preferably 0.4g; and the fruit flavoring is preferably 0.8-1.2g, more preferably 1g.

[0041] Soybean lecithin and glyceryl citrate were combined as a W1 / O interface emulsifier. Soybean lecithin is an amphoteric emulsifier, possessing both emulsifying and nourishing properties; glyceryl citrate is a nonionic emulsifier. The combination of the two produces a synergistic effect, forming a tightly packed emulsion film at the oil-water interface, effectively stabilizing the W1 / O primary emulsion.

[0042] Sucrose fatty acid esters were used as hydrophilic emulsifiers to stabilize the O / W2 interface. OSA-modified starch or pectin was combined as steric hindrance stabilizers to enhance the emulsion stability by strengthening the interfacial elastic layer.

[0043] Adding a tocopherol concentrate and rosemary extract to the oil phase as a natural antioxidant can produce a synergistic antioxidant effect, protecting fat-soluble vitamins A and D2 from oxidative degradation.

[0044] Adding EDTA-2Na as a metal ion chelating agent to the external aqueous phase complexes Fe in the solution. 3+ Cu 2+ Trace amounts of metal ions are used to block their catalytic oxidation of vitamins. A citric acid-sodium citrate buffer is employed to precisely maintain the solution pH at 3.4–3.8, providing the most stable chemical environment for all active ingredients. Citric acid itself also has a weak metal chelating effect, which can assist EDTA-2Na in inhibiting metal ion-catalyzed oxidation reactions.

[0045] Pectin and chitosan are adsorbed onto the surface of emulsion droplets in the external aqueous phase through electrostatic interaction, forming a thick biopolymer coating on the droplet surface to prevent emulsion aggregation and stratification. The pectin-chitosan complex has pH-responsive properties and can form a gel-like protective layer in the acidic environment of the stomach. The complex adheres to the surface of the gastric mucosa, reducing the direct irritation of the stomach wall by components such as vitamin C.

[0046] This invention also provides a method for preparing a highly stable five-dimensional lysine oral solution, comprising the following steps: (1) Preparation of internal aqueous phase: Vitamin C, vitamin B6, nicotinamide, lysine hydrochloride, hydroxypropyl-β-cyclodextrin, reduced glutathione and some water are mixed to obtain an internal aqueous phase solution; Preparation of the oil phase: Vitamin A, vitamin D2, water-oil interface emulsifier, oil phase antioxidant and oil phase solvent are mixed to obtain an oil phase solution; Preparation of external aqueous phase: The oil-water interface emulsifier, hydroxypropyl-β-cyclodextrin, metal ion chelating agent, osmotic pressure regulator, non-reducing sweetener, colloid, preservative, fruit flavoring and the balance water are mixed to obtain an external aqueous phase solution; (2) Add the aqueous phase solution to the oil phase solution and perform shear emulsification to obtain W1 / O primary emulsion; (3) Add W1 / O primary emulsion to the external aqueous phase solution and mix and disperse to obtain W1 / O / W2 double emulsion; (4) Homogenize the W1 / O / W2 double emulsion; (5) Adjust the pH of the homogenized W1 / O / W2 double emulsion to 3.4~3.8, fill it under a protective atmosphere; after filling, purge the headspace with nitrogen and seal it to obtain a five-dimensional lysine oral solution. Steps (1) to (5) are carried out in a light-proof and protective atmosphere.

[0047] In this invention, unless otherwise specified, the protective atmosphere can be nitrogen.

[0048] In this invention, the method of mixing vitamin C, vitamin B6, nicotinamide, lysine hydrochloride, hydroxypropyl-β-cyclodextrin, reduced glutathione and a portion of water in step (1) specifically includes: mixing hydroxypropyl-β-cyclodextrin and a portion of water in a water bath at 40~50℃ (more preferably 42~48℃, more preferably 45℃); cooling to below 30℃, and then sequentially adding vitamin C, vitamin B6, nicotinamide, lysine hydrochloride and reduced glutathione for mixing.

[0049] In this invention, the method of mixing vitamin A, vitamin D2, water-oil interface emulsifier, oil phase antioxidant and oil phase solvent in step (1) specifically includes: mixing the oil phase solvent and water-oil interface emulsifier in a water bath at 50~60℃ (more preferably 53~57℃, more preferably 55℃); cooling to 40~50℃ (more preferably 43~47℃, more preferably 45℃), adding vitamin A and vitamin D2, stirring to completely dissolve; and then adding the oil phase antioxidant and mixing.

[0050] In this invention, the preparation of the external aqueous phase in step (1) specifically includes the following method: mixing the oil-water interface emulsifier, hydroxypropyl-β-cyclodextrin, metal ion chelating agent, osmotic pressure regulator, non-reducing sweetener, colloid, preservative, fruit flavoring and the remaining water. Then, the colloid and the remaining water are mixed in a water bath at 50~60℃ (more preferably 52~58℃, more preferably 55℃), added to the aforementioned mixture for mixing and dispersion, and then water is added to make up to the required volume.

[0051] In this invention, when the stabilizer is included in the preparation of the external aqueous phase in step (1), the stabilizer is mixed with the colloid and a portion of water in a water bath at 50~60°C (more preferably 52~58°C, more preferably 55°C) and then added to the mixture of other external aqueous phases.

[0052] In this invention, the shear rate of the shear emulsification in step (2) is preferably 8000~15000 r / min, more preferably 10000~14000 r / min, and even more preferably 12000 r / min; the emulsification time is preferably 10~30 min, more preferably 10~20 min, and even more preferably 15 min.

[0053] In this invention, the stirring rate for mixing and dispersing in step (3) is preferably 300~600 r / min, more preferably 300~500 r / min, and even more preferably 400 r / min; the dispersion time is preferably 10~20 min, more preferably 12~18 min, and even more preferably 15 min.

[0054] In this invention, the homogenization pressure of the homogenization process in step (4) is preferably 50~80MPa, more preferably 50~70MPa, and even more preferably 60MPa; the number of homogenizations is preferably 1~3 times, more preferably 1~2 times, and even more preferably 2 times.

[0055] In this invention, the average droplet size of the W1 / O / W2 dual emulsion after homogenization in step (4) is preferably 200~800nm.

[0056] In this invention, there are no limitations on the source of raw materials or other preparation parameters; commercially available products or solutions well known in the art can be used.

[0057] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0058] Some of the raw materials (pharmaceutical grade) used in the examples and comparative examples were from the following manufacturers: Soybean phospholipid SPC-80A oral phospholipid, Aivito (Shanghai) Pharmaceutical Technology Co., Ltd., pharmaceutical excipient, CAS No. 8030-76-0; Mixed tocopherol concentrate (50% concentration), Hubei Chengfeng Chemical Co., Ltd. Rosemary extract (98% rosmarinic acid), Changsha Shanghe Biotechnology Co., Ltd. Medium-chain triglycerides, Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd., CAS No. 85409-09-2; Sucrose fatty acid ester OP-10, Shandong Fengtai Biotechnology Co., Ltd.; Pharmaceutical pectin ALA0406C, Xibao Biotechnology (Shanghai) Co., Ltd.; Chitosan, product number ACJ0074, Xibao Biotechnology (Shanghai) Co., Ltd.; OSA modified starch, octenyl succinate starch, Suzhou Kemei Biosynthesis Co., Ltd., CAS No. 66829-29-6; Orange flavoring, peach flavoring, and strawberry flavoring, produced by Shenzhen Hengnuo Biotechnology Co., Ltd.

[0059] Example 1

[0060] The formulation for preparing 1000 mL of pentavirgic lysine oral solution is as follows: Internal aqueous phase: Vitamin C 5g, Vitamin B6 0.2g, Nicotinamide 2g, Lysine hydrochloride 6g, Hydroxypropyl-β-cyclodextrin 3g, Reduced glutathione 0.2g, add water for injection to 30mL.

[0061] Oil phase: Vitamin A 300,000 units, Vitamin D2 20,000 units, soybean lecithin 1.5g, monoglyceride citrate 1.5g, tocopherol mixture concentrate 0.3g, rosemary extract 0.03g, medium chain triglycerides 50mL.

[0062] External aqueous phase: 5g sucrose fatty acid ester, 2g hydroxypropyl-β-cyclodextrin, 0.2g EDTA-2Na, 50g xylitol, 0.5g sucralose, 1.5g pectin, 1.5g chitosan, 5g OSA modified starch, 0.4g ethylparaben, 1g orange flavoring, and water for injection to 1000mL. Adjust the final pH to 3.5 with citric acid-sodium citrate (mass ratio 1:1).

[0063] The following preparation steps were carried out under light-protected and nitrogen-protected conditions: (1) Take a clean glass beaker, add 20 mL of water for injection, and purge with nitrogen to remove oxygen. Add hydroxypropyl-β-cyclodextrin and stir at 150 r / min in a 45°C water bath until completely dissolved, forming a colorless and clear solution. Cool the above solution in the water bath to below 25°C, and while maintaining stirring, slowly add vitamin C, vitamin B6, nicotinamide, lysine hydrochloride, and reduced glutathione in sequence, stirring for 5 min after each addition to ensure complete dissolution. Add nitrogen-saturated water for injection to a total volume of 30 mL, and continue stirring for 10 min to obtain an internal aqueous phase solution. Seal and temporarily store under a nitrogen atmosphere.

[0064] (2) Take a clean flask, add medium-chain triglycerides, and purge with nitrogen. Add soybean lecithin and glyceryl monocitrate, and place in a 55°C water bath. Stir at 200 r / min until completely transparent and dissolved. Lower the water bath temperature to 45°C, and add vitamin A and vitamin D2 with gentle stirring. Continue stirring until completely dissolved. Add tocopherol concentrate and rosemary extract, and stir until evenly dispersed to obtain an oil phase solution. Keep it at 45°C and purge with nitrogen for temporary storage.

[0065] (3) Take a clean large beaker, add about 800 mL of water for injection, and purge with nitrogen. Add sucrose fatty acid ester, hydroxypropyl-β-cyclodextrin, EDTA-2Na, xylitol, sucralose, ethylparaben, and orange flavoring in sequence, and stir at 300 r / min at room temperature until completely dissolved to obtain a mixture. Take another small beaker, add about 80 mL of water for injection, add pectin, chitosan, and OSA modified starch, and place in a 55℃ water bath. Stir at 250 r / min for 20 min to swell and form a uniform, semi-transparent colloidal solution. Pour the colloidal solution into the mixture while hot, stir well, and dilute to volume with nitrogen-treated water for injection. Continue stirring for 15 min to ensure thorough mixing to obtain an external aqueous phase solution, and maintain nitrogen protection.

[0066] (4) Transfer the entire aqueous phase solution to a constant pressure dropping funnel, with the outlet submerged below the surface of the oil phase solution. Using a high-speed shear emulsifier, set the rotation speed to 12000 r / min, maintain a 45°C water bath jacket, and drip the aqueous phase solution into the oil phase at a rate of approximately 3 mL / min. After dripping, continue shearing for 15 min. Protect from light throughout the process and continuously purge nitrogen gas above the liquid surface. Finally, obtain the W1 / O primary emulsion.

[0067] (5) Place the external aqueous phase solution in a sealable stirred tank, introduce nitrogen gas, and turn on the mechanical stirrer at a speed of 400 r / min. Slowly pour all of the W1 / O primary emulsion into the stirred external aqueous phase solution, completing the addition within 5 min. After the addition is complete, continue stirring at 400 r / min for 15 min to obtain a milky white homogeneous dispersion, which is the crude W1 / O / W2 double emulsion.

[0068] (6) The crude double emulsion was homogenized using a high-pressure homogenizer at a pressure of 60 MPa, and homogenized twice. During the circulation, a cooling jacket was used to keep the temperature of the liquid below 30°C. After homogenization, a nano-sized double emulsion with more uniform particle size was obtained.

[0069] (7) After homogenization, the emulsion is gently mixed with magnetic stirring. The pH is measured, and citrate-sodium citrate (1:1) buffer solution (prepared as a concentrated solution) is added dropwise to adjust the pH to 3.60±0.05. The total volume is checked. If it is less than 1000mL, it is added to the mark with water for injection, and then stirred for 10 minutes to homogenize. The filling process is carried out in a glove box under nitrogen protection. The emulsion is dispensed into 10mL brown borosilicate glass oral solution bottles. After filling, the headspace of the bottle is immediately replaced with nitrogen, the cap is sealed, and the five-dimensional lysine oral solution is obtained after passing the light inspection.

[0070] Example 2

[0071] The formulation for preparing 1000 mL of pentavirgic lysine oral solution is as follows: Internal aqueous phase: Vitamin C 5g, Vitamin B6 0.2g, Nicotinamide 2g, Lysine hydrochloride 6g, Hydroxypropyl-β-cyclodextrin 5g, Reduced glutathione 0.5g, water added to 35mL.

[0072] Oil phase: Vitamin A 300,000 units, Vitamin D2 20,000 units, Soy lecithin 2g, Citric acid monoglyceride 2g, Tocopherol mixture concentrate 0.4g, Rosemary extract 0.1g, Caprylic / Capric triglyceride 70mL.

[0073] External aqueous phase: 8g sucrose fatty acid ester, 5g hydroxypropyl-β-cyclodextrin, 0.3g EDTA-2Na, 70g sorbitol, 1g sucralose, 2g pectin, 2g chitosan, 8g pectin (stabilizer), 0.5g ethylparaben, 1.5g peach flavoring, water for injection added to 1000mL, pH adjusted to 3.5 with sodium citrate-citrate.

[0074] Preparation: Step (4) shearing at 15000 r / min for 10 min, Step (5) mixing and dispersing at 500 r / min for 15 min, Step (6) homogenizing at 80 MPa for one cycle, the rest is the same as in Example 1.

[0075] Example 3

[0076] The formulation for preparing 1000 mL of pentavirgic lysine oral solution is as follows: Internal aqueous phase: Vitamin C 5g, Vitamin B6 0.2g, Nicotinamide 2g, Lysine hydrochloride 6g, Hydroxypropyl-β-cyclodextrin 1g, Reduced glutathione 0.05g, water to 30mL.

[0077] Oil phase: Vitamin A 300,000 units, Vitamin D2 20,000 units, Soy lecithin 0.5g, Citric acid monoglyceride 0.5g, Tocopherol mixture concentrate 0.05g, Rosemary extract 0.01g, MCT 50mL.

[0078] External aqueous phase: 1g sucrose fatty acid ester, 1g hydroxypropyl-β-cyclodextrin, 0.1g EDTA-2Na, 30g xylitol, 0.2g sucralose, 0.5g pectin, 0.5g chitosan, 1g OSA modified starch, 0.3g ethylparaben, 0.5g strawberry flavoring, water for injection added to 1000mL, pH adjusted to 3.5.

[0079] Preparation: Step (4) shearing at 8000 r / min for 30 min, Step (5) mixing and dispersing at 300 r / min for 20 min, Step (6) homogenizing at 50 MPa for 3 cycles, the rest is the same as in Example 1.

[0080] Comparative Example 1: No reduced glutathione was added to the internal aqueous phase; the rest was the same as in Example 1.

[0081] Comparative Example 2: Neither the internal nor external aqueous phase contained hydroxypropyl-β-cyclodextrin, and the rest was the same as in Example 1.

[0082] Comparative Example 3: The water-oil interface emulsifier used only 3g of soybean lecithin, and glyceryl monocitrate was removed; the oil phase antioxidant used only 0.33g of tocopherol mixture concentrate, and rosemary extract was removed, and the rest was the same as in Example 1.

[0083] Comparative Example 4: The external aqueous phase colloid used only 3g of pectin, removed chitosan, and did not add OSA modified starch, otherwise it was the same as Example 1.

[0084] Comparative Example 5: In the oil phase, soybean lecithin and glyceryl citrate were not used, and Tween 80 3g was used instead as the W1 / O emulsifier; in the aqueous phase, sucrose fatty acid ester was not used, and Tween 80 5g was used instead as the O / W2 emulsifier; OSA modified starch and pectin-chitosan composite colloid were not added, and the rest was the same as in Example 1.

[0085] Performance testing

[0086] 1) Appearance and physical stability

[0087] Visually inspect the sample for signs of stratification, precipitation, flocculation, or discoloration.

[0088] Centrifugation stability: Take 10 mL of sample and centrifuge at 4000 r / min for 15 min. Observe whether it separates into layers and determine whether the upper layer of oil precipitates or the lower layer precipitates.

[0089] Emulsion particle size and Zeta potential: The droplet average size (Z-average), polydispersity index (PDI) and Zeta potential (measured after matching the conductivity of the external aqueous phase) of the W1 / O / W2 dual emulsion were determined using Malvern Zetasizer Nano ZS at 25℃.

[0090] pH monitoring: Measured at 25°C using a calibrated pH meter.

[0091] Vitamin encapsulation efficiency: The external aqueous phase and the double emulsion droplets were separated by ultrafiltration centrifugation (molecular weight cutoff 100kDa). The free vitamin C content in the external aqueous phase was determined by HPLC. The vitamin C encapsulation efficiency (%) was calculated as (1 - external aqueous phase VC content / total VC content) × 100%.

[0092] 2) Accelerated stability test

[0093] Each sample was sealed in a brown bottle and placed in a constant temperature and humidity chamber at 40℃±2℃ and RH 75%±5%. Samples were taken at 0, 30, 60, and 90 days. Detection was performed on appearance, pH, vitamin A content (HPLC), vitamin C content (HPLC), and vitamin B6 content (HPLC), and the retention rate (%) was calculated. The change in emulsion particle size was also measured.

[0094] The test results are shown in Tables 1 to 3.

[0095] Table 1. Physicochemical properties of fresh samples (0 days)

[0096] Table 2. pH changes during accelerated stability testing

[0097] Table 3. Vitamin retention rate and particle size change after 90 days of accelerated stability testing

[0098] The results in Tables 1 to 3 show that the pH fluctuation in Examples 1-3 did not exceed 0.05 within 90 days of accelerated aging, proving that the citrate-sodium citrate buffer pair can efficiently stabilize the pH of the system at pH=3.5. In Comparative Examples 1-4, due to increased oxidation, vitamin C degradation produced acidic products such as diketogulonic acid, leading to varying degrees of pH decrease. In Comparative Example 5, complete demulsification resulted in a large release and rapid oxidative degradation of vitamin C in the aqueous phase, causing the pH to drop sharply to 2.95, far below the set value, indicating a severe imbalance in the system.

[0099] In the examples, the initial particle size was less than 550 nm and the PDI was low, with an absolute Zeta potential >28 mV. After 90 days, the particle size increased only slightly, and the appearance was uniform. This was attributed to the dense W1 / O interfacial film composed of soybean lecithin and glyceryl citrate, and the O / W2 interfacial elastic layer constructed from sucrose fatty acid esters and OSA modified starch / pectin. Comparative Examples 3 and 4 had larger initial particle sizes, and after 90 days, significant stratification and a sharp increase in particle size were observed, indicating that synergistic emulsification and stabilizers are indispensable for maintaining the dual emulsion structure. In Comparative Example 5, after completely replacing the composite emulsification system of this invention with Tween 80, the initial particle size reached 850 nm and the PDI was as high as 0.48, with a Zeta potential of only -18.6 mV, indicating insufficient emulsion interfacial film strength and weak electrostatic repulsion. After 90 days, the particle size increased to 1150 nm and the oil and water were completely separated, indicating that relying solely on synthetic small molecule emulsifiers cannot provide sufficient interfacial stability for the W1 / O / W2 multi-structure. In particular, the lack of steric hindrance protection from colloids and stabilizers makes the emulsion extremely unstable thermodynamically.

[0100] In the examples, the vitamin C retention rate was ≥96%, and the encapsulation rate was >93%, indicating that the internal aqueous phase was effectively isolated. Reduced glutathione can consume dissolved oxygen and regenerate vitamin C, while hydroxypropyl-β-cyclodextrin partially encapsulates vitamin C, B6, etc., improving chemical stability. Comparative Example 1 showed a vitamin C retention rate of only 89.2%, and Comparative Example 2 showed a retention rate of 86.1%, both accompanied by yellowing, confirming the protective effect of reduced glutathione and HP-β-CD on vitamin C. Comparative Examples 3-5 showed significant leakage and oxidation of vitamin C, with retention rates dropping below 79%.

[0101] In the examples, the vitamin A retention rate was >98%, while in Comparative Example 3, the retention rate dropped to 90.6%, indicating that the tocopherol-rosemary extract combination effectively protects vitamins A and D2 through a relay antioxidant mechanism. Comparative Example 5 had the lowest retention rate due to emulsion demulsification, resulting in direct exposure of the oil phase and accelerated oxidation.

[0102] The retention trend of vitamin B6 was consistent with that of vitamins A and C, with a retention rate of >98% in the example and 84.5% in the comparative example 5.

[0103] In summary, under the optimal condition of a uniform pH of 3.5, the four mechanisms of the present invention—composite emulsification system, antioxidant combination, inclusion protection, and steric stability—are indispensable, collectively achieving a highly stable W1 / O / W2 dual emulsion structure and ultra-efficient vitamin retention of up to 90 days for the five-dimensional lysine oral solution. The absence or substitution of any single component leads to a significant deterioration in stability, with the replacement of the emulsification system (Comparative Example 5) causing the most severe damage.

[0104] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A highly stable five-dimensional lysine oral solution, characterized in that, The five-dimensional lysine oral solution has a W1 / O / W2 dual emulsion structure, where W1 is the inner aqueous phase, O is the oil phase, and W2 is the outer aqueous phase; the pH of the five-dimensional lysine oral solution is 3.4~3.

8. The five-dimensional lysine oral solution, per 1000 mL, comprises the following components: The aqueous phase comprises: 5g vitamin C, 0.2g vitamin B6, 2g nicotinamide, 6g lysine hydrochloride, 1-5g hydroxypropyl-β-cyclodextrin, 0.05-0.5g reduced glutathione, and a portion of water; the volume ratio of the aqueous phase to the oil phase is 1:2-3:

5. The oil phase comprises: 300,000 units of vitamin A, 20,000 units of vitamin D2, 1-6 g of water-oil interface emulsifier, 0.06-0.6 g of oil phase antioxidant, and 20-100 mL of oil phase solvent; The external aqueous phase comprises: 1-10g of oil-water interface emulsifier, 1-5g of hydroxypropyl-β-cyclodextrin, 0.1-0.3g of metal ion chelating agent, 30-80g of osmotic pressure regulator, 0.2-1g of non-reducing sweetener, 1-5g of colloid, 0.3-0.5g of preservative, 0.5-2g of fruit flavoring, and the balance being water; The water-oil interface emulsifier comprises a mixture of soybean lecithin and glyceryl citrate; the oil phase antioxidant comprises a mixture of tocopherol concentrate and rosemary extract. The oil-water interface emulsifier is a sucrose fatty acid ester.

2. The highly stable five-dimensional lysine oral solution according to claim 1, characterized in that, The mass ratio of soybean lecithin to glyceryl citrate is 0.5~3:0.5~3; the mass ratio of the tocopherol concentrate to the rosemary extract is 0.05~0.5:0.01~0.

1.

3. A highly stable five-dimensional lysine oral solution according to claim 1 or 2, characterized in that, The oil phase solvent includes medium-chain triglycerides or caprylic / capric triglycerides.

4. The highly stable five-dimensional lysine oral solution according to claim 1, characterized in that, The metal ion chelating agent is EDTA-2Na; the osmotic pressure regulator includes xylitol or sorbitol; the non-reducing sweetener is sucralose; the colloid is a mixture of pectin and chitosan in a mass ratio of 0.5~2.5:0.5~2.5; the preservative is ethylparaben; and the fruit flavoring includes orange flavoring, peach flavoring, or strawberry flavoring.

5. A highly stable five-dimensional lysine oral solution according to claim 1 or 4, characterized in that, Based on 1000 mL of the five-dimensional lysine oral solution, the external aqueous phase also includes 1-10 g of stabilizer; the stabilizer includes OSA modified starch or pectin.

6. The highly stable five-dimensional lysine oral solution according to claim 1, characterized in that, The reagent used to adjust the pH of the 5-dimensional lysine oral solution to 3.4-3.8 is a mixture of citric acid and sodium citrate.

7. A method for preparing a highly stable five-dimensional lysine oral solution according to any one of claims 1 to 6, characterized in that, Includes the following steps: (1) Preparation of internal aqueous phase: Vitamin C, vitamin B6, nicotinamide, lysine hydrochloride, hydroxypropyl-β-cyclodextrin, reduced glutathione and some water are mixed to obtain an internal aqueous phase solution; Preparation of the oil phase: Vitamin A, vitamin D2, water-oil interface emulsifier, oil phase antioxidant and oil phase solvent are mixed to obtain an oil phase solution; Preparation of external aqueous phase: The oil-water interface emulsifier, hydroxypropyl-β-cyclodextrin, metal ion chelating agent, osmotic pressure regulator, non-reducing sweetener, colloid, preservative, fruit flavoring and the balance water are mixed to obtain an external aqueous phase solution; (2) Add the aqueous phase solution to the oil phase solution and perform shear emulsification to obtain W1 / O primary emulsion; (3) Add W1 / O primary emulsion to the external aqueous phase solution and mix and disperse to obtain W1 / O / W2 double emulsion; (4) Homogenize the W1 / O / W2 double emulsion; (5) Adjust the pH of the homogenized W1 / O / W2 double emulsion to 3.4~3.8, fill it under a protective atmosphere; after filling, purge the headspace with nitrogen and seal it to obtain a five-dimensional lysine oral solution. Steps (1) to (5) are carried out in a light-proof and protective atmosphere.

8. The preparation method according to claim 7, characterized in that, The shear rate of the shear emulsification in step (2) is 8000~15000 r / min, and the emulsification time is 10~30 min.

9. The preparation method according to claim 7 or 8, characterized in that, The stirring rate for mixing and dispersing in step (3) is 300~600 r / min, and the dispersion time is 10~20 min.

10. The preparation method according to claim 9, characterized in that, The homogenization pressure in step (4) is 50~80MPa, and the number of homogenization cycles is 1~3.

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