Lycopene ethyl polyenoate capsule and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a lycopene ethyl polyenoate capsule and a preparation method thereof. The lycopene ethyl polyenoate capsule comprises a content and a capsule shell, and the content is prepared from the following raw materials in parts by weight: 40 to 60 parts of lycopene, 280 to 320 parts of ethyl polyenoate, 90 to 115 parts of medium chain triglyceride, 25 to 33 parts of enzymolysis lecithin, 8 to 12 parts of mixed tocopherol, 4 to 6 parts of rosemary extract, 0.45 to 0.55 part of ethylene diamine tetraacetic acid and 4 to 5 parts of fumed silica; and the capsule shell is a hydroxypropyl methylcellulose plant capsule. Through the design of the enzymolysis lecithin emulsifier, the medium-chain triglyceride carrier oil and an anti-caking system compounded by fumed silica and ethylene diamine tetraacetic acid, the technical problem that fat-soluble components are easy to oxidize and difficult to disperse is solved.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparations, and in particular to a lycopene polyenoic acid ethyl ester capsule and its preparation method. Background Technology

[0002] Blood lipids are a general term for lipid substances in blood plasma, including triglycerides, phospholipids, cholesterol, cholesterol esters, and non-esterified fatty acids. With the continuous improvement of people's living standards, hyperlipidemia easily leads to cardiovascular and cerebrovascular diseases, such as hypertension, coronary heart disease, and arteriosclerosis. Therefore, only by maintaining blood lipid levels within a certain range can the risk of cardiovascular and cerebrovascular diseases be reduced.

[0003] Lycopene is a natural pigment with various physiological activities, and it plays a role in preventing cancer and cardiovascular diseases. The lycopene content in human blood plasma is negatively correlated with the incidence of various cancers, including prostate cancer and digestive tract cancer, as well as atherosclerosis and coronary heart disease. Ethyl polyenoate, mainly composed of ethyl eicosapentaenoate and ethyl docosahexaenoate, is used for hyperlipidemia, coronary atherosclerotic heart disease (coronary heart disease), and cerebral thrombosis.

[0004] Lycopene is a fat-soluble crystal, while ethyl polyunsaturated fatty acids (EPOFAs) have high liquid viscosity, resulting in poor compatibility between the two; furthermore, EPOFAs are highly susceptible to oxidation. Existing solutions either dissolve lycopene in vegetable oil or encapsulate it separately in fish oil soft capsules; direct mixing easily leads to separation and spoilage. Therefore, improving compatibility is a pressing issue that needs to be addressed. Summary of the Invention

[0005] To improve the compatibility of lycopene and ethyl polyunsaturate in lycopene polyunsaturate capsules, this application provides a lycopene polyunsaturate capsule and its preparation method.

[0006] In the first aspect, this application provides a lycopene polyunsaturated ester capsule, which adopts the following technical solution.

[0007] A lycopene polyunsaturated ester capsule, comprising contents and a capsule shell,

[0008] By weight, the contents comprise the following raw materials: 40-60 parts lycopene, 280-320 parts ethyl polyenoate, 90-115 parts medium-chain triglycerides, 25-33 parts enzymatically hydrolyzed lecithin, 8-12 parts mixed tocopherols, 4-6 parts rosemary extract, 0.45-0.55 parts disodium EDTA, and 4-5 parts fumed silica;

[0009] The capsule shell is a hydroxypropyl methylcellulose plant capsule.

[0010] By adopting the above technical solutions, lycopene, a powerful fat-soluble antioxidant, can scavenge free radicals, inhibit low-density lipoprotein oxidation, and reduce the risk of cardiovascular disease; at the same time, it has a potential protective effect on prostate health.

[0011] Ethyl polyunsaturated fatty acids (Omega-3 fatty acids): Contains EPA and DHA, which can lower triglyceride levels, regulate blood lipids, improve blood viscosity, and synergistically enhance the protective effect of vascular endothelium with lycopene.

[0012] This product combines tocopherol and rosemary extracts, creating a dual antioxidant system that delays the oxidation and rancidity of oils, protects the activity of lycopene and ethyl polyunsaturates, and enhances the body's antioxidant capacity.

[0013] Medium-chain triglycerides (MCTs) have better water solubility than long-chain fatty acids and can be directly absorbed through the portal vein. They act as carriers to promote the dissolution and absorption of fat-soluble components such as lycopene and ethyl polyunsaturates, thus improving bioavailability. As a lycopene solvent, it dissolves crystalline lycopene at high temperatures to form a molecular dispersion, with a solubility 3.2 times that of corn oil. As a diluent for ethyl polyunsaturates, it reduces viscosity, improves filling precision, and avoids competition from long-chain fats for pancreatic lipases. It can also delay the oxidation of ethyl polyunsaturates.

[0014] Enzymatic hydrolysis of lecithin acts as an emulsifier, enabling the oil components to form a uniformly dispersed system, reducing particle aggregation, and further improving absorption efficiency.

[0015] Fumed silica, acting as a flow aid and anti-caking agent, adsorbs trace amounts of moisture in the system, preventing the contents from clumping and ensuring uniform dispersion of the capsule contents, facilitating precise dosage control.

[0016] This proposed solution integrates antioxidant properties, lipid regulation, and absorption enhancement, making it suitable for middle-aged and elderly individuals, those managing cardiovascular health, and consumers requiring antioxidant supplementation. Through the design of emulsifiers (enzymatically hydrolyzed lecithin), carrier oil (MCT), and an anti-caking system (fumed silica + EDTA), the technical challenges of easy oxidation and poor dispersion of fat-soluble components are solved. The use of plant-based capsule shells and food-grade additives reduces the risk of allergies, expands the applicable population, and the formulation meets the safety standards for health supplements or pharmaceuticals.

[0017] Furthermore, the fumed silica portion is replaced with microcrystalline cellulose, and the substitution rate of microcrystalline cellulose for fumed silica is 40-50% by weight.

[0018] By adopting the above technical solution, fumed silica is partially replaced with microcrystalline cellulose, while the remaining part can still adsorb trace amounts of moisture, prevent contents from clumping, maintain the fluidity of the capsules during filling, and avoid particle aggregation problems caused by complete replacement.

[0019] Crystalline cellulose (MCC), as an inert excipient, increases the bulk density of the contents and adjusts the weight uniformity of the formulation, making it particularly suitable for systems with a high proportion of ethyl polyunsaturated fatty acids (EFAs) to ensure precise dosage per capsule. MCC exhibits capillary action and water-absorbing swelling properties, accelerating capsule shell disintegration in the gastrointestinal tract and promoting rapid release of the contents. Compared to fumed silica, it has higher disintegration efficiency, shortening the release cycle of fat-soluble components such as lycopene and EFAs. Combined with the carrier effect of medium-chain triglycerides, it further enhances the absorption rate.

[0020] The porous structure of microcrystalline cellulose can adsorb oil phase components, forming a microporous network. When the capsule disintegrates, the contents are more easily dispersed into fine particles in the gastrointestinal tract, increasing the contact area with digestive juices. Combined with the emulsifying effect of enzymatic hydrolysis of lecithin, an emulsion can be rapidly formed, promoting the dissolution of fat-soluble components such as lycopene.

[0021] Ethyl polyunsaturated fatty acid is a liquid oil. When fumed silica is used alone, the system may settle due to gravity. After adding microcrystalline cellulose, its water absorption and swelling can increase the viscosity of the system, reduce the sedimentation and stratification of the oil components, keep the contents uniformly dispersed in the capsule, and further ensure the consistency of dosage.

[0022] The replacement solution addresses the issues of slow disintegration and delayed release in fat-soluble capsules by employing a "dual-function synergy of anti-caking and disintegration" without affecting the original formula's antioxidant and absorption efficiency. At the same time, the introduction of natural excipients enhances safety and process adaptability.

[0023] Furthermore, it also includes 12-17 parts of hydroxypropyl-β-cyclodextrin.

[0024] By adopting the above technical solution, the hydrophobic cavity of hydroxypropyl-β-cyclodextrin can form a 1:1 inclusion complex with lycopene. After inclusion, the conjugated double bond of lycopene is shielded, avoiding direct contact with oxygen and ultraviolet rays in the air, thus reducing its photo-oxidation rate. The hydroxyl groups of hydroxypropyl-β-cyclodextrin can chelate trace metal ions, weakening their catalytic effect on lipid oxidation and reducing the rate of peroxide value increase.

[0025] The synergistic effect of hydroxypropyl-β-cyclodextrin and ethyl polyunsaturate forms a ternary network of "cyclodextrin-oil-antioxidant" in the inclusion system. Mixed tocopherol and rosemary extract can be more evenly distributed on the surface of the inclusion complex, forming an "antioxidant barrier" and prolonging the rancidity induction period.

[0026] Through dual optimization of "microcrystalline cellulose replacement + hydroxypropyl-β-cyclodextrin introduction," this capsule formulation achieves a three-dimensional improvement in "stability, release, and safety": On the one hand, microcrystalline cellulose balances anti-caking properties and moisture control, avoiding the oxidation risks caused by excessive fumed silica; on the other hand, the inclusion effect of hydroxypropyl-β-cyclodextrin isolates oxidizing factors at the molecular level while improving dissolution efficiency. The synergistic effect of these two factors extends the product's shelf life at room temperature and eliminates the need for special storage conditions.

[0027] Furthermore, the medium-chain triglyceride is a pharmaceutical-grade medium-chain triglyceride with a C8 / C10 ratio of 60 / 40.

[0028] By adopting the above technical solution, the viscosity of medium-chain triglycerides at this ratio is 32-35 cS at 37℃, which can not only ensure the full dissolution of lycopene, but also form micro-droplets in the intestine, increase the specific surface area, and promote the contact efficiency with intestinal villi. In vitro experiments show that the intestinal absorption rate constant of polyunsaturated ethyl ester is improved.

[0029] Through triple optimization of metabolism, stability, and process, a key breakthrough has been achieved in the formulation of this lycopene capsule: it utilizes the rapid metabolic characteristics of C8 to improve bioavailability, while C10 regulates physical properties and safety, forming a synergistic network with hydroxypropyl-β-cyclodextrin and microcrystalline cellulose, ultimately achieving a balance between clinical efficacy, stability, and production adaptability.

[0030] Furthermore, the fumed silica has a water contact angle ≥120°, a specific surface area of ​​90-130 m² / g, and a particle size of 12-20 nm.

[0031] By adopting the above technical solution, the fumed silica with these parameters achieves multi-dimensional optimization in lycopene capsules through a triple mechanism of "hydrophobic surface anti-hygroscopicity - nano-interface stable dispersion - high specific surface area strong adsorption". It not only solves the oxidation and hygroscopic problems of the oil system, but also improves the rheological stability and production applicability of the contents through nano-level dispersion control. It forms a synergistic network with medium-chain triglycerides, hydroxypropyl-β-cyclodextrin and microcrystalline cellulose in the formula, ultimately extending the shelf life and improving the bioavailability of the product.

[0032] Furthermore, the fumed silica undergoes a surface modification treatment with hexamethyldisilazane.

[0033] By adopting the above technical solution, the order-of-magnitude improvement in the hydrophobicity of the modified fumed silica significantly reduces the risk of moisture absorption and oxidation. Combined with medium-chain triglycerides, it forms a double insurance system of "hydrophobic barrier + antioxidant enrichment". It solves the problem of agglomeration of traditional powders and forms a "nano-micro" composite skeleton with microcrystalline cellulose, which maintains fluidity and prevents agglomeration.

[0034] Secondly, this application provides a method for preparing lycopene polyunsaturated ester capsules, using the following technical solution.

[0035] A method for preparing lycopene polyunsaturated ester capsules includes the following steps:

[0036] S1. Lycopene predispersion

[0037] Lycopene powder and optional hydroxypropyl-β-cyclodextrin were added to medium-chain triglycerides preheated to 70-80℃ and vacuum sheared for 30 min to obtain a pre-dispersion.

[0038] S2. Lipid-phase mixing and homogenization

[0039] Add polyurethane ethyl ester and lecithin to the pre-dispersion solution, keep the system temperature at 68-75℃, mix for 15 minutes under normal pressure, and then homogenize.

[0040] S3. Antioxidant system addition and final mixing

[0041] The system was cooled to 48-52℃, and mixed tocopherols, rosemary extract, disodium EDTA, and fumed silica were added. The mixture was then stirred under vacuum to obtain the contents.

[0042] S4. Filling

[0043] Maintain the temperature of the contents at 38-42℃ and fill them into capsule shells;

[0044] S5. Cooling and Packaging

[0045] After filling, the capsules are cooled and cured for 30 minutes at 15-20℃ and ≤40%RH before being packaged.

[0046] By adopting the above technical solution, the preparation process, through a multi-dimensional design of "encapsulation-emulsification-antioxidation-stabilization", overcomes the bottleneck of easy oxidation and difficult dispersion of fat-soluble components. Compared with traditional capsule processes, it achieves significant improvements in active ingredient retention rate, bioavailability and production efficiency.

[0047] Furthermore, S1. Lycopene predispersion specifically involves:

[0048] One-third of the weight of medium-chain triglycerides was heated to 50°C, and then lycopene and optional hydroxypropyl-β-cyclodextrin were added. The mixture was sheared and dispersed at 2000 rpm for 10 min to obtain a premixed system. Meanwhile, the remaining two-thirds of the weight of medium-chain triglycerides was preheated to 70°C.

[0049] The premixed system was heated to 75°C, and then preheated medium-chain triglycerides were added. The mixture was sheared at 8000 rpm for 20 min under a vacuum of -0.009 MPa.

[0050] By adopting the above technical solutions, the pre-dispersion process, through a combination of "temperature gradient control + batch shearing + vacuum protection," overcomes the bottlenecks of difficult dispersion and easy oxidation of high-viscosity systems containing fat-soluble components. Compared with the traditional one-step method, it achieves triple improvements in inclusion rate, particle size control, and antioxidant properties, providing a high-quality pre-dispersion system for subsequent emulsification and filling processes, ultimately improving the dissolution rate and stability of capsule products.

[0051] Furthermore, the specific details of homogenization in S2. lipid phase mixing and homogenization are as follows:

[0052] First-stage homogenization: pressure 60MPa, temperature 65℃, 2 cycles;

[0053] Secondary homogenization: pressure 20MPa, temperature 40℃, 1 cycle.

[0054] In summary, this application has the following beneficial effects:

[0055] This application solves the technical problem of easy oxidation and difficult dispersion of fat-soluble components by designing an enzymatic hydrolyzed lecithin emulsifier, a medium-chain triglyceride carrier oil, and an anti-caking system composed of fumed silica and disodium EDTA. Detailed Implementation

[0056] The present application will be further described in detail below with reference to the embodiments.

[0057] Example of raw material and intermediate preparation

[0058] raw material

[0059] All raw materials used in the embodiments of this application are commercially available.

[0060] Lycopene, crystalline form, purity ≥95%;

[0061] Ethyl polyunsaturated fatty acids, EPA+DHA≥85%, ethyl ester type;

[0062] Medium-chain triglycerides, C8 / C10=60 / 40, pharmaceutical grade;

[0063] Enzymatically hydrolyzed lecithin, pharmaceutical grade, lysophospholipid content ≥60%, acid value ≤15mgKOH / g;

[0064] Mixed tocopherols, with a total tocopherol content ≥96%, γ+δ content ≥70%, and residual solvent ≤10ppm;

[0065] Rosemary extract, with ≥6% sarcopenic acid;

[0066] Disodium EDTA, food grade;

[0067] Fumed silica, with a water contact angle ≥120°, a specific surface area of ​​90-130 m² / g, and a particle size of 12-20 nm;

[0068] Microcrystalline cellulose, model PH-105, particle size 15μm;

[0069] Hydroxypropyl-β-cyclodextrin, degree of substitution 5.5-7.0, molecular weight 1300-1600 Da, water content less than 5%;

[0070] Capsule shell, hydroxypropyl methylcellulose plant capsule.

[0071] Preparation Example

[0072] Preparation Example 1

[0073] A modified fumed silica, the preparation method of which is as follows:

[0074] 1. Vacuum dry fumed silica at 180℃ for 4 hours to remove physically adsorbed water from the surface; the moisture content should be ≤0.1%.

[0075] 2. Add fumed silica to anhydrous toluene solvent, heat to 1100℃, and then add hexamethyldisilazane dropwise, with the weight of hexamethyldisilazane being 10% of the weight of fumed silica. After the addition is complete, reflux the reaction for hours.

[0076] 3. After the reaction was completed, the product was cooled to room temperature and separated by filtration. It was washed three times with anhydrous toluene and then twice with anhydrous ethanol. It was then dried under vacuum at 120°C for 6 hours to obtain modified fumed silica.

[0077] Example

[0078] Examples 1-5

[0079] A lycopene polyunsaturated ester capsule, the preparation method of which is as follows:

[0080] S1. Lycopene predispersion

[0081] According to the raw material ratio in Table 1, lycopene powder and optional hydroxypropyl-β-cyclodextrin were added to medium-chain triglycerides preheated to 75°C, and vacuum sheared for 30 min to obtain a pre-dispersion.

[0082] S2. Lipid-phase mixing and homogenization

[0083] Add polyurethane ethyl ester and lecithin to the pre-dispersion solution, keep the system temperature at 70℃, mix for 15 min under normal pressure, and then homogenize.

[0084] S3. Antioxidant system addition and final mixing

[0085] The system was cooled to 50°C, and mixed tocopherols, rosemary extract, disodium EDTA, and fumed silica were added. The mixture was then stirred under vacuum to obtain the contents.

[0086] S4. Filling

[0087] Maintain the temperature of the contents at 40°C and fill them into capsule shells;

[0088] S5. Cooling and Packaging

[0089] After filling, the capsules are cooled and solidified for 30 minutes at 20℃ and ≤40%RH before being packaged.

[0090] Table 1. Raw material ratios for Examples 1-5 (10g)

[0091] Example 1 Example 2 Example 3 Example 4 Example 5 Lycopene 40 50 60 50 50 Ethyl polyunsaturate 320 300 280 300 300 medium-chain triglycerides 90 100 115 95 110 Enzymatic hydrolysis of lecithin 33 30 25 30 30 Mixed Tocopherols 8 10 12 10 10 Rosemary extract 6 5 4 5 5 Disodium ethylenediaminetetraacetate 0.45 0.50 0.55 0.50 0.50 Fumed silica 5.0 4.5 4.0 4.5 4.5

[0092] Example 6

[0093] Unlike Example 2, Example 6 also includes 120g of hydroxypropyl-β-cyclodextrin.

[0094] Example 7

[0095] Unlike Example 2, Example 7 also includes 150g of hydroxypropyl-β-cyclodextrin.

[0096] Example 8

[0097] Unlike Example 2, Example 8 also includes 170g of hydroxypropyl-β-cyclodextrin.

[0098] Example 9

[0099] Unlike Example 7, in Example 9, 25g of microcrystalline cellulose was used instead of fumed silica.

[0100] Example 10

[0101] Unlike Example 9, in Example 10, 30g of microcrystalline cellulose was used instead of fumed silica.

[0102] Example 11

[0103] Unlike Example 9, the fumed silica in Example 11 was modified according to the method of Preparation Example 1.

[0104] Comparative Example

[0105] Comparative Example 1

[0106] Unlike Example 1, in Comparative Example 1, an equal amount of corn oil was used to replace the medium-chain triglycerides.

[0107] Performance testing

[0108] The particle size and distribution (D90) and polydispersity index (PDI) of lycopene particles in the contents of the examples and comparative examples were determined using a laser particle size analyzer. The results are shown in Table 2.

[0109] Table 2 Performance Test Results

[0110] Particle size / nm PDI Example 1 78.6 0.15 Example 2 75.5 0.15 Example 3 79.0 0.15 Example 4 77.8 0.15 Example 5 78.7 0.15 Example 6 68.5 0.14 Example 7 66.2 0.14 Example 8 67.6 0.14 Example 9 64.7 0.12 Example 10 65.2 0.12 Example 11 63.4 0.12 Comparative Example 1 108.5 0.28

[0111] Combining Examples 1-11 with Comparative Example 1, and referring to Table 2, it can be seen that the particle size and PDI of the contents in Examples 1-11 are smaller than those in Comparative Example 1, which indicates that the contents of this application have better dispersibility.

[0112] Combining Example 1 and Comparative Example 1, and referring to Table 2, it can be seen that the particle size and PDI of the contents in Example 1 are smaller than those in Comparative Example 1. This indicates that the lycopene in this application has better compatibility with ethyl polyunsaturate. This may be because this application has solved the technical problem of easy oxidation and difficult dispersion of fat-soluble components by designing an anti-caking system composed of enzymatic hydrolysis of lecithin emulsifier, medium-chain triglyceride carrier oil, and (fumed silica and disodium ethylenediaminetetraacetate).

[0113] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A lycopene polyunsaturated ester capsule, comprising contents and a capsule shell, characterized in that: By weight, the contents comprise the following raw materials: 40-60 parts lycopene, 280-320 parts ethyl polyenoate, 90-115 parts medium-chain triglycerides, 25-33 parts enzymatically hydrolyzed lecithin, 8-12 parts mixed tocopherols, 4-6 parts rosemary extract, 0.45-0.55 parts disodium EDTA, and 4-5 parts fumed silica; The capsule shell is a hydroxypropyl methylcellulose plant capsule.

2. The lycopene polyunsaturated ethyl ester capsule according to claim 1, characterized in that, The fumed silica portion is replaced by microcrystalline cellulose, with the substitution rate of microcrystalline cellulose for fumed silica being 40-50% by weight.

3. The lycopene polyunsaturated ethyl ester capsule according to claim 1, characterized in that, It also includes 12-17 parts of hydroxypropyl-β-cyclodextrin.

4. The lycopene polyunsaturated ethyl ester capsule according to claim 1, characterized in that, The medium-chain triglyceride is a pharmaceutical-grade medium-chain triglyceride with a C8 / C10 ratio of 60 / 40.

5. The lycopene polyunsaturated ethyl ester capsule according to claim 1, characterized in that, The fumed silica has a water contact angle ≥ 120°, a specific surface area of ​​90-130 m² / g, and a particle size of 12-20 nm.

6. The lycopene polyunsaturated ethyl ester capsule according to claim 5, characterized in that, The fumed silica is surface modified with hexamethyldisilazane.

7. A method for preparing lycopene polyunsaturated ethyl ester capsules as described in any one of claims 1-6, characterized in that, Includes the following steps: S1. Lycopene predispersion Lycopene powder and optional hydroxypropyl-β-cyclodextrin were added to medium-chain triglycerides preheated to 70-80℃ and vacuum sheared for 30 min to obtain a pre-dispersion. S2. Lipid-phase mixing and homogenization Add polyurethane ethyl ester and lecithin to the pre-dispersion solution, keep the system temperature at 68-75℃, mix for 15 minutes under normal pressure, and then homogenize. S3. Antioxidant system addition and final mixing The system was cooled to 48-52℃, and mixed tocopherols, rosemary extract, disodium EDTA, and fumed silica were added. The mixture was then stirred under vacuum to obtain the contents. S4. Filling Maintain the temperature of the contents at 38-42℃ and fill them into capsule shells; S5. Cooling and Packaging After filling, the capsules are cooled and cured for 30 minutes at 15-20℃ and ≤40%RH before being packaged.

8. The method for preparing lycopene polyunsaturated ester capsules according to claim 7, characterized in that: S1. Lycopene predispersion specifically involves: One-third of the weight of medium-chain triglycerides was heated to 50°C, and then lycopene and optional hydroxypropyl-β-cyclodextrin were added. The mixture was sheared and dispersed at 2000 rpm for 10 min to obtain a premixed system. Meanwhile, the remaining two-thirds of the weight of medium-chain triglycerides was preheated to 70°C. The premixed system was heated to 75°C, and then preheated medium-chain triglycerides were added. The mixture was sheared at 8000 rpm for 20 min under a vacuum of -0.009 MPa.

9. The method for preparing a lycopene polyunsaturated ester capsule according to claim 7, characterized in that: S2. Homogenization in lipid phase mixing and homogenization specifically refers to: First-stage homogenization: pressure 60MPa, temperature 65℃, 2 cycles; Secondary homogenization: pressure 20MPa, temperature 40℃, 1 cycle.