High-stability black wolfberry fruit lipid-regulating oral liquid and preparation method thereof

Abstract

The invention provides a high-stability black wolfberry fruit lipid-regulating oral liquid and a preparation method thereof, and relates to the technical field of medicines. The semen cassiae and fructus lycii lipid-regulating oral liquid is prepared from semen cassiae ethanol extract, mixed water extract, aromatic water, a flavoring agent, a bacteriostatic agent, a pH regulator and a solubilizer. By optimizing the preparation process, the provided black wolfberry fruit lipid-regulating oral liquid is under the action of the specific flavoring agent, the bacteriostatic agent, the pH regulator and the solubilizer, the solubilizer is polyethylene glycol 400 or a mixture of polyethylene glycol 400 and polyethylene glycol 600, the content degradation speed of stilbene glucoside is obviously slowed down, the validity period of the product is prolonged from 18 months to 24 months, and the stability of the product is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a highly stable oral liquid for regulating lipids from wolfberry and its preparation method. Background Technology

[0002] Chinese invention patent application CN1586598A discloses a traditional Chinese medicine preparation for treating hyperlipidemia. This preparation is an oral liquid made from seven traditional Chinese medicinal materials: 266.5g of Polygonum multiflorum, 266.5g of Lycium barbarum, 266.5g of Cassia tora, 166.5g of Chrysanthemum morifolium, 100g of Carthamus tinctorius, 266.5g of Crataegus pinnatifida, and 100g of Citrus reticulata peel. One quality control method involves detecting the content of 2,3,5,4'-tetrahydroxystilbene 2-O-β-D glucoside. 2,3,5,4'-tetrahydroxystilbene 2-O-β-D glucoside (referred to as stilbene glycoside) is a water-soluble active ingredient in Polygonum multiflorum with significant pharmacological activity. However, the aqueous solution of stilbene glycoside is unstable at high temperatures (80℃), and its content shows a negative correlation with temperature. Stilbene glycoside readily reacts with oxygen in ethanol solution, conforming to the apparent zero-order reaction law, and the reaction rate increases with increasing temperature. Existing technologies have conducted extensive research on how to improve the stability of stilbene glycosides. For example, the journal article "Study on the stability of stilbene glycosides and their β-cyclodextrin inclusion complexes" (Wang Wenjing, Liu Dongli, Wang Wei, et al., Global Chinese Medicine, 2016, 9(04):414-418) shows that stilbene glycosides and their β-cyclodextrin inclusion complexes are more stable in acidic environments than in alkaline environments. The journal article "Study on the stability of stilbene glycoside oral solution and its regulation of LPS-induced iNOS expression in microglia" (Wang Yuzhe, Nantong University, 2013) shows that the addition of polyethylene glycol and parabens to stilbene glycoside oral solution can effectively slow down the degradation of stilbene glycosides. However, existing technologies have not effectively solved the technical problem of poor stability of stilbene glycosides in Wuqi lipid-regulating oral solution.

[0003] There is an urgent need to optimize the preparation process of Wuqi lipid-regulating oral liquid to improve product stability and quality. Summary of the Invention

[0004] This invention addresses the problems existing in the prior art by providing a highly stable oral liquid for regulating lipids from wolfberry. Through optimization of the preparation process, the degradation rate of stilbene glycosides is significantly slowed down, and the product shelf life is increased from 18 months to 24 months, thereby improving product stability.

[0005] The raw materials of Wuqi lipid-regulating oral liquid are composed of 266.5 parts by weight of processed Polygonum multiflorum, 266.5 parts of wolfberry, 266.5 parts of cassia seed, 166.5 parts of chrysanthemum, 100 parts of safflower, 266.5 parts of hawthorn, and 100 parts of dried tangerine peel.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The first aspect of the present invention is to provide a highly stable oral liquid for regulating lipids by jujube, which is composed of cassia seed ethanol extract, mixed water extract, aromatic water, flavoring agent, antibacterial agent, pH adjuster and solubilizer.

[0007] Preferably, the proportions of the cassia seed ethanol extract, mixed water extract, aromatic water, flavoring agent, antibacterial agent, pH adjuster and solubilizer are 24.0%-26.0%: 25.2%-28.25%: 30%: 0.3%: 0.2%: 0.25%-0.3%: 15%-20%.

[0008] Preferably, in 100mL of the Cassia Seed Lipid-Regulating Oral Solution, the Cassia Seed ethanol extract is 24.0-26.0g, the mixed water extract is 25.2-28.25mL, the aromatic water is 30mL, the flavoring agent is 0.3g, the antibacterial agent is 0.2g, the pH adjuster is 0.25-0.3g, and the solubilizer is 15-20g.

[0009] Preferably, the solubilizer is polyethylene glycol 400 or a mixture of polyethylene glycol 400 and polyethylene glycol 600.

[0010] More preferably, the solubilizer is a mixture of polyethylene glycol 400 and polyethylene glycol 600 in a mass ratio of 1-2:1-2.

[0011] Preferably, the flavoring agent is selected from cyclamate or sucralose.

[0012] Preferably, the antibacterial agent is potassium sorbate.

[0013] Preferably, the pH adjuster is a NaOH solution with a concentration of 30%-60%.

[0014] Preferably, the preparation process of the cassia seed ethanol extract is as follows: crush the prescribed amount of cassia seeds, reflux the ethanol solution for extraction, recover the ethanol from the extract under reduced pressure, and concentrate the extract to obtain the final product.

[0015] More preferably, the volume fraction of the ethanol solution is 50%-70%, and the extraction is carried out by reflux 1-3 times. The amount of ethanol solution added each time is independently selected from 6-8 times the mass of cassia seeds. The extraction time for each extraction is 1-3 hours. The concentration is carried out at 60°C to a relative density of 1.15-1.30.

[0016] Preferably, the preparation process of the mixed water extract is as follows: (1) Water extraction: The prescribed amount of prepared Polygonum multiflorum is crushed into the coarsest powder, mixed with the prescribed amount of wolfberry, chrysanthemum, safflower, hawthorn, tangerine peel and cassia seed after alcohol extraction, water is added for extraction, filtered, and the filtrate is concentrated under reduced pressure to obtain the water extract; (2) Alcohol precipitation: The water extract is added to ethanol, allowed to stand, filtered, the ethanol is recovered from the filtrate, and concentrated under reduced pressure to obtain the mixed water extract.

[0017] More preferably, the water extraction in step (1) is performed 1-3 times, the amount of water added each time is independently selected from 6-8 times the amount of medicinal material, the extraction time each time is independently selected from 1-3 hours, and the vacuum concentration is concentrated at 60°C to a relative density of 1.05-1.10.

[0018] More preferably, the alcohol precipitation in step (2) specifically involves adding ethanol to the water extract until the alcohol content is 60%-70%, letting it stand for 12-18 hours, and then concentrating it under reduced pressure at 60°C until the relative density is 1.15-1.30.

[0019] Preferably, the preparation process of the aromatic water is as follows: during the first extraction with water, 300 mL of distillate is collected simultaneously when mixing the prescribed amount of raw Polygonum multiflorum powder with the prescribed amounts of lycium barbarum, chrysanthemum, safflower, hawthorn, tangerine peel and cassia seed residue after alcohol extraction.

[0020] The second aspect of the present invention relates to a method for preparing the above-mentioned *Scutellaria baicalensis* lipid-regulating oral liquid, the method comprising the following steps: adding cassia seed ethanol extract, aromatic water, flavoring agent, antibacterial agent, and solubilizer to a mixed aqueous extract, stirring evenly, refrigerating at 4℃-8℃ and standing for 24 hours, centrifuging, adjusting the pH of the supernatant to 5.0-6.0 with a pH adjuster, then adding purified water to adjust the total volume to 1000mL, filling, sterilizing, and thus obtaining the *Scutellaria baicalensis* lipid-regulating oral liquid.

[0021] Compared with the prior art, the present invention has the following beneficial effects: Through the optimization of the preparation process, the present invention provides a blood-nourishing oral liquid for regulating lipids. Under the action of specific flavoring agents, antibacterial agents, pH adjusters and solubilizers, the solubilizer is polyethylene glycol 400 or a mixture of polyethylene glycol 400 and polyethylene glycol 600. The degradation rate of stilbene glycoside content is significantly slowed down, the product shelf life is increased from 18 months to 24 months, and the product stability is improved. Detailed Implementation

[0022] It is worth noting that the raw materials used in this invention are all commercially available products, and their sources are not specifically limited.

[0023] The cassia seed ethanol extract, mixed aqueous extract, and aromatic water in Examples 1-5 and Comparative Examples 1-6 were prepared by the following process: Prepared Polygonum multiflorum 266.5g, wolfberry 266.5g, cassia seed 266.5g, chrysanthemum 166.5g, safflower 100g, hawthorn 266.5g, dried tangerine peel 100g. The above seven herbs were used as follows: Cassia seed was crushed into the coarsest powder and extracted twice by reflux with 50% ethanol. The first extraction was with 7 times the amount of ethanol for 2 hours; the second extraction was with 6 times the amount of ethanol for 1.5 hours. The two extracts were combined, filtered, and the ethanol was recovered from the filtrate under reduced pressure until the relative density was above 1.15 (60℃), yielding the cassia seed ethanol extract for later use. Prepared Polygonum multiflorum was crushed into the coarsest powder and mixed with Lycium barbarum, Chrysanthemum morifolium, Carthamus tinctorius, Hawthorn, Citrus reticulata peel, and the residue after the ethanol extraction of cassia seed. Water was added and extracted three times. The first extraction was with 8 times the amount of ethanol for 2 hours, while collecting approximately 300 mL of aromatic water for later use. The second extraction was with 7 times the amount of ethanol for 1.5 hours; the third extraction was with 6 times the amount of ethanol for 1 hour. The three decoctions were combined, filtered, and the filtrate was concentrated under reduced pressure until the relative density was 1.06 (60℃). Ethanol was slowly added under stirring to achieve an alcohol content of 60%. The mixture was allowed to stand for 16 hours, filtered, and the ethanol was recovered from the filtrate. The mixture was then concentrated under reduced pressure until the relative density was 1.15 (60℃), yielding a mixed aqueous extract.

[0024] The formulation composition of the *Wuqi* lipid-regulating oral liquid in Examples 1-5 and Comparative Examples 1-6 is shown in Table 1.

[0025] Table 1: Formulation composition of the Lycium barbarum lipid-regulating oral liquid in Examples 1-5 and Comparative Examples 1-6

[0026] The preparation methods of Examples 1-3 are as follows: Add cassia seed ethanol extract, aromatic water, cyclamate, potassium sorbate, PEG400 and PEG600 to the mixed water extract, stir evenly, refrigerate at 4°C for 24 hours, centrifuge, adjust the pH of the supernatant with 50% NaOH solution, add purified water to adjust the total volume to 1000mL, fill and sterilize to obtain the product.

[0027] The preparation methods for Examples 4-5 and Comparative Example 4 are as follows: Add cassia seed ethanol extract, aromatic water, cyclamate, potassium sorbate, and PEG400 to the mixed water extract, stir evenly, refrigerate at 4°C for 24 hours, centrifuge, adjust the pH of the supernatant with 50% NaOH solution, add purified water to adjust the total volume to 1000 mL, fill, sterilize, and the product is obtained.

[0028] The preparation method of Comparative Example 1 is as follows: Add cassia seed ethanol extract, aromatic water, cyclamate and potassium sorbate to the mixed water extract, stir evenly, refrigerate at 4°C for 24 hours, centrifuge, add purified water to the supernatant to adjust the total volume to 1000mL, fill and sterilize to obtain the product.

[0029] The preparation method of Comparative Example 2 is as follows: Add cassia seed ethanol extract, aromatic water, cyclamate and potassium sorbate to the mixed water extract, stir evenly, refrigerate at 4°C for 24 hours, centrifuge, adjust the pH of the supernatant with 50% NaOH solution, add purified water to adjust the total volume to 1000mL, fill and sterilize to obtain the product.

[0030] The preparation method of Comparative Example 3 is as follows: Add cassia seed ethanol extract, aromatic water, cyclamate, potassium sorbate, and sodium metabisulfite to the mixed water extract, stir evenly, refrigerate at 4°C for 24 hours, centrifuge, adjust the pH of the supernatant with 50% NaOH solution, add purified water to adjust the total volume to 1000 mL, fill and sterilize to obtain the final product.

[0031] The preparation method of Comparative Example 5 is as follows: Add cassia seed ethanol extract, aromatic water, cyclamate, potassium sorbate, and PEG600 to the mixed water extract, stir evenly, refrigerate at 4°C for 24 hours, centrifuge, adjust the pH of the supernatant with 50% NaOH solution, add purified water to adjust the total volume to 1000 mL, fill and sterilize to obtain the final product.

[0032] The preparation method of Comparative Example 6 is as follows: Add cassia seed ethanol extract, aromatic water, cyclamate, potassium sorbate, PEG400 and sodium metabisulfite to the mixed water extract, stir evenly, refrigerate at 4°C for 24 hours, centrifuge, adjust the pH of the supernatant with 50% NaOH solution, add purified water to adjust the total volume to 1000 mL, fill and sterilize to obtain the product.

[0033] The stilbene glycoside content of the oral liquid prepared in Examples 1-5 and Comparative Examples 1-6 was determined according to the stilbene glycoside content determination method in Chinese Invention Patent Application CN1586598A. The liquid was stored at 25±2℃ and 60%±5% relative humidity for 24 months, and samples were taken at 18 and 24 months to determine the stilbene glycoside content (unit: mg / 10mL). The decrease was calculated as (current content - 0-month content) ÷ 0-month content × 100%. The results are shown in Table 2.

[0034] Table 2: Detection results of stilbene glycoside content in Examples 1-5 and Comparative Examples 1-6

[0035] Based on the long-term stability study results of each formulation under conditions of 25±2℃ and 60%±5% relative humidity, it can be seen that in Examples 1-5, with specific concentrations of the pH adjuster sodium hydroxide and PEG400 or PEG400 and PEG600, the stilbene glycoside content was within the limits required by the quality standard (not less than 10 mg / 10 mL), and the content decrease was less than 4%, meeting the requirements for drug stability and content change. After 24 months of storage, the content decrease was not significant, and the product quality could still be guaranteed. In Comparative Examples 1-6, although the stilbene glycoside content was still within the standard requirement range after 18 months of storage, the content decreased significantly, reaching a maximum of 36.42%. After 24 months of storage, the content continued to decrease, with a maximum decrease of 64.81%, and the product quality could not be guaranteed.

[0036] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A highly stable oral liquid for regulating lipids using wolfberry, characterized in that, The oral liquid for regulating lipids of cassia seed is composed of ethanol extract of cassia seed, mixed water extract, aromatic water, flavoring agent, antibacterial agent, pH adjuster and solubilizer.

2. The oral liquid for regulating lipids according to claim 1, characterized in that, The 100mL of Wuqi lipid-regulating oral liquid contains 24.0-26.0g of cassia seed ethanol extract, 25.2-28.25mL of mixed water extract, 30mL of aromatic water, 0.3g of flavoring agent, 0.2g of antibacterial agent, 0.25-0.3g of pH adjuster, and 15-20g of solubilizer.

3. The oral liquid for regulating lipids according to claim 1, characterized in that, The solubilizer is polyethylene glycol 400 or a mixture of polyethylene glycol 400 and polyethylene glycol 600.

4. The oral liquid for regulating lipids according to claim 1, characterized in that, The solubilizer is a mixture of polyethylene glycol 400 and polyethylene glycol 600, with a mass ratio of 1-2:1-2.

5. The oral liquid for regulating lipids according to claim 1, characterized in that, The flavoring agent is selected from cyclamate or sucralose; the antibacterial agent is potassium sorbate; and the pH adjuster is NaOH solution with a concentration of 30-60%.

6. The oral liquid for regulating lipids according to claim 1, characterized in that, The preparation process of the cassia seed ethanol extract is as follows: crush the prescribed amount of cassia seeds, reflux the ethanol solution for extraction, recover the ethanol from the extract under reduced pressure, and concentrate the extract to obtain the final product.

7. The oral liquid for regulating lipids according to claim 6, characterized in that, The volume fraction of the ethanol solution is 50%-70%, and the extraction is carried out by reflux 1-3 times. The amount of ethanol solution added each time is independently selected from 6-8 times the mass of cassia seeds, and the extraction time for each extraction is 1-3 hours.

8. The oral liquid for regulating lipids according to claim 1, characterized in that, The preparation process of the mixed water extract is as follows: (1) Water extraction: The prescribed amount of prepared Polygonum multiflorum is crushed into the coarsest powder, mixed with the prescribed amount of wolfberry, chrysanthemum, safflower, hawthorn, tangerine peel and cassia seed after alcohol extraction, water is added for extraction, filtered, and the filtrate is concentrated under reduced pressure to obtain the water extract; (2) Alcohol precipitation: The water extract is added to ethanol, allowed to stand, filtered, the ethanol is recovered from the filtrate, and concentrated under reduced pressure to obtain the mixed water extract.

9. The oral liquid for regulating lipids according to claim 1, characterized in that, The preparation process of the aromatic water is as follows: during the first extraction of the first batch of water by mixing the prescribed amount of raw Polygonum multiflorum powder with the prescribed amounts of lycium barbarum, chrysanthemum, safflower, hawthorn, tangerine peel and cassia seed residue after alcohol extraction, 300 mL of distillate is collected simultaneously.

10. A method for preparing the *Wuqi* lipid-regulating oral liquid according to any one of claims 1-9, characterized in that, The method includes the following steps: adding cassia seed ethanol extract, aromatic water, flavoring agent, antibacterial agent, and solubilizer to the mixed water extract, stirring evenly, refrigerating at 4℃-8℃ and standing for 24 hours, centrifuging, adjusting the pH of the supernatant to 5.0-6.0 with a pH adjuster, adding purified water to adjust the total volume to 1000mL, filling, sterilizing, and obtaining the cassia seed lipid-regulating oral liquid.

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