Preparation process and application of a compound preparation of astaxanthin, lycopene and proanthocyanidins for anti-aging and preventing prostate diseases

Abstract

The present invention discloses a preparation process and application of a compound preparation of astaxanthin, lycopene and proanthocyanidins for anti-aging and prevention of prostate diseases, belonging to the field of biomedicine. The preparation is composed of astaxanthin (1-10 parts), proanthocyanidins (5-30 parts), lycopene (2-15 parts), black cumin seed oil (0.5-3 parts), Phyllanthus emblica extract (3-8 parts) and Withania somnifera extract (1-5 parts), and is prepared by high-efficiency wet granulation technology. The components act synergistically to significantly enhance antioxidant, anti-inflammatory and anti-cancer activities, and have dual effects of anti-aging and prevention and treatment of prostate diseases. Experiments show that the hydroxyl radical scavenging rate of the compound preparation is 2.3 times higher than that of the single ingredient, the inflammatory factors in the prostatitis model are reduced by 68%, the skin antioxidant capacity is increased by 55%, and the combination with finasteride can reduce the dosage of chemical drugs by 80% and reduce the risk of sexual dysfunction. Black cumin seed oil significantly improves the bioavailability of lycopene (29.7%), and the drug concentration in the prostate tissue reaches 6.5 times that in the blood, achieving high efficiency with low dosage.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically discloses a preparation process and application of a compound preparation of astaxanthin, lycopene and proanthocyanidins for anti-aging and preventing prostate diseases. Background Art

[0002] In the fields of anti-aging and the treatment of prostate diseases, existing technical solutions face multi-dimensional challenges. Traditional anti-aging drugs highly rely on single components. For example, vitamin E only exerts its effect by blocking lipid peroxidation, and the mechanism of action of coenzyme Q10 is limited to regulating mitochondrial energy metabolism. Such drugs generally have inherent defects such as a single action target, low bioavailability (for example, fat-soluble components need to be taken with meals), and the need for long-term large-dose use (for example, hundreds of milligrams need to be ingested daily). The drugs for treating prostate diseases show a polarization: chemical drugs such as finasteride can specifically inhibit the activity of 5α-reductase, but may cause irreversible sexual dysfunction (the incidence rate reaches 3.8%-15.8%); natural products such as saw palmetto extract have good safety, but due to complex components and unclear action mechanisms, the onset of action is slow (usually 8-12 weeks), and there is a lack of multi-target synergistic effects. Summary of the Invention

[0003] In view of the above problems, the present invention discloses a preparation process and application of a compound preparation of astaxanthin, lycopene and proanthocyanidins for anti-aging and preventing prostate diseases.

[0004] The object of the present invention is achieved by the following technical solutions.

[0005] A compound preparation of astaxanthin, lycopene and proanthocyanidins for anti-aging and preventing prostate diseases is prepared from the following raw materials in parts by weight:

[0006] 1-10 parts of astaxanthin, 5-30 parts of proanthocyanidins, 2-15 parts of lycopene, 0.5-3 parts of black cumin seed oil, 3-8 parts of Phyllanthus emblica extract, 1-5 parts of Withania somnifera extract;

[0007] The preparation method of the Phyllanthus emblica extract includes:

[0008] (a) Crushing fresh Phyllanthus emblica fruits and mixing them with a 1-2 wt% citric acid solution in a mass ratio of 1:5-10;

[0009] (b) Performing ultrasonic-assisted extraction at 50-60°C for 30-60 min, filtering and concentrating to a relative density of 1.1-1.2 g / mL;

[0010] (c) Spray-drying to obtain a powder with a water content of less than 8%.

[0011] Further, for the above-mentioned astaxanthin, lycopene, and proanthocyanidin compound preparation for anti-aging and preventing prostate diseases, the Withania somnifera extract is prepared by the following method:

[0012] After drying the Withania somnifera, it is crushed and sieved through a 50 - 100 mesh sieve, and refluxed with 50 - 70wt% ethanol for 1 - 3 times. After combining the extraction solutions, they are purified by macroporous resin AB - 8, the 50% ethanol elution part is collected, and concentrated and dried to a water content of less than 10% to obtain the Withania somnifera extract.

[0013] Further, for the above-mentioned astaxanthin, lycopene, and proanthocyanidin compound preparation for anti-aging and preventing prostate diseases, the black cumin seed oil is purified by molecular distillation.

[0014] The present invention also discloses a drug containing the above-mentioned compound preparation.

[0015] The present invention also discloses a preparation method of the above-mentioned drug, including the following steps:

[0016] (1) Dissolve astaxanthin and lycopene in black cumin seed oil, and stir at 35 - 45°C until completely dissolved to obtain an oil-phase component;

[0017] (2) Mix proanthocyanidins, Phyllanthus emblica extract, and Withania somnifera extract with pharmaceutical excipients, and sieve through a 50 - 100 mesh sieve to obtain a powder;

[0018] (3) Mix the oil-phase component in step (1) with the powder component in step (2) through a high-efficiency wet granulator;

[0019] (4) Dry and size the granules at 40 - 50°C, and then press tablets or fill capsules.

[0020] Further, for the above-mentioned preparation method, in step (3), control the water activity of the mixture ≤ 0.3, and use a 10% polyvinylpyrrolidone ethanol solution as a binder during granulation.

[0021] The present invention also discloses the application of the above-mentioned compound preparation in the preparation of anti-aging drugs.

[0022] The present invention also discloses the application of the above-mentioned compound preparation in the preparation of drugs for treating prostate hyperplasia.

[0023] The present invention also discloses the application of the above-mentioned compound preparation in the preparation of drugs for inhibiting prostate tumors.

[0024] The present invention also discloses a pharmaceutical composition for treating prostate hyperplasia, comprising:

[0025] (a) 5 - 500 mg of the compound preparation disclosed in the present invention;

[0026] (b) 0.1 - 0.5 mg of finasteride.

[0027] The present invention also discloses the use of the above compound preparation in the preparation of soft capsule preparations.

[0028] The present invention also discloses a soft capsule preparation containing the above compound preparation.

[0029] Compared with the existing technology, the present invention has the following advantages and beneficial effects:

[0030] The present invention discloses a preparation process and application of an astaxanthin, lycopene, and proanthocyanidin compound preparation for anti-aging and preventing prostate diseases. This compound preparation achieves a significant efficacy breakthrough through a multi-target synergistic mechanism: Astaxanthin, proanthocyanidins, and lycopene synergistically extend the free radical scavenging chain reaction through the π-π conjugation system, combined with the combined activation effect of Withania somnifera and Phyllanthus emblica extracts on the Nrf2 pathway, forming a double synergistic effect of antioxidant and anti-inflammatory effects. Among them, the hydroxyl radical scavenging rate is increased by 2.3 times compared with the single ingredient, and the inflammatory factor level in the prostatitis model is reduced by 68%. The preparation design innovatively integrates the functions of anti-aging and prevention and treatment of prostate diseases. Preclinical data show that 8 weeks of oral administration can significantly increase the skin SOD activity by 55% and reduce the MDA level by 48.6%. At the same time, when combined with finasteride for the treatment of benign prostatic hyperplasia, while retaining 85% of the efficacy, the dosage of chemical drugs is reduced by 80%, and the incidence of sexual dysfunction is reduced. Through the absorption-promoting effect of thymol quinone in black cumin seed oil, the bioavailability of fat-soluble components such as lycopene is increased by 139%, and the drug concentration in the prostate tissue reaches 6.5 times that in the blood, achieving precise targeted delivery. In addition, the use of plant ingredient compatibility and low-temperature granulation technology significantly reduces the side effects of chemical drugs, and the retention rate of the main components is still ≥95% after 3 months of accelerated stability test, comprehensively optimizing the safety and preparation stability. Detailed implementation manners

[0031] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below. However, it should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the scope of the present invention. In addition, in the following description, the descriptions of well-known structures and technologies are omitted to avoid unnecessarily confusing the concepts of the present invention. All raw materials in the embodiments of the present invention can be obtained through commercial channels.

[0032] It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. The present invention will be described in detail below with reference to the embodiments.

[0033] The main reagents and instruments used in the present invention are shown in Table 1 below.

[0034]

[0035] Example 1

[0036] An astaxanthin, lycopene and proanthocyanidin compound preparation for anti-aging and prostate disease prevention is prepared from the following raw materials in parts by weight:

[0037] 1 part of astaxanthin, 5 parts of proanthocyanidins, 2 parts of lycopene, 0.5 parts of black cumin seed oil, 3 parts of emblica extract, 1 part of ashwagandha extract;

[0038] The preparation method of the emblica extract comprises:

[0039] (a) crushing fresh emblica fruit and mixing it with 1 wt % citric acid solution in a mass ratio of 1:5;

[0040] (b) Ultrasonic-assisted extraction at 50 °C for 60 min, filtered and concentrated to a relative density of 1.1 g / mL;

[0041] (c) spray drying to obtain a powder having a moisture content of less than 8%;

[0042] The ashwagandha extract is prepared by the following method:

[0043] After the ashwagandha is dried, it is crushed and passed through a 50-100 mesh sieve, and refluxed and extracted once with 50wt% ethanol. After the extracts are combined, they are purified by macroporous resin AB-8, and the 50% ethanol elution fraction is collected by gradient elution, and concentrated and dried to a water content of less than 10%, thereby obtaining an ashwagandha extract.

[0044] The black cumin seed oil is purified by molecular distillation.

[0045] The preparation method of the above-mentioned compound preparation is to grind the raw materials at room temperature, pass them through a 100-200 mesh sieve, and then mix them evenly.

[0046] Example 2

[0047] An astaxanthin, lycopene and proanthocyanidin compound preparation for anti-aging and prostate disease prevention is prepared from the following raw materials in parts by weight:

[0048] 5 parts of astaxanthin, 15 parts of proanthocyanidins, 8 parts of lycopene, 1.5 parts of black cumin seed oil, 5 parts of emblica extract, 3 parts of ashwagandha extract;

[0049] The preparation method of the emblica extract comprises:

[0050] (a) crushing fresh emblica fruit and mixing it with 1.5wt% citric acid solution in a mass ratio of 1:8;

[0051] (b) Ultrasonic-assisted extraction at 55 °C for 45 min, filtered and concentrated to a relative density of 1.15 g / mL;

[0052] (c) Obtain a powder with a water content of less than 8% by spray drying;

[0053] The Withania somnifera extract is prepared by the following method:

[0054] After drying the Withania somnifera, it is crushed and sieved through a 50-100 mesh sieve, refluxed and extracted twice with 60wt% ethanol, the extraction solutions are combined and purified by macroporous resin AB-8, the 50% ethanol elution fraction is collected by gradient elution, concentrated and dried to a water content of less than 10% to obtain the Withania somnifera extract;

[0055] The Nigella sativa seed oil is purified by molecular distillation.

[0056] The preparation method of the above compound preparation is to crush the raw materials through a 200-mesh sieve at room temperature and then mix them evenly.

[0057] Example 3

[0058] A compound preparation of astaxanthin, lycopene and proanthocyanidins for anti-aging and preventing prostate diseases is made from the following raw materials by weight:

[0059] 10 parts of astaxanthin, 30 parts of proanthocyanidins, 15 parts of lycopene, 3 parts of Nigella sativa seed oil, 8 parts of Phyllanthus emblica extract, 5 parts of Withania somnifera extract;

[0060] The preparation method of the Phyllanthus emblica extract includes:

[0061] (a) Crush the fresh Phyllanthus emblica fruits and mix them with a 2wt% citric acid solution in a mass ratio of 1:10;

[0062] (b) Ultrasonic-assisted extraction at 60°C for 30 min, filter and concentrate to a relative density of 1.2 g / mL;

[0063] (c) Obtain a powder with a water content of less than 8% by spray drying;

[0064] The Withania somnifera extract is prepared by the following method:

[0065] After drying the Withania somnifera, it is crushed and sieved through a 100-mesh sieve, refluxed and extracted three times with 70wt% ethanol, the extraction solutions are combined and purified by macroporous resin AB-8, the 50% ethanol elution fraction is collected by gradient elution, concentrated and dried to a water content of less than 10% to obtain the Withania somnifera extract;

[0066] The Nigella sativa seed oil is purified by molecular distillation.

[0067] The preparation method of the above compound preparation is to crush the raw materials through a 100-200 mesh sieve at room temperature and then mix them evenly.

[0068] Control Example 1

[0069] A preparation is made from the following raw materials by weight parts:

[0070] 5 parts of astaxanthin, 15 parts of proanthocyanidins, 8 parts of lycopene, 5 parts of Phyllanthus emblica extract, 3 parts of Withania somnifera extract; (excluding black cumin seed oil).

[0071] The rest is the same as in Example 2.

[0072] Comparative Example 2

[0073] A preparation is made from the following raw materials by weight parts:

[0074] 5 parts of astaxanthin, 15 parts of proanthocyanidins, 8 parts of lycopene, 1.5 parts of black cumin seed oil, 3 parts of Withania somnifera extract; (excluding Phyllanthus emblica extract).

[0075] The rest is the same as in Example 2.

[0076] Comparative Example 3

[0077] A preparation is made from the following raw materials by weight parts:

[0078] 5 parts of astaxanthin, 15 parts of proanthocyanidins, 8 parts of lycopene, 1.5 parts of black cumin seed oil, 5 parts of Phyllanthus emblica extract; (excluding Withania somnifera extract).

[0079] The rest is the same as in Example 2.

[0080] Comparative Example 4

[0081] A preparation is made from the following raw materials by weight parts:

[0082] 5 parts of astaxanthin, 15 parts of proanthocyanidins, 8 parts of lycopene, 3 parts of Withania somnifera extract; (excluding black cumin seed oil and Phyllanthus emblica extract).

[0083] The rest is the same as in Example 2.

[0084] Comparative Example 5

[0085] A preparation is made from the following raw materials by weight parts:

[0086] 5 parts of astaxanthin, 15 parts of proanthocyanidins, 8 parts of lycopene; (excluding black cumin seed oil, Phyllanthus emblica extract and Withania somnifera extract).

[0087] The rest is the same as in Example 2.

[0088] Test Example 1

[0089] Free radical scavenging ability comparison experiment

[0090] Purpose: To verify the antioxidant synergistic effect of the compound preparation

[0091] Method:

[0092] Prepare 0.1 mg / mL aqueous solutions of Preparation Example 2 and Comparative Examples 1-5

[0093] Generate hydroxyl radicals (·OH) using the Fenton reaction system

[0094] 1) Construction of the Fenton reaction system:

[0095] Accurately prepare the reaction solution:

[0096] 1 mL of 9 mmol / L FeSO4 solution

[0097] 2 mL of 9 mmol / L EDTA solution

[0098] 1 mL of 3% H2O2 solution

[0099] 1 mL of sample solutions at different concentrations (0.1 mg / mL)

[0100] After reacting in a 37°C water bath for 15 minutes, add 0.5% salicylic acid ethanol solution to terminate the reaction

[0101] 2) Detection method:

[0102] Use a UV-visible spectrophotometer (model: UV-2600, Shimadzu) to measure the absorbance at a wavelength of 515 nm

[0103] Calculation formula for the scavenging rate:

[0104] Each sample was measured in parallel 6 times, and the mean ± SD was taken

[0105] After adding different samples, detect the absorbance at 515 nm by colorimetry and calculate the scavenging rate

[0106] The results are shown in Table 2

[0107]

[0108] The scavenging rate of Example 2 (92.3%) was significantly higher than that of each comparative example with missing components (P < 0.01). The possible reason is that thymoquinone in black cumin seed oil enhances the activity of endogenous antioxidant enzymes by activating the Nrf2 pathway. At the same time, ellagic acid in Phyllanthus emblica extract combines with astaxanthin to form a π-π conjugate system, prolonging the free radical scavenging chain reaction and synergistically enhancing the free radical scavenging ability. As can be seen from the table

[0109] The scavenging rate is positively correlated with the number of components (R² = 0.93), indicating the necessity of multi-component synergy

[0110] Conclusion: The complete compound clearance rate is 2.02 times that of Comparative Example 5, and black cumin seed oil and Phyllanthus emblica extract synergistically enhance the antioxidant effect.

[0111] Test Example 2

[0112] Anti-inflammatory effect on prostatitis model

[0113] Objective: To evaluate the improvement effect on prostate inflammation

[0114] Method:

[0115] Establish a rat prostatitis model (induced by estradiol benzoate)

[0116] Model establishment:

[0117] SD rats (200±20 g) were subcutaneously injected with estradiol benzoate (0.25 mg / kg / d) for 21 consecutive days;

[0118] Model verification: Prostatic gland hyperplasia (glandular cavity area increase ≥ 50%) and inflammatory cell infiltration were confirmed by HE staining;

[0119] Detection indexes:

[0120] After homogenizing the prostate tissue, the contents of IL-6 and TNF-α were detected using an ELISA kit (R&D Systems);

[0121] CD68 immunohistochemical staining was performed on pathological sections to evaluate the degree of macrophage infiltration;

[0122] Group intragastric administration (50 mg / kg / d): Example 2, Comparative Examples 1-5, positive drug (celecoxib)

[0123] After 4 weeks, the levels of IL-6 and TNF-α in the prostate tissue were detected.

[0124] The results are shown in Table 3.

[0125]

[0126] (*P<0.01 vs model group)

[0127] Conclusion: The inflammatory factors in Example 2 were reduced by 68%, significantly better than the single-component deletion group, suggesting that Withania somnifera and Phyllanthus emblica have synergistic anti-inflammatory effects.

[0128] Test Example 3

[0129] Experiment on improving skin antioxidant capacity

[0130] Method:

[0131] Recruit 60 volunteers aged 45 - 60 years old, randomly divided into the Example 2 group (200 mg / d) and the Coenzyme Q10 group (300 mg / d).

[0132] Subject management:

[0133] Inclusion criteria: Aged 45 - 60 years old, Fitzpatrick skin type III - IV, excluding those who have used antioxidant supplements within 3 months.

[0134] Double - blind design: Neither the subjects nor the evaluators know the grouping.

[0135] Detection technology:

[0136] SOD activity: Using the WST - 8 method (Dojindo kit), unit U / mg protein

[0137] MDA content: Thiobarbituric acid (TBA) fluorescence method (Ex / Em = 532 / 553 nm

[0138] After 8 weeks, detect the forearm skin:

[0139] SOD activity (colorimetric method)

[0140] Lipid peroxide (MDA content)

[0141] The results are shown in Table 4

[0142]

[0143] (*P < 0.05 vs Coenzyme Q10 group)

[0144] Conclusion: The compound preparation significantly improves the skin antioxidant capacity, and the effect is better than that of the traditional single - agent.

[0145] Test Example 4

[0146] Combined treatment experiment for benign prostatic hyperplasia

[0147] Objective: To verify the synergistic effect with finasteride

[0148] Methods:

[0149] Establish a canine model of benign prostatic hyperplasia (induced by androgen)

[0150] 1) Model construction:

[0151] Beagle dogs (10 - 12 kg) were subcutaneously injected with dihydrotestosterone (DHT, 0.5 mg / kg / d) continuously for 12 weeks

[0152] The prostate volume was measured by transrectal ultrasound (formula: V = 0.52×length×width×height).

[0153] 5 per group.

[0154] 2) Urodynamics:

[0155] The maximum urinary flow rate (Qmax) was recorded using the Urodyn 1000 system, and the mean value was taken after 3 repeated measurements.

[0156] Group treatment for 8 weeks:

[0157] Group A: Example 2 (10 mg) + Finasteride (0.2 mg)

[0158] Group B: Conventional Finasteride (1 mg)

[0159] Group C: Example 2 (10 mg)

[0160] 3) Mating behavior test:

[0161] It was carried out in a soundproof observation room. An estrous female dog (confirmed by vulvar swelling) was introduced, and

[0162] Mounting latency: The time from the introduction of the female dog to the first mount (seconds). The criteria for judging sexual dysfunction: Mounting latency > 300 seconds or Insertion success rate < 50.

[0163] The prostate volume (mean value), maximum urinary flow rate (Qmax) (mean value), and the incidence of sexual dysfunction were detected. The results are shown in Table 5.

[0164]

[0165] (*P < 0.05 vs Group B)

[0166] Conclusion: The combined medication can significantly reduce the side effects of chemical drugs while maintaining 85% efficacy.

[0167] Test Example 5

[0168] Study on the bioavailability of lycopene

[0169] Objective: To verify the absorption-promoting effect of black cumin seed oil

[0170] Methods:

[0171] Rats were gavaged with: containing lycopene (10 mg / kg)

[0172] Example 2 (containing black cumin seed oil)

[0173] Control Example 1 (without black cumin seed oil)

[0174] The blood drug concentration and prostate tissue distribution at 0 - 24 h were determined by HPLC,

[0175] Pharmacokinetics:

[0176] Plasma treatment: Add 0.1% BHT ethanol solution to prevent oxidation. HPLC detection conditions:

[0177] Chromatographic column: C30 (4.6×250 mm, 5 μm)

[0178] Mobile phase: Methanol - methyl tert - butyl ether (90:10)

[0179] Detection wavelength: 472 nm

[0180] Tissue distribution:

[0181] Homogenize the prostate tissue and extract it with n - hexane, then redissolve it by nitrogen blowing for injection.

[0182] The results are shown in Table 6.

[0183]

[0184] (*P<0.01)

[0185] Conclusion: Black cumin seed oil increases the bioavailability of lycopene by 139% and targets and enriches in the prostate tissue.

[0186] Test Example 6

[0187] Experiment on inducing apoptosis of prostate cancer cells

[0188] Purpose: To verify the anti - tumor potential

[0189] Methods:

[0190] Culture LNCaP prostate cancer cells

[0191] Respectively add Example 2 (50 μg / mL), lycopene alone (50 μg / mL)

[0192] Detect the apoptosis rate of cells after 24 h by flow cytometry. Cell treatment:

[0193] Culture LNCaP cells in RPMI - 1640 + 10% FBS, 5% CO2 environment

[0194] Double - stain with Annexin V - FITC / PI and detect apoptosis by flow cytometer (BD FACSCanto II)

[0195] The results are shown in Table 7.

[0196]

[0197] (*P<0.01 vs alone)

[0198] Conclusion: The compound preparation significantly enhances the induction of cancer cell apoptosis through the synergy of multiple components.

[0199] Example 4

[0200] Preparation experimental example.

[0201] Formulation composition (according to the ratio of Example 2):

[0202] 5 parts of astaxanthin, 15 parts of procyanidins, 8 parts of lycopene, 1.5 parts of black cumin seed oil, 5 parts of Phyllanthus emblica extract, 3 parts of Withania somnifera extract, pharmaceutical excipients (30 parts of microcrystalline cellulose, 20 parts of lactose, 1 part of magnesium stearate).

[0203] Detailed description of the preparation steps

[0204] Step 1: Preparation of the oil phase

[0205] Dissolution process:

[0206] Preheat the black cumin seed oil to 35 ± 2 °C, add astaxanthin and lycopene, and maintain the temperature within the range of 35 - 45 °C.

[0207] Continuously stir with a magnetic stirrer (rotation speed 500 ± 50 rpm) for 45 - 60 minutes until a uniform and transparent orange - red oil solution is formed.

[0208] Key control point: The determination criterion for the dissolution end point is that there is no particle residue visually, and if necessary, confirm complete dissolution by microscopic detection.

[0209] Step 2: Pretreatment of the powder

[0210] Mixing of raw materials:

[0211] Put procyanidins, Phyllanthus emblica extract, Withania somnifera extract, microcrystalline cellulose, and lactose into a three - dimensional motion mixer according to the ratio.

[0212] Mixing parameters: rotation speed 15 - 20 rpm, mixing time 30 minutes, mixing uniformity RSD ≤ 5% (detect the deviation of the main component content by HPLC).

[0213] Sieving treatment:

[0214] The mixed powder is sieved twice through a 100 - mesh vibrating sieve (amplitude 2 - 3 mm) to ensure that the powder particle size ≤ 150 μm.

[0215] Step 3: High - efficiency wet granulation

[0216] Preparation of the binder:

[0217] Dissolve polyvinylpyrrolidone (PVP K30) in 70% ethanol to prepare a 10% w / v PVP ethanol solution, and let it stand for 30 minutes to remove bubbles for later use.

[0218] Granulation process:

[0219] Slowly add the oil-phase components (product of step 1) to the powder (product of step 2), and premix for 5 minutes using a high-efficiency wet granulator (stirring paddle speed: 200 rpm, chopping knife speed: 1500 rpm).

[0220] While continuously stirring, add the PVP ethanol solution in a spray manner (the addition amount accounts for 8 - 10% of the total weight of the powder), and control the liquid addition rate at 10 mL / min.

[0221] Key control point: Monitor the water activity of the mixture in real time (Aw ≤ 0.3, detected using a water activity meter). The judgment criterion for the granulation end point is to form a soft material that "can be formed into a ball by hand and can be easily dispersed by light pressure".

[0222] Step 4: Drying and sieving

[0223] Fluidized bed drying:

[0224] Lay the wet granules flat on the tray of the fluidized bed dryer (thickness ≤ 3 cm), set the inlet air temperature at 40 - 45 °C, the air velocity at 1.5 - 2.0 m³ / min, and dry until the moisture content ≤ 3.0% (determined by the Karl Fischer method).

[0225] Sieving treatment:

[0226] Sieve the dried granules through a 20-mesh sieve, and collect the granules with a particle size range of 0.5 - 1.2 mm for later use.

[0227] Step 5: Tabletting / capsule filling

[0228] Final mixing and lubrication:

[0229] Mix the sieved granules with magnesium stearate (1% w / w) in a V-shaped mixer for 10 minutes (rotation speed: 12 rpm).

[0230] Tabletting parameters:

[0231] Use a rotary tabletting machine, set the tablet weight at 500 ± 10 mg, the hardness at 8 - 12 kp, and the disintegration time limit ≤ 30 minutes (in purified water medium).

[0232] Soft capsule filling (alternative):

[0233] Select size 0 vegetable capsule shells, the filling amount is 500 ± 10 mg / capsule, and the capsule moisture content ≤ 6.0%.

[0234] The above-mentioned tablet and capsule preparation processes were detected, and the results are shown in Table 8.

[0235]

[0236] Technical advantages

[0237] Improved stability: By encapsulating lipophilic components (astaxanthin, lycopene) in the oil phase and combining water activity control, the accelerated stability test (40°C / 75% RH, 3 months) shows that the retention rate of the main components is ≥95%.

[0238] Optimized dissolution: The in vitro dissolution rate (in 0.5% SDS medium) reaches over 85% within 45 minutes, significantly better than the physically mixed preparation (only 62%).

[0239] Production feasibility: The temperature throughout the process is ≤45°C, avoiding the degradation of heat-sensitive components, and it is suitable for industrial production.

[0240] Conclusion: The above experimental data systematically verified the multi-dimensional advantages of the compound preparation: in terms of antioxidant synergy, the hydroxyl radical scavenging rate of Example 2 reached 92.3%, significantly higher than that of the control group lacking any component (P<0.01), and the scavenging efficiency was strongly positively correlated with the number of active components (R² = 0.93). In the anti-inflammatory and organ protection experiments, the levels of IL-6 and TNF-α in the prostatitis model decreased by 68% and 67% respectively. The combined treatment with finasteride could reduce the prostate hyperplasia volume by 42.3% and increase the urine flow rate by 68%, while reducing the incidence of drug side effects by 75%. Pharmacokinetic studies showed that black cumin seed oil made the prostate-targeted concentration ratio of lycopene reach 6.5, significantly enhancing the tissue accumulation ability. It is worth noting that in the exploration of anti-cancer potential, the apoptosis rate of LNCaP prostate cancer cells induced by the compound preparation reached 43.6%, which was 2.3 times higher than that of the single component, revealing a new mechanism of multi-component synergistic anti-tumor. These results fully verified the scientific logic of the "multi-target synergistic - dual efficacy integration - bioavailability optimization" trinity of the compound design from the molecular, cellular to animal model levels.

[0241] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Therefore, based on the innovative concept of the present invention, the changes and modifications made to the embodiments described herein, or the equivalent structural or equivalent process transformations made using the content of the specification of the present invention, and directly or indirectly applying the above technical solutions to other related technical fields, are all included in the protection scope of the present invention patent.

Claims

1. A composite preparation of astaxanthin, lycopene and proanthocyanidins for anti-aging and prostate disease prevention, characterized in that: Made from the following raw materials by weight: 1-10 parts of astaxanthin, 5-30 parts of proanthocyanidins, 2-15 parts of lycopene, 0.5-3 parts of black cumin seed oil, 3-8 parts of emblica extract, 1-5 parts of ashwagandha extract; The preparation method of the emblica extract comprises: (a) crushing fresh emblica fruit and mixing with 1-2wt% citric acid solution in a mass ratio of 1:5-10; (b) Ultrasonic-assisted extraction at 50-60°C for 30-60 min, followed by filtration and concentration to a relative density of 1.1-1.2 g / mL; (c) Spray drying to obtain a powder with a moisture content of less than 8%.

2. The compound preparation according to claim 1, characterized in that: The ashwagandha extract is prepared by the following method: After the ashwagandha is dried, it is crushed and passed through a 50-100 mesh sieve, and 50-70wt% ethanol is used for reflux extraction 1-3 times. After the extracts are combined, they are purified by macroporous resin AB-8, and the 50% ethanol elution fraction is collected, concentrated and dried to a water content of less than 10%, thereby obtaining the ashwagandha extract.

3. The compound preparation according to claim 1, characterized in that: The black cumin seed oil is purified by molecular distillation.

4. A drug, characterized in that A compound preparation containing any one of claims 1 to 3.

5. The method for preparing the drug according to claim 4, characterized in that: The following steps are involved: (1) Dissolving astaxanthin and lycopene in black cumin seed oil and stirring at 35-45° C. until completely dissolved to obtain an oil phase component; (2) mixing proanthocyanidins, emblica fruit extract, ashwagandha extract and pharmaceutical excipients, and passing through a 50-100 mesh sieve to obtain a powder; (3) mixing the oil phase component of step (1) and the powder component of step (2) by a high-efficiency wet granulator; (4) After drying at 40-50℃, the granules are shaped into whole particles and compressed into tablets or filled into capsules.

6. The preparation method according to claim 5, characterized in that: In step (3), the water activity of the mixture is controlled to be ≤0.3, and 10% polyvinyl pyrrolidone ethanol solution is used as a binder during granulation.

7. Use of the compound preparation according to any one of claims 1 to 3 in the preparation of the medicine according to any one of 1) to 3) below, 1) Anti-aging drugs; 2) Drugs for the treatment of prostate hyperplasia; 3) Drugs that inhibit prostate tumors.

8. A pharmaceutical composition for treating prostatic hyperplasia, characterized in that: Include: (a) 5-500 mg of the compound preparation according to any one of claims 1 to 3; (b) Finasteride 0.1-0.5 mg.

9. Use of the compound preparation according to any one of claims 1 to 3 in the preparation of soft capsule preparations.

10. A soft capsule preparation, characterized in that: Contains the compound preparation according to any one of claims 1 to 3.

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