Preparation method of fructus momordicae effervescent tablets

Abstract

The invention discloses a preparation method of fructus momordicae effervescent tablets, and belongs to the technical field of effervescent tablet preparation. The method comprises the following steps: performing ultrasonic-assisted decoction extraction, concentration and spray drying on siraitia grosvenorii to obtain extract dry powder; mixing with alginic acid and malic acid to form a suspension, and drying and crushing to obtain composite powder; then, a hydroxypropyl-beta-cyclodextrin solution is used for carrying out clathration on the composite powder, and clathrated composite powder is obtained after drying; and finally, respectively granulating with auxiliary materials such as an effervescing alkali source, an effervescing acid source, a filling agent and the like through acid and alkali, drying, totally mixing and tabletting to prepare the effervescent tablets. Alginic acid and malic acid are compounded to improve the hydrophilicity and dispersity of the fructus momordicae extract, hydroxypropyl-beta-cyclodextrin is used for inclusion to improve the stability and moisture resistance of effective components, the problems that in a traditional technology, the extract is not uniform in dissolution and prone to moisture absorption, and active components are prone to degradation are solved, and the product is fast in disintegration, good in taste and long in storage life.

Description

Technical Field

[0001] This invention belongs to the field of effervescent tablet preparation technology, and particularly relates to a method for preparing monk fruit effervescent tablets. Background Technology

[0002] Monk fruit, the dried fruit of a plant in the genus *Siraitia* of the Cucurbitaceae family, is a traditional Chinese food and medicine. Rich in mogroside V, flavonoids, vitamins, and various minerals, it possesses properties that clear heat and moisten the lungs, soothe the throat and relieve pain, and promote bowel movements. It effectively treats symptoms such as sore throat and dry cough due to lung heat. High in sweetness and low in calories, it is suitable for all types of people. Effervescent tablets, a novel oral preparation, rapidly disintegrate in water, releasing a large amount of carbon dioxide to form a uniform suspension. They offer advantages such as rapid dissolution, good absorption of active ingredients, and convenient administration, making them more suitable for the convenient and standardized consumption needs of modern consumers compared to traditional monk fruit slices and decoctions.

[0003] In the prior art, several preparation methods for monk fruit effervescent tablets have been disclosed. For example, patent publication number CN201710568510.2 discloses a monk fruit effervescent tablet and its preparation method. The effervescent tablet contains 100-250 parts by weight of monk fruit extract, 100-250 parts by weight of sodium bicarbonate, 200-500 parts by weight of citric acid, 200-500 parts by weight of lactose monohydrate, 40-100 parts by weight of PEG 6000, 30-80 parts by weight of povidone K30, and 5-20 parts by weight of orange flavoring, etc. In the preparation, PEG 6000 is used to melt-encapsulate sodium bicarbonate and granulate the citric acid separately, which effectively separates the effervescent disintegrant. At the same time, the lubricating effect of PEG 6000 ensures smooth tableting. The resulting tablets are flat, smooth, and uniform in color, and have the characteristics of simple process and convenient carrying. However, this technical solution still has many shortcomings that need improvement: First, the stability of the active ingredients is insufficient. The PEG 6000 melt encapsulation process requires high temperature, while the core component of monk fruit extract, mogroside, is a heat-sensitive substance. High temperature can easily cause its degradation, reducing the product's efficacy and activity. Moreover, the process does not perform targeted protective treatment on the extract, and mogroside components are easily affected by oxidation during subsequent drying and storage, further aggravating losses. Second, the water solubility and dissolution effect are poor. Monk fruit extract itself is highly hydrophobic, and it is difficult to improve its solubility by relying solely on conventional excipients. This results in uneven dissolution and local clumping after the effervescent tablets disintegrate, affecting the release rate of the active ingredients and the human body's absorption efficiency. Third, the moisture-proof performance is lacking. Effervescent alkaline sources such as sodium bicarbonate are inherently hygroscopic, and the moisture barrier effect of the PEG 6000 encapsulation layer is limited. Furthermore, the extract is not modified to prevent moisture absorption, making the product susceptible to moisture absorption, clumping, and deterioration during production and storage due to environmental humidity, significantly shortening the shelf life. Summary of the Invention

[0004] To address the above issues and overcome the shortcomings of existing technologies, this invention first obtains monk fruit extract powder through ultrasonic-assisted decoction, then combines it with alginic acid and malic acid to form a suspension, which is then dried and pulverized to obtain a composite powder. Subsequently, hydroxypropyl-β-cyclodextrin is used to encapsulate the composite powder. Finally, excipients such as effervescent base source, effervescent acid source, and fillers are added, and the finished product is prepared through acid-base granulation, drying, sizing, total mixing, and tableting. This invention optimizes the stability, water solubility, and user experience of the core components of monk fruit, effectively solving problems such as uneven dissolution of extracts, easy deterioration due to moisture absorption, and easy degradation of active ingredients in traditional preparation processes. It extends the product's shelf life, ensures rapid disintegration and convenient consumption, and maintains stable active ingredient content.

[0005] To achieve the above objectives, the following technical solution is adopted: This invention provides a method for preparing monk fruit effervescent tablets, comprising the following steps:

[0006] (1) Remove the stem from fresh monk fruit, cut it into small pieces, dry it to obtain dried monk fruit; extract monk fruit by ultrasonic-assisted decoction, filter the extract, combine the extracts and concentrate them under reduced pressure to obtain monk fruit concentrate, and spray dry the product to obtain monk fruit extract powder.

[0007] (2) Take the monk fruit extract, alginic acid and malic acid obtained in step (1) in proportion, first prepare alginic acid solution, then add monk fruit extract and malic acid and mix evenly to form a suspension. The suspension is dried, pulverized and sieved to obtain monk fruit extract-alginic acid-malic acid composite powder.

[0008] (3) Prepare an aqueous solution of hydroxypropyl-β-cyclodextrin, add the composite powder obtained in step (2) to carry out the inclusion reaction, and dry, pulverize and sieve the reaction solution to obtain hydroxypropyl-β-cyclodextrin inclusion composite powder;

[0009] (4) Take the composite powder obtained in step (3) according to the ratio, and mix it with effervescent alkali source, effervescent acid source, filler, binder and lubricant. After mixing, acid and alkali are granulated separately, dried, sized, acid and alkali granules are mixed together and tableted to obtain Luo Han Guo effervescent tablets. After tableting, quality inspection is carried out, and the finished product is sealed and packaged for storage.

[0010] Furthermore, in the ultrasonic-assisted decoction extraction, the material-to-liquid ratio is 1:20~1:15 (g / mL), the extraction temperature is 100℃, the ultrasonic power is 300W, the extraction time is 40min, the extraction is performed twice, and the filtrates are combined; in step (1), the vacuum concentration adopts a single-effect external circulation concentrator, the vacuum concentration temperature of the extract is 50~70℃, the vacuum degree is -0.08MPa, and the concentration is carried out until the solid content is 10~20%.

[0011] Further, in step (2), the mass ratio of the monk fruit extract, alginic acid, and malic acid is 5~10:1~3:1~3; the mass concentration of the alginic acid solution is 2%.

[0012] Further, in step (3), the mass ratio of hydroxypropyl-β-cyclodextrin to the composite powder is 2:1 to 3:1; the material-to-liquid ratio of the hydroxypropyl-β-cyclodextrin aqueous solution is 1:10 (g / mL), and it is stirred at 60°C for 20 min until dissolved; the inclusion reaction temperature is 60°C, the stirring speed is 300 r / min, and the reaction time is 1.5 h; the drying is spray drying, with an inlet air temperature of 150°C, an outlet air temperature of 65°C, and a feed rate of 3 mL / min; after drying, it is passed through an 80-mesh sieve, and the moisture absorption rate of the powder after inclusion is ≤3%.

[0013] Further, the effervescent base source is selected from at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and ammonium bicarbonate; the effervescent acid source is at least one of tartaric acid, citric acid, fumaric acid, adipic acid, monosodium citrate, and succinic acid; the filler is selected from at least one of mannitol, lactose, microcrystalline cellulose, and sorbitol; the binder is at least one of povidone K30, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; and the lubricant is at least one of magnesium stearate, calcium stearate, talc, and sodium stearate fumarate.

[0014] Furthermore, the mass ratio of the inclusion composite powder to the effervescent alkali source, effervescent acid source, filler, binder and lubricant is 6~18:15~24:20~30:32~45:2.5~8:0.2~1.5.

[0015] Further, the mixing step in step (4) specifically includes: taking the formula amount of effervescent acid source, inclusion complex powder and 50%~60% filler, putting them into a mixer, setting the speed to 15~20 r / min, mixing for 8~12 min until the material is uniform in color and has no obvious lumps, and then discharging it for later use; taking the formula amount of effervescent alkali source and the remaining filler, putting them into another clean mixer, setting the speed to 15~20 r / min, mixing for 8~12 min, ensuring that the material is evenly dispersed, and then discharging it for later use; during the mixing process, controlling the ambient humidity ≤45% and the temperature 20~25℃.

[0016] Further, the acid-base granulation step in step (4) specifically includes: taking the binder according to the formula, adding purified water at a solid-liquid ratio of 1:5~1:10 (g / mL), stirring and dissolving at 60~70℃, cooling to room temperature to prepare a binder solution for later use; putting the mixed acid phase material into a high-speed stirring granulator, stirring at a speed of 150~200r / min, slowly spraying 50%~60% binder solution at a spraying speed of 3~5mL / min, stirring and granulating for 3~5min until a uniform soft material is formed, then passing it through a 20-mesh nylon screen, using a swing granulator to granulate, and collecting the wet acid phase particles; similar to the acid phase granulation process, putting the alkali phase mixture into a granulator, spraying the remaining binder solution, granulating, and then passing it through a 20-mesh nylon screen to collect the wet alkali phase particles.

[0017] Furthermore, in step (4), the drying temperature is 50~60℃, the wind speed is 0.8~1.2m / s, the drying time is 2~4h, and the moisture content of the dried particles is controlled at 1.5%~3.0%.

[0018] Further, the acid-base particle mixing and tableting steps in step (4) specifically include: putting the granulated acid-phase dry particles and base-phase dry particles into a three-dimensional motion mixer, adding the formula amount of lubricant, rotating at 15~20 r / min, and mixing for 3~5 min; using a rotary tableting machine, adjusting the die size according to the tablet specifications, and continuously tableting to obtain the Luo Han Guo effervescent tablet product.

[0019] The beneficial effects of this invention are:

[0020] This invention achieves synergistic optimization of the stability, water solubility, and user experience of the core active ingredients by combining monk fruit extract, alginic acid, and malic acid, followed by a progressive treatment involving inclusion with hydroxypropyl-β-cyclodextrin, combined with conventional effervescent tablet preparation processes. Specific beneficial effects are as follows:

[0021] Alginic acid, as a water-soluble polymer, can uniformly adhere to the surface of monk fruit extract particles, forming a hydrophilic film. Upon entering water, alginic acid rapidly absorbs water and swells, effectively breaking the hydrophobic aggregation state of the monk fruit extract, increasing its contact area with water, and significantly improving the dissolution rate. Malic acid can adjust the pH value of the system to a suitable range for the dissolution of monk fruit extract, further promoting its dissolution. On the other hand, malic acid and subsequently added sodium bicarbonate form an effervescent system, which reacts to generate a large amount of carbon dioxide upon entering water, which can drive the composite particles to disperse evenly, avoid local clumping, and achieve rapid release of active ingredients, solving the technical pain points of poor water solubility and uneven dissolution of traditional monk fruit extract.

[0022] Hydroxypropyl-β-cyclodextrin possesses a cavity structure with an inner hydrophobic layer and an outer hydrophilic layer. During the inclusion process, its hydrophobic inner cavity precisely encapsulates the hydrophobic groups of the monk fruit extract, while simultaneously embedding alginic acid and malic acid adhering to the extract surface into the cavity, forming a dense molecular barrier. This barrier effectively blocks the intrusion of external moisture, significantly reducing the risk of moisture absorption by the monk fruit extract and malic acid, preventing the core components from clumping and deteriorating due to moisture absorption, and extending the product's shelf life. At the same time, the cyclodextrin encapsulation protects effective components such as monk fruit glycoside V, reducing their degradation caused by high temperatures and oxidation during drying, tableting, and other processes, ensuring stable glycoside content in the finished product. The outer hydrophilic group of hydroxypropyl-β-cyclodextrin further enhances the hydrophilicity of the encapsulated monk fruit extract, reducing the disintegration time of effervescent tablets and meeting the requirements for rapid disintegration. Attached Figure Description

[0023] Figure 1 The flowchart shows the process of preparing Luo Han Guo effervescent tablets according to various embodiments of the present invention.

[0024] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the embodiments of the invention to explain the invention and do not constitute a limitation thereof. Detailed Implementation

[0025] 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. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this application.

[0027] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all purchased from commercial channels. The preparation process of the Luo Han Guo effervescent tablets in each embodiment of the present invention is attached. Figure 1 As shown.

[0028] Example 1: A method for preparing monk fruit effervescent tablets

[0029] The preparation method includes the following steps:

[0030] (1) Remove the stem from fresh monk fruit, cut it into small pieces, dry it to obtain dried monk fruit; extract monk fruit by ultrasonic-assisted decoction, filter the extract, combine the extracts and concentrate them under reduced pressure to obtain monk fruit concentrate, and spray dry the product to obtain monk fruit extract powder.

[0031] (2) Take the monk fruit extract, alginic acid and malic acid obtained in step (1) in proportion, first prepare alginic acid solution, then add monk fruit extract and malic acid and mix evenly to form a suspension. The suspension is dried, pulverized and sieved to obtain monk fruit extract-alginic acid-malic acid composite powder.

[0032] (3) Prepare an aqueous solution of hydroxypropyl-β-cyclodextrin, add the composite powder obtained in step (2) to carry out the inclusion reaction, and dry, pulverize and sieve the reaction solution to obtain hydroxypropyl-β-cyclodextrin inclusion composite powder;

[0033] (4) Take the composite powder obtained in step (3) according to the ratio, and mix it with effervescent alkali source, effervescent acid source, filler, binder and lubricant. After mixing, acid and alkali are granulated separately, dried, sized, acid and alkali granules are mixed together and tableted to obtain Luo Han Guo effervescent tablets. After tableting, quality inspection is carried out, and the finished product is sealed and packaged for storage.

[0034] In the ultrasonic-assisted decoction extraction, the material-to-liquid ratio is 1:20 (g / mL), the extraction temperature is 100℃, the ultrasonic power is 300W, the extraction time is 40min, the extraction is performed twice and the filtrates are combined; in step (1), the vacuum concentration is performed using a single-effect external circulation concentrator, the vacuum concentration temperature of the extract is 50℃, the vacuum degree is -0.08MPa, and the concentration is performed until the solid content is 10%.

[0035] In step (2), the mass ratio of the monk fruit extract, alginic acid, and malic acid is 5:1:1; the mass concentration of the alginic acid solution is 2%.

[0036] In step (3), the mass ratio of hydroxypropyl-β-cyclodextrin to the composite powder is 2:1; the material-to-liquid ratio of the hydroxypropyl-β-cyclodextrin aqueous solution is 1:10 (g / mL), and it is stirred at 60℃ for 20 min until dissolved; the inclusion reaction temperature is 60℃, the stirring speed is 300 r / min, and the reaction time is 1.5 h; the drying is spray drying, with an inlet air temperature of 150℃, an outlet air temperature of 65℃, and a feed rate of 3 mL / min. After drying, it is passed through an 80-mesh sieve, and the moisture absorption rate of the powder after inclusion is ≤3%.

[0037] The mass ratio of the composite powder, effervescent alkali source (sodium bicarbonate), effervescent acid source (citric acid), filler (mannitol), binder (povidone K30), and lubricant (magnesium stearate) is 6:15:20:32:2.5:0.2.

[0038] The mixing step in step (4) specifically includes: taking the formula amount of effervescent acid source, inclusion complex powder and 50% filler, putting them into a mixer, setting the speed to 15 r / min, mixing for 8 min until the material is uniform in color and has no obvious lumps, and then discharging it for later use; taking the formula amount of effervescent alkali source and the remaining filler, putting them into another clean mixer, setting the speed to 15 r / min, mixing for 8 min, ensuring that the material is evenly dispersed, and then discharging it for later use; during the mixing process, controlling the ambient humidity ≤45% and the temperature 20℃.

[0039] The specific steps of acid-base granulation in step (4) include: taking the binder according to the formula, adding purified water at a solid-liquid ratio of 1:5 (g / mL), stirring and dissolving at 60°C, cooling to room temperature to prepare a binder solution for later use; putting the mixed acid phase material into a high-speed stirring granulator, stirring at 150r / min, slowly spraying 50% binder solution at a spraying speed of 3mL / min, stirring and granulating for 3min until a uniform soft material is formed, then passing it through a 20-mesh nylon screen and granulating it using a swing granulator to collect the wet acid phase particles; using the same acid phase granulation process, putting the alkali phase mixture into a granulator, spraying the remaining binder solution, granulating it, and then passing it through a 20-mesh nylon screen to collect the wet alkali phase particles.

[0040] The drying temperature in step (4) is 50℃, the wind speed is 0.8m / s, the drying time is 2h, and the moisture content of the dried particles is controlled at 1.5%.

[0041] The specific steps of mixing and tableting acid-base particles in step (4) include: putting the granulated acid-phase dry particles and alkali-phase dry particles into a three-dimensional motion mixer, adding the formula amount of lubricant, rotating at 15 r / min, and mixing for 3 min; using a rotary tablet press, adjusting the die size according to the tablet specifications, and continuously tableting to obtain the Luo Han Guo effervescent tablet product.

[0042] Example 2: A method for preparing monk fruit effervescent tablets

[0043] The preparation method includes the same steps as in Example 1.

[0044] The preparation method includes the following steps:

[0045] (1) Remove the stem from fresh monk fruit, cut it into small pieces, dry it to obtain dried monk fruit; extract monk fruit by ultrasonic-assisted decoction, filter the extract, combine the extracts and concentrate them under reduced pressure to obtain monk fruit concentrate, and spray dry the product to obtain monk fruit extract powder.

[0046] (2) Take the monk fruit extract, alginic acid and malic acid obtained in step (1) in proportion, first prepare alginic acid solution, then add monk fruit extract and malic acid and mix evenly to form a suspension. The suspension is dried, pulverized and sieved to obtain monk fruit extract-alginic acid-malic acid composite powder.

[0047] (3) Prepare an aqueous solution of hydroxypropyl-β-cyclodextrin, add the composite powder obtained in step (2) to carry out the inclusion reaction, and dry, pulverize and sieve the reaction solution to obtain hydroxypropyl-β-cyclodextrin inclusion composite powder;

[0048] (4) Take the composite powder obtained in step (3) according to the ratio, and mix it with effervescent alkali source, effervescent acid source, filler, binder and lubricant. After mixing, acid and alkali are granulated separately, dried, sized, acid and alkali granules are mixed together and tableted to obtain Luo Han Guo effervescent tablets. After tableting, quality inspection is carried out, and the finished product is sealed and packaged for storage.

[0049] In the ultrasonic-assisted decoction extraction, the material-to-liquid ratio is 1:15 (g / mL), the extraction temperature is 100℃, the ultrasonic power is 300W, the extraction time is 40min, the extraction is performed twice and the filtrates are combined; in step (1), the vacuum concentration is performed using a single-effect external circulation concentrator, the vacuum concentration temperature of the extract is 70℃, the vacuum degree is -0.08MPa, and the concentration is performed until the solid content is 20%.

[0050] In step (2), the mass ratio of the monk fruit extract, alginic acid, and malic acid is 10:3:3; the mass concentration of the alginic acid solution is 2%.

[0051] In step (3), the mass ratio of hydroxypropyl-β-cyclodextrin to the composite powder is 3:1; the material-to-liquid ratio of the hydroxypropyl-β-cyclodextrin aqueous solution is 1:10 (g / mL), and it is stirred at 60℃ for 20 min until dissolved; the inclusion reaction temperature is 60℃, the stirring speed is 300 r / min, and the reaction time is 1.5 h; the drying is spray drying, with an inlet air temperature of 150℃, an outlet air temperature of 65℃, and a feed rate of 3 mL / min; after drying, it is passed through an 80-mesh sieve, and the moisture absorption rate of the powder after inclusion is ≤3%.

[0052] The mass ratio of the encapsulated composite powder, effervescent alkali source (composed of potassium bicarbonate and sodium carbonate in a mass ratio of 1:1), effervescent acid source (composed of fumaric acid and malic acid in a mass ratio of 1:1), filler (composed of lactose and microcrystalline cellulose in a mass ratio of 1:2), binder (hydroxypropyl methylcellulose), and lubricant (talc) is 18:24:30:45:8:1.5.

[0053] The mixing step in step (4) specifically includes: taking the formula amount of effervescent acid source, inclusion complex powder and 60% filler, putting them into a mixer, setting the speed to 20 r / min, mixing for 12 min until the material is uniform in color and has no obvious lumps, and then discharging it for later use; taking the formula amount of effervescent alkali source and the remaining filler, putting them into another clean mixer, setting the speed to 20 r / min, mixing for 12 min, ensuring that the material is evenly dispersed, and then discharging it for later use; during the mixing process, controlling the ambient humidity ≤45% and the temperature 25℃.

[0054] The acid-base granulation steps in step (4) specifically include: taking the binder according to the formula, adding purified water at a solid-liquid ratio of 1:10 (g / mL), stirring and dissolving at 70℃, cooling to room temperature to prepare a binder solution for later use; putting the mixed acid phase material into a high-speed stirring granulator, stirring at 200r / min, slowly spraying 60% binder solution at a spraying speed of 5mL / min, stirring and granulating for 5min until a uniform soft material is formed, then passing it through a 20-mesh nylon screen, using a swing granulator to granulate, and collecting the acid phase wet particles; using the same acid phase granulation process, putting the alkali phase mixture into a granulator, spraying the remaining binder solution, granulating, and then passing it through a 20-mesh nylon screen to collect the alkali phase wet particles.

[0055] The drying temperature in step (4) is 60℃, the wind speed is 1.2m / s, the drying time is 4h, and the moisture content of the dried particles is controlled at 3.0%.

[0056] The specific steps of mixing and tableting acid and alkali particles in step (4) include: putting the granulated acid-phase dry particles and alkali-phase dry particles into a three-dimensional motion mixer, adding the formula amount of lubricant, rotating at 20 r / min, and mixing for 5 min; using a rotary tablet press, adjusting the die size according to the tablet specifications, and continuously tableting to obtain the Luo Han Guo effervescent tablet product.

[0057] Example 3: A method for preparing monk fruit effervescent tablets

[0058] The preparation method includes the same steps as in Example 1.

[0059] The preparation method includes the following steps:

[0060] (1) Remove the stem from fresh monk fruit, cut it into small pieces, dry it to obtain dried monk fruit; extract monk fruit by ultrasonic-assisted decoction, filter the extract, combine the extracts and concentrate them under reduced pressure to obtain monk fruit concentrate, and spray dry the product to obtain monk fruit extract powder.

[0061] (2) Take the monk fruit extract, alginic acid and malic acid obtained in step (1) in proportion, first prepare alginic acid solution, then add monk fruit extract and malic acid and mix evenly to form a suspension. The suspension is dried, pulverized and sieved to obtain monk fruit extract-alginic acid-malic acid composite powder.

[0062] (3) Prepare an aqueous solution of hydroxypropyl-β-cyclodextrin, add the composite powder obtained in step (2) to carry out the inclusion reaction, and dry, pulverize and sieve the reaction solution to obtain hydroxypropyl-β-cyclodextrin inclusion composite powder;

[0063] (4) Take the composite powder obtained in step (3) according to the ratio, and mix it with effervescent alkali source, effervescent acid source, filler, binder and lubricant. After mixing, acid and alkali are granulated separately, dried, sized, acid and alkali granules are mixed together and tableted to obtain Luo Han Guo effervescent tablets. After tableting, quality inspection is carried out, and the finished product is sealed and packaged for storage.

[0064] In the ultrasonic-assisted decoction extraction, the material-to-liquid ratio is 1:18 (g / mL), the extraction temperature is 100℃, the ultrasonic power is 300W, the extraction time is 40min, the extraction is performed twice, and the filtrates are combined. In step (1), the vacuum concentration is performed using a single-effect external circulation concentrator. The vacuum concentration temperature of the extract is 60℃, the vacuum degree is -0.08MPa, and the concentration is carried out until the solid content is 15%.

[0065] In step (2), the mass ratio of the monk fruit extract, alginic acid, and malic acid is 7:2:2; the mass concentration of the alginic acid solution is 2%.

[0066] In step (3), the mass ratio of hydroxypropyl-β-cyclodextrin to the composite powder is 2.5:1; the material-to-liquid ratio of the hydroxypropyl-β-cyclodextrin aqueous solution is 1:10 (g / mL), and it is stirred at 60℃ for 20 min until dissolved; the inclusion reaction temperature is 60℃, the stirring speed is 300 r / min, and the reaction time is 1.5 h; the drying is spray drying, with an inlet air temperature of 150℃, an outlet air temperature of 65℃, and a feed rate of 3 mL / min. After drying, it is passed through an 80-mesh sieve, and the moisture absorption rate of the powder after inclusion is ≤3%.

[0067] The mass ratio of the encapsulated composite powder, effervescent base source (sodium carbonate), effervescent acid source (composed of sodium citrate and succinic acid in a mass ratio of 2:1), filler (composed of sorbitol and mannitol in a mass ratio of 1:2), binder (hydroxypropyl cellulose), and lubricant (sodium stearate fumarate) is 12:20:25:38:5:0.8.

[0068] The mixing step in step (4) specifically includes: taking the formula amount of effervescent acid source, inclusion complex powder and 55% filler, putting them into a mixer, setting the speed to 18 r / min, mixing for 10 min until the material is uniform in color and has no obvious lumps, and then discharging the material for later use; taking the formula amount of effervescent alkali source and the remaining filler, putting them into another clean mixer, setting the speed to 18 r / min, mixing for 10 min, ensuring that the material is evenly dispersed, and then discharging the material for later use; during the mixing process, controlling the ambient humidity ≤45% and the temperature 23℃.

[0069] The specific steps of acid-base granulation in step (4) include: taking the binder according to the formula, adding purified water at a solid-liquid ratio of 1:7.5 (g / mL), stirring and dissolving at 65°C, cooling to room temperature to prepare a binder solution for later use; putting the mixed acid phase material into a high-speed stirring granulator, stirring at 175r / min, slowly spraying 55% binder solution at a spraying speed of 4mL / min, stirring and granulating for 4min until a uniform soft material is formed, then passing it through a 20-mesh nylon screen, using a swing granulator to granulate, and collecting the wet acid phase particles; using the same acid phase granulation process, putting the alkali phase mixture into a granulator, spraying the remaining binder solution, granulating, and then passing it through a 20-mesh nylon screen to collect the wet alkali phase particles.

[0070] The drying temperature in step (4) is 55℃, the wind speed is 1.0m / s, the drying time is 3h, and the moisture content of the dried particles is controlled at 2.5%.

[0071] The specific steps of mixing and tableting acid and alkali particles in step (4) include: putting the granulated acid-phase dry particles and alkali-phase dry particles into a three-dimensional motion mixer, adding the formula amount of lubricant, rotating at 18 r / min, and mixing for 4 min; using a rotary tablet press, adjusting the die size according to the tablet specifications, and continuously tableting to obtain the Luo Han Guo effervescent tablet product.

[0072] Example 4: A method for preparing monk fruit effervescent tablets

[0073] The effervescent base source is composed of sodium bicarbonate and ammonium bicarbonate in a mass ratio of 1:1; the effervescent acid source is composed of tartaric acid, fumaric acid, and sodium citrate in a mass ratio of 1:1:1; the filler is composed of mannitol, lactose, and microcrystalline cellulose in a mass ratio of 1:1:1; the binder is composed of hydroxypropyl methylcellulose and hydroxypropyl cellulose in a mass ratio of 1:1; and the lubricant is composed of calcium stearate and talc in a mass ratio of 1:1.

[0074] Everything else is the same as in Example 3.

[0075] Example 5: A method for preparing monk fruit effervescent tablets

[0076] The effervescent base source is potassium bicarbonate; the effervescent acid source is composed of citric acid and adipic acid in a mass ratio of 2:1; the filler is microcrystalline cellulose; the binder is polyvinyl ketone K30; and the lubricant is magnesium stearate.

[0077] Everything else is the same as in Example 3.

[0078] Example 6: A method for preparing monk fruit effervescent tablets

[0079] The effervescent base source is composed of sodium bicarbonate and potassium carbonate in a mass ratio of 2:1; the effervescent acid source is malic acid; the filler is composed of mannitol and sorbitol in a mass ratio of 1:3; the binder is hydroxypropyl methylcellulose; and the lubricant is composed of sodium stearate fumarate and talc in a mass ratio of 3:1.

[0080] Everything else is the same as in Example 3.

[0081] Comparative Example 1: The difference between this comparative example and Example 3 is that the alginic acid-malic acid complexation step is omitted, and the monk fruit extract powder is used instead of the complex powder. It undergoes an inclusion reaction with the hydroxypropyl-β-cyclodextrin aqueous solution to obtain monk fruit extract powder that is only included by cyclodextrin. All other aspects are the same as in Example 3.

[0082] Comparative Example 2: The difference between this comparative example and Example 3 is that the hydroxypropyl-β-cyclodextrin inclusion step is omitted, and the composite powder is used instead of the hydroxypropyl-β-cyclodextrin inclusion composite powder. All other aspects are the same as in Example 3.

[0083] Results Analysis

[0084] The effervescent tablets after compression in each group of embodiments and comparative examples of the present invention were tested as follows, and the results are shown in Table 1:

[0085] (1) Stability test of active ingredients:

[0086] Accurately weigh 0.1g of the powder after compression and grinding of each example and comparative example tablet, and place it in a 50mL volumetric flask.

[0087] Place the intact effervescent tablets in a constant temperature and humidity chamber and store them for 30 days at a temperature of 40℃±2℃ and a relative humidity of 75%±5%. After the expiration date, remove the tablets, grind them using the same method, and weigh and take samples.

[0088] Add approximately 40 mL of 50% methanol aqueous solution to a volumetric flask, and extract by sonication for 30 minutes (300 W, 40 °C). After cooling to room temperature, make up to volume and mix well. Filter through a 0.45 μm microporous membrane and use the filtrate as the test solution.

[0089] The content of mogroside V in each example and comparative example was determined by high performance liquid chromatography (HPLC).

[0090] Chromatographic conditions were as follows: column: C18 reversed-phase column (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile-water (25:75, v / v); flow rate: 1.0 mL / min; column temperature: 30 ℃; detection wavelength: 203 nm; injection volume: 10 μL.

[0091] Accurately weigh the standard of mogroside V and prepare a series of standard solutions of different concentrations. Inject the solutions under the chromatographic conditions described above. Perform linear regression on the peak area (A) against the concentration (C) to obtain the standard curve equation. Measure the peak area of ​​the test solution and calculate the content of mogroside V, thereby calculating the retention rate of the active ingredient.

[0092] Retention rate (%) = (content of glycoside V in the accelerated sample / content of glycoside V in the sample after 0 days) × 100%.

[0093] (2) Water solubility and disintegration performance test:

[0094] Take 400 mL of purified water and place it in a beaker. Maintain the water temperature at 20℃±1℃ using a water bath. Start the disintegration apparatus, place one effervescent tablet in a dry basket tube, lower it into the water, and start timing. Observe the tablet until it completely disintegrates and passes through the sieve. Stop timing when there is no hard core or undisintegrated particles present. This time is the disintegration time limit. Six tablets are measured in parallel for each sample group, and the average value is taken.

[0095] Take 200mL of warm water (50℃±2℃, simulating daily brewing) into a transparent beaker, add one effervescent tablet, and let it stand to dissolve naturally. Observe whether there are obvious clumps or particles floating on the surface of the liquid for a long time during the dissolution process. After it is completely dissolved and left to stand for 1 minute, stir gently and give a visual score: 1 point (extremely clear and transparent), 2 points (slightly opalescent), 3 points (slightly turbid), 4 points (turbid), 5 points (severely turbid or with a large amount of sediment).

[0096] (3) Moisture-proof performance test:

[0097] After equilibrating the sample in a desiccator for 24 hours, accurately weigh its initial weight (W0). Then, spread the sample evenly in an open weighing dish and place it in a constant temperature and humidity chamber stabilized at 40℃ and 75%RH. After 72 hours, quickly remove the sample, cover it, and cool it to room temperature in a dry environment before weighing it (W0). t ), calculate the moisture absorption weight gain rate.

[0098] Moisture absorption weight gain rate (%) = [(W t -W0) / W0]×100%. Plot the moisture absorption curve.

[0099] Store the unpackaged effervescent tablets in the above-mentioned constant temperature and humidity chamber for 30 days. After the expiration date, take them out and observe and record whether the appearance shows softening, sticking, deformation, darkening of color, or the appearance of spots.

[0100] Table 1 Comparison of Effervescent Tablet Finished Product Testing and Analysis Results

[0101] Group Retention rate (%) Disintegration timeout (s) clumping phenomenon Clarity Moisture absorption weight gain rate (%) Appearance after accelerated storage Example 1 95.2 52 No clumps Level 2 2.8 Basically intact Example 3 94.8 48 No clumps Level 2 2.5 intact Example 4 96.5 45 No clumps Level 1 2.1 intact Example 5 96.0 47 No clumps Level 2 2.3 intact Example 6 95.5 50 No clumps Level 2 2.7 intact Comparative Example 1 88.3 68 Obvious lumps Level 3 4.5 Significantly softened adhesions Comparative Example 2 85.1 55 Small amount of clumps Level 2 8.2 Severely softened and discolored

[0102] As shown in Table 1, the retention rate of glycoside V in each embodiment was significantly higher than that in the two comparative examples. This indicates that the treatment method of encapsulating the alginate, malic acid complex with hydroxypropyl-β-cyclodextrin effectively protects the heat-sensitive and easily oxidized active ingredients. The disintegration time of each embodiment was shorter than that of the comparative examples, and the dissolution was more uniform and the clarity was higher. This verifies that the hydrophilic promoting effect of alginate and the pH regulating and effervescent synergistic effect of malic acid effectively improve the dispersibility of monk fruit extract. The moisture absorption and weight gain rate of the embodiment groups were much lower than that of the comparative examples, and the appearance was also relatively intact after accelerated storage. In particular, comparative example 2, due to the absence of a cyclodextrin barrier, absorbed moisture extremely severely, causing the tablets to deteriorate rapidly under accelerated conditions. Comparative example 1, due to the inclusion of cyclodextrin, had better moisture resistance than comparative example 2, but not as good as the embodiment with the complete process, indicating that the alginate and malic acid complex itself has a certain degree of hygroscopicity and requires the outer layer of cyclodextrin to isolate moisture. In summary, the preparation process of this invention solves the technical problems of monk fruit effervescent tablets, such as easy degradation of active ingredients, poor water solubility and easy clumping, and easy moisture absorption and deterioration.

[0103] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

[0104] The present invention and its embodiments have been described above. This description is not restrictive, and the embodiments shown are only one of the embodiments of the present invention. The actual application is not limited to this. In conclusion, if those skilled in the art are inspired by this description and design similar methods and embodiments without departing from the spirit of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. A method for preparing monk fruit effervescent tablets, characterized in that: Includes the following steps: (1) Remove the stem from fresh monk fruit, cut it into small pieces, dry it to obtain dried monk fruit; extract monk fruit by ultrasonic-assisted decoction, filter the extract, combine the extracts and concentrate them under reduced pressure to obtain monk fruit concentrate, and spray dry the product to obtain monk fruit extract powder. (2) Take the monk fruit extract, alginic acid and malic acid obtained in step (1) in proportion, first prepare alginic acid solution, then add monk fruit extract and malic acid and mix evenly to form a suspension. The suspension is dried, pulverized and sieved to obtain monk fruit extract-alginic acid-malic acid composite powder. (3) Prepare an aqueous solution of hydroxypropyl-β-cyclodextrin, add the composite powder obtained in step (2) to carry out the inclusion reaction, and dry, pulverize and sieve the reaction solution to obtain hydroxypropyl-β-cyclodextrin inclusion composite powder; (4) Take the composite powder obtained in step (3) according to the ratio, and mix it with effervescent alkali source, effervescent acid source, filler, binder and lubricant. After mixing, acid and alkali are granulated separately, dried, sized, acid and alkali granules are mixed together and tableted to obtain Luo Han Guo effervescent tablets. After tableting, quality inspection is carried out, and the finished product is sealed and packaged for storage.

2. The method for preparing a monk fruit effervescent tablet according to claim 1, characterized in that: In the ultrasonic-assisted decoction extraction, the material-to-liquid ratio is 1:20~1:15 (g / mL), the extraction temperature is 100℃, the ultrasonic power is 300W, the extraction time is 40min, the extraction is performed twice and the filtrates are combined; in step (1), the vacuum concentration adopts a single-effect external circulation concentrator, the vacuum concentration temperature of the extract is 50~70℃, the vacuum degree is -0.08MPa, and the concentration is carried out until the solid content is 10~20%.

3. The method for preparing monk fruit effervescent tablets according to claim 2, characterized in that: In step (2), the mass ratio of the monk fruit extract, alginic acid, and malic acid is 5~10:1~3:1~3; the mass concentration of the alginic acid solution is 2%.

4. The method for preparing a monk fruit effervescent tablet according to claim 3, characterized in that: In step (3), the mass ratio of hydroxypropyl-β-cyclodextrin to the composite powder is 2:1 to 3:1; the material-to-liquid ratio of the hydroxypropyl-β-cyclodextrin aqueous solution is 1:10 (g / mL), and the mixture is stirred at 60°C for 20 min until dissolved; the inclusion reaction temperature is 60°C, the stirring speed is 300 r / min, and the reaction time is 1.5 h; the drying is spray drying with an inlet air temperature of 150°C, an outlet air temperature of 65°C, and a feed rate of 3 mL / min; after drying, the powder passes through an 80-mesh sieve, and the moisture absorption rate of the powder after inclusion is ≤3%.

5. The method for preparing a monk fruit effervescent tablet according to claim 4, characterized in that: The effervescent base source is selected from at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and ammonium bicarbonate; the effervescent acid source is at least one of tartaric acid, citric acid, fumaric acid, adipic acid, monosodium citrate, and succinic acid; the filler is selected from at least one of mannitol, lactose, microcrystalline cellulose, and sorbitol; the binder is at least one of povidone K30, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; and the lubricant is at least one of magnesium stearate, calcium stearate, talc, and sodium stearate fumarate.

6. The method for preparing a monk fruit effervescent tablet according to claim 5, characterized in that: The composite powder is formulated with effervescent alkali source, effervescent acid source, filler, binder and lubricant in a mass ratio of 6~18:15~24:20~30:32~45:2.5~8:0.2~1.

5.

7. The method for preparing a monk fruit effervescent tablet according to claim 6, characterized in that: The mixing step in step (4) specifically includes: taking the formula amount of effervescent acid source, inclusion complex powder and 50%~60% filler, putting them into a mixer, setting the speed to 15~20 r / min, mixing for 8~12 min until the material is uniform in color and has no obvious lumps, and then discharging it for later use; taking the formula amount of effervescent alkali source and the remaining filler, putting them into another clean mixer, setting the speed to 15~20 r / min, mixing for 8~12 min, ensuring that the material is evenly dispersed, and then discharging it for later use; during the mixing process, controlling the ambient humidity ≤45% and the temperature 20~25℃.

8. The method for preparing a monk fruit effervescent tablet according to claim 7, characterized in that: The specific steps of acid-base granulation in step (4) include: taking the binder according to the formula, adding purified water at a solid-liquid ratio of 1:5~1:10 (g / mL), stirring and dissolving at 60~70℃, cooling to room temperature to prepare a binder solution for later use; putting the mixed acid phase material into a high-speed stirring granulator, stirring at 150~200r / min, slowly spraying 50%~60% binder solution at a spraying speed of 3~5mL / min, stirring and granulating for 3~5min until a uniform soft material is formed, then passing it through a 20-mesh nylon screen and granulating it using a swing granulator to collect the wet acid phase particles; similar to the acid phase granulation process, putting the alkali phase mixture into a granulator, spraying the remaining binder solution, granulating it, and then passing it through a 20-mesh nylon screen to collect the wet alkali phase particles.

9. The method for preparing a monk fruit effervescent tablet according to claim 8, characterized in that: The drying temperature in step (4) is 50~60℃, the wind speed is 0.8~1.2m / s, the drying time is 2~4h, and the moisture content of the dried particles is controlled at 1.5%~3.0%.

10. The method for preparing a monk fruit effervescent tablet according to claim 9, characterized in that: The specific steps of mixing and tableting acid and alkali particles in step (4) include: putting the granulated acid-phase dry particles and alkali-phase dry particles into a three-dimensional motion mixer, adding the formula amount of lubricant, rotating at 15~20 r / min, and mixing for 3~5 min; using a rotary tablet press, adjusting the die size according to the tablet specifications, and continuously tableting to obtain the Luo Han Guo effervescent tablet product.

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