Preparation process of Jiangtangjiao capsule

Abstract

The application relates to the technical field of traditional Chinese medicine, and particularly discloses a preparation process of a Jiangtang Jia capsule, which comprises the following steps: S1, taking part of the radix pseudostellariae, performing cleaning, crushing, wet heat sterilization and cooling to prepare a standby solution; S2, mixing the remaining radix pseudostellariae, radix astragali, rhizoma polygonati nigrum, radix rehmanniae and water, and performing three times of decocting, combining the decocting liquid, filtering the decocting liquid while hot to obtain an extraction liquid; S3, adding ethanol to the extraction liquid in batches to perform two-stage alcohol precipitation, recovering ethanol in the supernatant, and concentrating the supernatant to a thick paste A; S4, performing hot water ultrasonic redissolution, chitosan flocculation, centrifugation, microfiltration and two-stage fractional ultrafiltration on the precipitate obtained in the alcohol precipitation, collecting the second-stage ultrafiltration retentate, and concentrating the second-stage ultrafiltration retentate to obtain a polysaccharide thick paste B; and S5, combining the thick paste A and the thick paste B, adding radix pseudostellariae sterilization powder, uniformly mixing, drying, crushing, mixing with auxiliary materials, filling into enteric-coated capsules, and obtaining the Jiangtang Jia capsule. The extraction liquid is removed and the polysaccharide component is recovered through step-by-step treatment, various active components are retained, the impurity content of the finished product is reduced, and the preparation quality and the medicinal effect are improved.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, specifically to a preparation process for hypoglycemic capsules. Background Technology

[0002] The hypoglycemic formula consists of equal amounts of five medicinal herbs: Astragalus membranaceus, Polygonatum sibiricum, Rehmannia glutinosa, Codonopsis pilosula, and Trichosanthes kirilowii. It has the effects of tonifying the middle energizer and replenishing qi, nourishing yin and promoting body fluid production. Clinically, it is often used to treat diabetes mellitus of the qi and yin deficiency type. It can improve symptoms such as thirst, excessive drinking, fatigue and weakness in patients with type 2 diabetes.

[0003] The preparation method of the hypoglycemic tablets listed in the Chinese Pharmacopoeia is as follows: Take one-fifth of the amount of Codonopsis pilosula and grind it into a fine powder for later use. Take the remaining four-fifths of the amount of Codonopsis pilosula and the other four medicinal materials such as Astragalus membranaceus and decoct them three times with water. The first decoction is for 2 hours, and the second and third decoctions are for 1 hour each. Filter, combine the filtrates and concentrate them. Add ethanol to make the alcohol content 75%. Stir well and let stand for 48 hours. Filter, concentrate the filtrate to a thick paste with a relative density of 1.25~1.30 at 50°C, add the Codonopsis pilosula fine powder and mix well. After drying, grind it into a fine powder, granulate it with 90% ethanol, dry it and compress it into tablets, and coat it with enteric coating to obtain the product.

[0004] The above-described preparation process is relatively simple, employing only a single alcohol precipitation to purify the extract. This method has limited effectiveness in removing a large number of water-soluble impurities from the extract, such as high molecular weight proteins, starch, and tannin complexes, resulting in a significant amount of inactive components mixed into the finished product. Furthermore, this process does not recover and utilize the polysaccharide components precipitated during alcohol precipitation, leading to some loss of polysaccharide components with auxiliary hypoglycemic effects in the formulation. Therefore, there is still room for improvement in the efficacy of the formulation, and the overall preparation process has potential for optimization. Summary of the Invention

[0005] To address the technical deficiencies in the background art, this invention proposes a preparation process for hypoglycemic capsules, which solves the aforementioned technical problems and meets practical needs. The specific technical solution is as follows:

[0006] A preparation process for a hypoglycemic capsule includes the following steps:

[0007] S1. Sterilized Codonopsis pilosula powder: Take a portion of Codonopsis pilosula, clean it, pulverize it, sterilize it with moist heat, and then cool it for later use.

[0008] S2. Water extraction: Take the remaining Codonopsis pilosula, Astragalus membranaceus, Polygonatum sibiricum, Rehmannia glutinosa, and Trichosanthes kirilowii, add water and decoct three times, combine the decoctions, filter while hot to obtain the extract;

[0009] S3. After concentrating the extract under reduced pressure, add ethanol in portions for two-stage alcohol precipitation. Collect the precipitate and supernatant separately, combine the precipitates, recover the ethanol from the supernatant and concentrate it to a thick paste to obtain thick paste A.

[0010] S4. After combining the precipitates obtained by fractional alcohol precipitation, the precipitates are successively re-dissolved by hot water and ultrasonication to form a complex solution. The complex solution is then subjected to chitosan flocculation, centrifugation, microfiltration, and two fractional ultrafiltration treatments. The second ultrafiltration retentate is collected and concentrated to a thick paste to obtain the polysaccharide effective fraction thick paste B.

[0011] S5. Merging and Formulation: Merge paste A and paste B to obtain hypoglycemic capsule extract, add raw Codonopsis pilosula powder and mix evenly, vacuum dry and pulverize to obtain dry extract powder, then mix with excipients and fill into enteric-coated capsules, and package to obtain the final product.

[0012] As a further technical solution of the present invention, in step S1, 120-140 parts of Codonopsis pilosula are taken by weight, cleaned, pulverized to 80 mesh, and sterilized by moist heat at 115-125℃ for 25-35 minutes. After cooling, they are ready for use.

[0013] As a further technical solution of the present invention, in step S2, by weight, 500-540 parts of Codonopsis pilosula, 620-660 parts of Astragalus membranaceus, 620-660 parts of Polygonatum sibiricum, 620-660 parts of Rehmannia glutinosa, and 620-660 parts of Trichosanthes kirilowii are taken for water extraction. The specific conditions for adding water and decocting three times are as follows: the first time, add 8-12 times the amount of water and boil for 1.5-2.5 hours; the second time, add 7-9 times the amount of water and boil for 0.8-1.2 hours; the third time, add 5-7 times the amount of water and boil for 0.8-1.2 hours. After combining the decoctions, filter them while hot through a 200-300 mesh filter cloth.

[0014] As a further technical solution of the present invention, step S3 specifically includes: concentrating the extract under reduced pressure to a concentrate with a relative density of 1.17-1.22 at 60°C; slowly adding 95% ethanol to the concentrate while stirring, adjusting the alcohol content to 45%-55%, letting it stand for 12-24 hours, and centrifuging to collect precipitate I and supernatant I; continuing to add 95% ethanol to supernatant I until the alcohol content is 70%-80%, stirring, and letting it stand for 40-56 hours, and centrifuging to collect precipitate II and supernatant II; combining precipitate I and precipitate II, washing 1-2 times with 70%-80% ethanol, and adding the washings to supernatant II; recovering ethanol from supernatant II under reduced pressure, and continuing to concentrate to a thick paste with a relative density of 1.25-1.30 at 50°C, thus obtaining thick paste A.

[0015] As a further technical solution of the present invention, in step S4, 8-12 times the amount of purified water is added to the combined precipitate I and precipitate II, and ultrasonic treatment is carried out at 50-70℃ and 260-300W power for 30-60 minutes to fully dissolve the polysaccharide.

[0016] As a further technical solution of the present invention, in step S4, the chitosan flocculation method is as follows: adjust the pH of the reconstituted solution to 5-6, slowly add a chitosan solution with a concentration of 0.1%-0.3% at 0.5%-1.0% of the volume of the reconstituted solution, stir for 15-30 minutes, and let it stand for flocculation for 1-2 hours.

[0017] As a further technical solution of the present invention, in step S4, the method of graded ultrafiltration is as follows: first, ultrafiltration is performed through an ultrafiltration membrane of 30000-50000 Da, and the permeate is collected; then, the permeate is ultrafiltered through an ultrafiltration membrane of 5000 Da, and the retentate is collected; the retentate is concentrated under reduced pressure to a thick paste with a relative density of 1.25-1.30 at 50°C, resulting in thick paste B of polysaccharide effective fraction.

[0018] As a further technical solution of the present invention, in step S5, the excipient is corn starch, and the mass ratio of the hypoglycemic capsule extract to corn starch is 220-330:2-5;

[0019] First, combine thick paste A and thick paste B to obtain hypoglycemic capsule extract. Add the sterilized Codonopsis pilosula powder prepared in step S1 and mix evenly. Vacuum dry the mixture at a temperature of 65-75℃ and a vacuum degree of -0.06~-0.08MPa until the moisture content is ≤5%. After pulverizing, pass the extract through an 80-mesh sieve to obtain dry powder. Then, put the dry powder and corn starch into a two-dimensional motion mixer and set the speed to 25-35 rpm. Mix for 30-50 minutes to obtain a total mixture. Finally, fill the total mixture into enteric-coated capsules at a ratio of 0.4-0.5g / capsule to obtain hypoglycemic capsules.

[0020] The beneficial effects of this invention are as follows: The purification method employing a two-stage alcohol precipitation process combining centrifugation and microfiltration can more effectively remove water-soluble impurities such as high molecular weight proteins and tannin complexes from the extract, reducing ineffective components in the finished product. Simultaneously, the process recovers the precipitate formed during alcohol precipitation, and after hot water ultrasonic resolution, chitosan flocculation, and fractional ultrafiltration, enriches the effective polysaccharide fractions with suitable molecular weight ranges, reducing the loss of polysaccharide components with auxiliary hypoglycemic effects during the preparation process to a certain extent. In the process, the fine powder of *Codonopsis pilosula* used in the medicine undergoes moist heat sterilization, and is combined with the recovered polysaccharide thick paste and the concentrated thick paste from the alcohol precipitation supernatant before being filled into enteric-coated capsules. The resulting hypoglycemic capsules retain the original effective components while supplementing polysaccharide components, which is beneficial for improving the hypoglycemic effect. Detailed Implementation

[0021] The embodiments of the present invention will be described below with reference to relevant examples. The embodiments of the present invention are not limited to the following examples, and the present invention relates to relevant necessary components in this technical field, which should be regarded as well-known technology in this technical field and can be known and mastered by those skilled in this technical field.

[0022] A preparation process for a hypoglycemic capsule includes the following steps:

[0023] S1. Sterilized Codonopsis pilosula powder: Take a portion of Codonopsis pilosula, clean it, pulverize it, sterilize it with moist heat, and then cool it for later use.

[0024] S2. Water extraction: Take the remaining Codonopsis pilosula, Astragalus membranaceus, Polygonatum sibiricum, Rehmannia glutinosa, and Trichosanthes kirilowii, add water and decoct three times, combine the decoctions, filter while hot to obtain the extract;

[0025] S3. After concentrating the extract under reduced pressure, add ethanol in portions for two-stage alcohol precipitation. Collect the precipitate and supernatant separately, combine the precipitates, recover the ethanol from the supernatant and concentrate it to a thick paste to obtain thick paste A.

[0026] S4. After combining the precipitates obtained by fractional alcohol precipitation, the precipitates are successively re-dissolved by hot water and ultrasonication to form a complex solution. The complex solution is then subjected to chitosan flocculation, centrifugation, microfiltration, and two fractional ultrafiltration treatments. The second ultrafiltration retentate is collected and concentrated to a thick paste to obtain the polysaccharide effective fraction thick paste B.

[0027] S5. Merging and Formulation: Merge paste A and paste B to obtain hypoglycemic capsule extract, add raw Codonopsis pilosula powder and mix evenly, vacuum dry and pulverize to obtain dry extract powder, then mix with excipients and fill into enteric-coated capsules, and package to obtain the final product.

[0028] This invention achieves further impurity removal and polysaccharide recovery from the extract through stepwise processing, improving the quality and efficacy of the formulation. S1 involves pulverizing and sterilizing a portion of the *Codonopsis pilosula* powder, controlling the microbial level while retaining the inherent components of the raw herb powder to meet the requirements for pharmaceutical use. S2 employs a water extraction process with multi-gradient water addition and decoction time to ensure full extraction of the active ingredients. S3 utilizes a two-stage alcohol precipitation process, which is more effective than single-stage alcohol precipitation in removing water-soluble impurities such as proteins and tannins. The concentrated supernatant yields a thick paste A, retaining small-molecule active ingredients such as flavonoids and saponins. S4 involves resolubilizing, flocculating, and fractionating ultrafiltration of the polysaccharide precipitate obtained from alcohol precipitation. This process retains polysaccharide components within the target molecular weight range, removes large-molecule impurities and small-molecule oligosaccharides, yielding a refined polysaccharide thick paste B, recovering to some extent the polysaccharide components lost in the original process. S5 combines the two thick pastes and mixes them with sterilized *Codonopsis pilosula* powder. After drying, the mixture is combined with excipients and filled into enteric-coated capsules, resulting in more comprehensive retention of active ingredients and better formulation quality stability.

[0029] As one of the preferred embodiments of the present invention, in step S1, 120-140 parts of Codonopsis pilosula are taken by weight, cleaned, pulverized to 80 mesh, and sterilized by moist heat at 115-125℃ for 25-35 minutes. After cooling, they are ready for use.

[0030] Step S1 involves retaining a portion of the Codonopsis pilosula in the form of raw powder, without participating in water decoction or alcohol precipitation. This reduces the loss of components in this part of the herb that are easily removed by alcohol precipitation. The Codonopsis pilosula is pulverized to 80 mesh, resulting in a suitable particle size that allows for more uniform dispersion when mixed with the extract, and also facilitates capsule filling. Moist heat sterilization at 115-125℃ for 25-35 minutes meets the sterilization requirements for the herb powder.

[0031] As one of the preferred embodiments of the present invention, in step S2, by weight, 500-540 parts of Codonopsis pilosula, 620-660 parts of Astragalus membranaceus, 620-660 parts of Polygonatum sibiricum, 620-660 parts of Rehmannia glutinosa, and 620-660 parts of Trichosanthes kirilowii are taken for water extraction. The specific conditions for decoction three times are as follows: the first time, add 8-12 times the amount of water and boil for 1.5-2.5 hours; the second time, add 7-9 times the amount of water and boil for 0.8-1.2 hours; the third time, add 5-7 times the amount of water and boil for 0.8-1.2 hours. After combining the decoctions, filter them while hot through a 200-300 mesh filter cloth.

[0032] In step S2, 500-540 parts of *Pseudostellaria heterophylla* are used for water extraction. Combined with the 120-140 parts of raw *Pseudostellaria heterophylla* powder from step S1, this is kept in roughly equal proportions with 620-660 parts each of *Astragalus membranaceus*, *Polygonatum sibiricum*, *Rehmannia glutinosa*, and *Trichosanthes kirilowii*. The first addition is 8-12 times the amount of water to facilitate the soaking of the herbs and the dissolution of components. The water volume is reduced in the subsequent two additions to 7-9 times and 5-7 times the amount of water, respectively, to ensure sufficient dissolution of the active ingredients while avoiding excessive impurities from prolonged decoction. The combined decoction is then filtered through a 200-300 mesh filter cloth while still hot to remove dregs and coarse particles, preventing some components from leaching out with the filter residue after cooling, resulting in a preliminarily clarified water extract.

[0033] As one of the preferred embodiments of the present invention, step S3 specifically includes: concentrating the extract under reduced pressure to a concentrate with a relative density of 1.17-1.22 at 60°C; slowly adding 95% ethanol to the concentrate while stirring, adjusting the alcohol content to 45%-55%, letting it stand for 12-24 hours, and centrifuging to collect precipitate I and supernatant I; continuing to add 95% ethanol to supernatant I until the alcohol content is 70%-80%, stirring, and letting it stand for 40-56 hours, and centrifuging to collect precipitate II and supernatant II; combining precipitate I and precipitate II, washing 1-2 times with 70%-80% ethanol, and adding the washings to supernatant II; recovering ethanol from supernatant II under reduced pressure, and continuing to concentrate to a thick paste with a relative density of 1.25-1.30 at 50°C, thus obtaining thick paste A.

[0034] In step S3, the extract is first concentrated under reduced pressure to a relative density of 1.17-1.22 at 60°C. To reduce the subsequent ethanol usage, 95% ethanol is slowly added to the concentrate while continuously stirring until the alcohol content reaches 45%-55%. The mixture is then allowed to stand for 12-24 hours. Under this alcohol concentration, high-molecular-weight proteins, tannin complexes, and other water-soluble impurities, as well as some large-molecular-weight polysaccharides, precipitate due to decreased solubility. After centrifugation, precipitate I and supernatant I are obtained. Supernatant I still retains most of the small-molecule active ingredients and some polysaccharides.

[0035] The concentration of the supernatant II after ethanol recovery was achieved using a double-effect concentrator. The secondary concentration control parameters were: first-effect temperature (80±5)℃, second-effect temperature (60±5)℃, first-effect vacuum (-0.04±0.02) MPa, second-effect vacuum (-0.06±0.02) MPa, concentrated to a relative density of 1.25-1.30 (measured at 50℃). The double-effect concentrator utilizes secondary steam from the first-effect to heat the second-effect, reducing energy consumption. Simultaneously, the lower temperature of the second-effect minimizes heat-sensitive component damage. Under the set vacuum, the higher evaporation temperature of the first-effect rapidly removes residual solvents and moisture, while the lower temperature of the second-effect helps maintain the stability of the liquid. The final concentrated extract A, with a relative density within the range of 1.25-1.30 at 50℃ and moderate moisture content, is suitable for mixing with concentrated extract B and sterilized Codonopsis pilosula powder before vacuum drying.

[0036] As one of the preferred embodiments of the present invention, in step S4, 8-12 times the amount of purified water is added to the combined precipitate I and precipitate II, and the mixture is ultrasonically treated at 50-70°C and 260-300W power for 30-60 minutes to fully dissolve the polysaccharide.

[0037] After alcohol precipitation, precipitates I and II have low water content. Adding 8-12 times the volume of purified water provides sufficient solvent to disperse and dissolve the polysaccharides. Heating at 50-70℃ combined with ultrasonic treatment at 260-300W for 30-60 minutes helps to break down the adhesion between precipitate particles, accelerates the release of polysaccharides from the precipitates into the aqueous phase, and reduces polysaccharide degradation that may be caused by prolonged high temperature.

[0038] As one of the preferred embodiments of the present invention, in step S4, the chitosan flocculation method is as follows: adjust the pH of the reconstituted solution to 5-6, slowly add a chitosan solution with a concentration of 0.1%-0.3% at 0.5%-1.0% of the volume of the reconstituted solution, stir for 15-30 minutes, and let it stand for flocculation for 1-2 hours.

[0039] Chitosan, under pH 5-6 conditions, undergoes protonation and becomes positively charged, enabling it to form flocs with impurities such as proteins in the reconstituted solution. Slowly adding a low-concentration chitosan solution and controlling the amount added can prevent localized over-addition that could result in small flocs or polysaccharide encapsulation. Stirring for 15-30 minutes ensures sufficient contact between the chitosan and impurities, followed by standing for 1-2 hours to allow the flocs to grow and settle. This process removes most large-molecule impurities under gentle conditions, minimizing polysaccharide loss. The reconstituted solution is then centrifuged at 10000-15000 rpm for 20-30 minutes, the precipitate is discarded, and the supernatant is filtered through a 0.45 μm microfiltration membrane to remove residual fine particles.

[0040] As one of the preferred embodiments of the present invention, in step S4, the method of graded ultrafiltration is as follows: first, ultrafiltration is performed through a 30000-50000 Da ultrafiltration membrane, and the permeate is collected; then, the permeate is ultrafiltered through a 5000 Da ultrafiltration membrane, and the retentate is collected; the retentate is concentrated under reduced pressure to a thick paste with a relative density of 1.25-1.30 at 50°C, resulting in thick paste B of polysaccharide effective fraction.

[0041] The fractional ultrafiltration process is performed using an ultrafiltration device. First, a 40,000 Da ultrafiltration membrane is used to remove impurities with larger molecular weights, such as protein complexes, from the reconstituted solution, allowing the target polysaccharide to enter the permeate. Then, the permeate is passed through a 5,000 Da ultrafiltration membrane to remove polysaccharide components with molecular weights greater than 5,000 Da, while smaller molecule impurities such as oligosaccharides, monosaccharides, and inorganic salts are discharged with the permeate. This yields the effective polysaccharide fraction with a relatively concentrated molecular weight. Finally, the fraction is concentrated under reduced pressure to a specified relative density for subsequent granulation.

[0042] In one of the preferred embodiments of the present invention, in step S5, the excipient is corn starch, and the mass ratio of the hypoglycemic capsule extract to corn starch is 220-330:2-5;

[0043] First, combine thick paste A and thick paste B to obtain hypoglycemic capsule extract. Add the sterilized Codonopsis pilosula powder prepared in step S1 and mix evenly. Vacuum dry the mixture at a temperature of 65-75℃ and a vacuum degree of -0.06~-0.08MPa until the moisture content is ≤5%. After pulverizing, pass the extract through an 80-mesh sieve to obtain dry powder. Then, put the dry powder and corn starch into a two-dimensional motion mixer and set the speed to 25-35 rpm. Mix for 30-50 minutes to obtain a total mixture. Finally, fill the total mixture into enteric-coated capsules at a ratio of 0.4-0.5g / capsule to obtain hypoglycemic capsules.

[0044] After combining thick extract A and thick extract B, sterilized Codonopsis pilosula powder is added to combine the water-purified portion with the effective components of the raw herb powder and polysaccharides. Vacuum drying at 65-75℃ reduces damage to heat-sensitive components, and moisture content is controlled below 5% to facilitate pulverization and subsequent filling. The amount of corn starch used as an excipient is low, mainly to improve the flowability and uniformity of the dry extract powder. Mixing in a two-dimensional motion mixer at 25-35 rpm for 30-50 minutes ensures uniform material distribution, resulting in a total mixture. The total mixture is then filled into enteric-coated capsules at a ratio of 0.45g / capsule to obtain hypoglycemic capsules.

[0045] The present invention will be further described below through examples and comparative examples.

[0046] Example 1

[0047] S1 Codonopsis pilosula sterilized powder: Take 130 parts of Codonopsis pilosula, clean it, grind it to 80 mesh, sterilize it at 120℃ for 30 minutes, and cool it for later use.

[0048] S2 Water Extraction: 520 parts of Codonopsis pilosula were used for water extraction, combined with 640 parts each of Astragalus membranaceus, Polygonatum sibiricum, Rehmannia glutinosa, and Trichosanthes kirilowii. The mixture was decocted three times: the first time, 10 times the amount of water was added and the mixture was boiled for 2 hours; the second time, 8 times the amount of water was added and the mixture was decocted for 1 hour; the third time, 6 times the amount of water was added and the mixture was decocted for 1 hour. The decoctions were combined and filtered through a 250-mesh filter cloth while hot to obtain the extract.

[0049] S3 Two-stage alcohol precipitation: The extract was concentrated under reduced pressure to a relative density of 1.17 at 60°C; 95% ethanol was slowly added to adjust the alcohol content to 45%, stirred and allowed to stand for 12 hours, and the precipitate I and supernatant I were collected by centrifugation; 95% ethanol was added to supernatant I to a alcohol content of 70%, allowed to stand for 40 hours, and the precipitate II and supernatant II were collected by centrifugation; precipitates I and II were combined and washed once with 70% ethanol, and the washings were added to supernatant II; the ethanol in supernatant II was recovered under reduced pressure and concentrated to a relative density of 1.25 at 50°C to obtain thick paste A.

[0050] S4 Polysaccharide Refining: Add 8 times the volume of purified water to the combined precipitates, and reconstitute by sonication at 50℃ and 260W for 30 min; adjust the pH of the reconstituted solution to 5.0, add 0.1% chitosan solution at a volume ratio of 0.5%, stir for 15 min, and let stand for flocculation for 1 h; centrifuge at 10000 r / min for 20 min, and filter the supernatant through a 0.45 μm microfiltration membrane; ultrafilter the microfiltrate through a 30000 Da ultrafiltration membrane and collect the permeate; ultrafilter the permeate again through a 5000 Da ultrafiltration membrane and collect the retentate; concentrate under reduced pressure to a relative density of 1.25 at 50℃ to obtain thick paste B.

[0051] S5 Formulation: Combine thick paste A and thick paste B, add sterilized Codonopsis pilosula powder and mix well; vacuum dry at 65℃ and -0.06MPa until the moisture content is ≤5%, pulverize through 80 mesh to obtain dry paste powder; put the dry paste powder and corn starch into a two-dimensional mixer at a mass ratio of 220:2, mix at 25r / min for 30min; fill enteric-coated capsules at 0.4g / capsule, and package to obtain the final product.

[0052] Example 2

[0053] S1 Codonopsis pilosula sterilized powder: Take 130 parts of Codonopsis pilosula, clean it, grind it to 80 mesh, sterilize it at 120℃ for 30 minutes, and cool it for later use.

[0054] S2 Water Extraction: 520 parts of Codonopsis pilosula were used for water extraction, combined with 640 parts each of Astragalus membranaceus, Polygonatum sibiricum, Rehmannia glutinosa, and Trichosanthes kirilowii. The mixture was decocted three times: the first time, 10 times the amount of water was added and the mixture was boiled for 2 hours; the second time, 8 times the amount of water was added and the mixture was decocted for 1 hour; the third time, 6 times the amount of water was added and the mixture was decocted for 1 hour. The decoctions were combined and filtered through a 250-mesh filter cloth while hot to obtain the extract.

[0055] S3 Two-stage alcohol precipitation: The extract was concentrated under reduced pressure to a relative density of 1.20 at 60℃; 95% ethanol was slowly added to adjust the alcohol content to 50%, stirred, and allowed to stand for 18 hours. The precipitate I and supernatant I were collected by centrifugation; 95% ethanol was added to supernatant I to bring the alcohol content to 75%, and the mixture was allowed to stand for 48 hours. The precipitate II and supernatant II were collected by centrifugation; precipitates I and II were combined and washed once with 75% ethanol, and the washings were added to supernatant II; supernatant II was concentrated by double-effect concentration to recover ethanol (first effect 80℃, -0.04MPa; second effect 60℃, -0.06MPa), and concentrated to a relative density of 1.28 at 50℃ to obtain thick paste A.

[0056] S4 Polysaccharide Refining: Add 10 times the volume of purified water to the combined precipitates, and sonicate at 60℃ and 280W for 45 min to reconstitute; adjust the pH of the reconstituted solution to 5.5, add 0.2% chitosan solution at a volume ratio of 0.8%, stir for 20 min, and let stand for flocculation for 1.5 h; centrifuge at 12000 r / min for 25 min, and filter the supernatant through a 0.45 μm microfiltration membrane; ultrafilter the microfiltrate through a 40000 Da ultrafiltration membrane and collect the permeate; ultrafilter the permeate again through a 5000 Da ultrafiltration membrane and collect the retentate; concentrate under reduced pressure to a relative density of 1.28 at 50℃ to obtain thick paste B.

[0057] S5 Formulation: Combine thick paste A and thick paste B, add sterilized Codonopsis pilosula powder and mix well; vacuum dry at 70℃ and -0.07MPa until the moisture content is ≤5%, pulverize through 80 mesh to obtain dry paste powder; put the dry paste powder and corn starch into a two-dimensional mixer at a mass ratio of 275:3.5, mix at 30r / min for 40min; fill enteric-coated capsules at 0.45g / capsule, and package to obtain the final product.

[0058] Example 3

[0059] S1 Codonopsis pilosula sterilized powder: Take 130 parts of Codonopsis pilosula, clean it, grind it to 80 mesh, sterilize it at 120℃ for 30 minutes, and cool it for later use.

[0060] S2 Water Extraction: 520 parts of Codonopsis pilosula were used for water extraction, combined with 640 parts each of Astragalus membranaceus, Polygonatum sibiricum, Rehmannia glutinosa, and Trichosanthes kirilowii. The mixture was decocted three times: the first time, 10 times the amount of water was added and the mixture was boiled for 2 hours; the second time, 8 times the amount of water was added and the mixture was decocted for 1 hour; the third time, 6 times the amount of water was added and the mixture was decocted for 1 hour. The decoctions were combined and filtered through a 250-mesh filter cloth while hot to obtain the extract.

[0061] S3 Two-stage alcohol precipitation: The extract was concentrated under reduced pressure to a relative density of 1.22 at 60°C; 95% ethanol was slowly added to adjust the alcohol content to 55%, stirred, and allowed to stand for 24 hours. The precipitate I and supernatant I were collected by centrifugation; 95% ethanol was added to supernatant I to bring the alcohol content to 80%, and the mixture was allowed to stand for 56 hours. The precipitate II and supernatant II were collected by centrifugation; precipitates I and II were combined and washed twice with 80% ethanol, and the washings were added to supernatant II; the ethanol in supernatant II was recovered under reduced pressure and concentrated to a relative density of 1.30 at 50°C to obtain thick paste A.

[0062] S4 Polysaccharide Refining: Add 12 times the volume of purified water to the combined precipitates, and reconstitute by sonication at 70℃ and 300W for 60 min; adjust the pH of the reconstituted solution to 6.0, add 0.3% chitosan solution at a volume ratio of 1.0%, stir for 30 min, and let stand for flocculation for 2 h; centrifuge at 15000 r / min for 30 min, and filter the supernatant through a 0.45 μm microfiltration membrane; ultrafilter the microfiltrate through a 50000 Da ultrafiltration membrane and collect the permeate; ultrafilter the permeate again through a 5000 Da ultrafiltration membrane and collect the retentate; concentrate under reduced pressure to a relative density of 1.30 at 50℃ to obtain thick paste B.

[0063] S5 Formulation: Combine thick paste A and thick paste B, add sterilized Codonopsis pilosula powder and mix well; vacuum dry at 75℃ and -0.08MPa until the moisture content is ≤5%, pulverize through 80 mesh to obtain dry paste powder; put the dry paste powder and corn starch into a two-dimensional mixer at a mass ratio of 330:5, mix at 35r / min for 50min; fill enteric-coated capsules at 0.5g / capsule, and package to obtain the final product.

[0064] Comparative Example 1

[0065] Step S3 is changed to single-stage alcohol precipitation with 50% ethanol concentration. The specific operation is as follows: the extract is concentrated to a relative density of 1.20 at 60℃, 95% ethanol is added to adjust the alcohol content to 50%, stirred and allowed to stand for 48 hours, and the precipitate and supernatant are collected by centrifugation; the precipitate is washed once with 50% ethanol, and the washings are added to the supernatant; the ethanol in the supernatant is recovered and concentrated to thick paste A; the precipitate is directly sent to S4 to prepare thick paste B. The remaining steps and parameters are the same as in Example 2.

[0066] Comparative Example 2

[0067] Step S3 is changed to single-stage alcohol precipitation with 75% ethanol concentration. The specific operation is as follows: the extract is concentrated to a relative density of 1.20 at 60℃, 95% ethanol is added to adjust the alcohol content to 75%, stirred and allowed to stand for 48 hours, and the precipitate and supernatant are collected by centrifugation; the precipitate is washed once with 75% ethanol, and the washings are added to the supernatant; the ethanol in the supernatant is recovered and concentrated to thick paste A; the precipitate is directly sent to S4 to prepare thick paste B. The remaining steps and parameters are the same as in Example 2.

[0068] Comparative Example 3

[0069] Except for the S4 ultrafiltration step, the remaining steps and parameters are the same as in Example 2:

[0070] S4: After flocculation, centrifugation, and microfiltration, the reconstituted solution is directly ultrafiltered through a 40000Da ultrafiltration membrane. The retentate is collected and concentrated under reduced pressure using the retentate from the 40000Da ultrafiltration membrane to prepare viscous paste B, without performing secondary ultrafiltration at 5000Da.

[0071] Comparative Example 4

[0072] Except for the S4 ultrafiltration step, the remaining steps and parameters are the same as in Example 2:

[0073] S4: After flocculation, centrifugation, and microfiltration, the reconstituted solution is first passed through a 40000 Da ultrafiltration membrane to obtain the permeate. The permeate is then ultrafiltered through a 5000 Da ultrafiltration membrane, and the permeate is collected. The permeate from the 5000 Da ultrafiltration membrane is concentrated under reduced pressure to prepare viscous paste B.

[0074] Comparative Example 5

[0075] Except for step S4, which omits the chitosan flocculation step, the remaining steps and parameters are the same as in Example 2:

[0076] S4: After reconstitution of the precipitate, centrifuge and microfilter directly, followed by fractional ultrafiltration to prepare thick paste B.

[0077] Animal experiments and results

[0078] Diabetic mouse model: Several ICR mice were collected, some of which were fed a normal diet and the remaining mice were fed a high-fat diet. After 3 weeks, the mice in the normal diet control group were given an intraperitoneal injection of 100 mg / kg of citrate buffer (pH 4.4), and the mice in the high-fat diet group were given an intraperitoneal injection of STZ solution (100 mg / kg). Continue feeding with the same diet. One week after injection, blood was collected from the tail vein of the mice, and blood glucose was measured using a glucometer. Ten mice fed with normal diet were randomly selected as the control group, and 90 successfully modeled diabetic mice (blood glucose level > 11.1 mmol / L) were randomly selected and divided into 9 groups according to experimental requirements. The contents of the hypoglycemic capsules prepared in Examples 1-3 and Comparative Examples 1-5 were administered orally to mice in groups 1-8 at a dose of 0.5 g / kg / time. Mice in group 9 were administered an equal amount of physiological saline as the model group. The administration was carried out twice a day for 30 consecutive days. During the entire period, the mice were fed with normal diet. The basal blood glucose level of the mice on the first day of administration (day 0) and the changes in blood glucose level of the mice after 30 days of administration were measured. The results are shown in the table below:

[0079]

[0080] Based on the blood glucose results of Examples 1-3 and Comparative Examples 1-5, the blood glucose levels after administration in Examples 1-3 were all lower than those in the comparative examples, with Example 2 showing the largest decrease at 13.12 mmol / L. Compared with the single-stage alcohol precipitation in Comparative Examples 1 and 2, the product obtained by two-stage alcohol precipitation had a more significant hypoglycemic effect, indicating that multi-stage alcohol precipitation is more reasonable than single-stage alcohol precipitation in terms of reducing impurities and retaining active ingredients. Comparative Example 5 did not undergo chitosan flocculation, and its blood glucose level after administration was 13.54 mmol / L, higher than that in Example 2, indicating that this step has a certain effect on improving the purity of the effective polysaccharide fraction, and the efficacy decreased after its removal.

[0081] The results of Comparative Examples 3 and 4 further illustrate the importance of ultrafiltration conditions. Comparative Example 3 collected a 40,000 Da retentate, which did not effectively remove large molecular impurities; Comparative Example 4 collected a 5,000 Da permeate, ensuring that the target polysaccharide was not retained. After administration, the blood glucose levels in both examples were 14.86 mmol / L and 15.72 mmol / L, respectively, both higher than in Example 2. Comparative Example 4 showed the weakest hypoglycemic effect, indicating that the method of first ultrafiltration at 40,000 Da to obtain the permeate, and then ultrafiltration at 5,000 Da to obtain the retentate, is a necessary condition for retaining active polysaccharides.

[0082] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A preparation process for a hypoglycemic capsule, characterized in that, Includes the following steps: S1. Sterilized Codonopsis pilosula powder: Take a portion of Codonopsis pilosula, clean it, pulverize it, sterilize it with moist heat, and then cool it for later use. S2. Water extraction: Take the remaining Codonopsis pilosula, Astragalus membranaceus, Polygonatum sibiricum, Rehmannia glutinosa, and Trichosanthes kirilowii, add water and decoct three times, combine the decoctions, filter while hot to obtain the extract; S3. After concentrating the extract under reduced pressure, add ethanol in portions for two-stage alcohol precipitation. Collect the precipitate and supernatant separately, combine the precipitates, recover the ethanol from the supernatant and concentrate it to a thick paste to obtain thick paste A. S4. After combining the precipitates obtained by fractional alcohol precipitation, the precipitates are successively re-dissolved by hot water and ultrasonication to form a complex solution. The complex solution is then subjected to chitosan flocculation, centrifugation, microfiltration, and two fractional ultrafiltration treatments. The second ultrafiltration retentate is collected and concentrated to a thick paste to obtain the polysaccharide effective fraction thick paste B. S5. Merging and Formulation: Merge paste A and paste B to obtain hypoglycemic capsule extract, add raw Codonopsis pilosula powder and mix evenly, vacuum dry and pulverize to obtain dry extract powder, then mix with excipients and fill into enteric-coated capsules, and package to obtain the final product.

2. The preparation process of the hypoglycemic capsule according to claim 1, characterized in that, In step S1, take 120-140 parts of Codonopsis pilosula by weight, clean it, grind it to 80 mesh, sterilize it with moist heat at 115-125℃ for 25-35 minutes, and then cool it for later use.

3. The preparation process of the hypoglycemic capsule according to claim 1, characterized in that, In step S2, by weight, extract 500-540 parts of Codonopsis pilosula, 620-660 parts of Astragalus membranaceus, 620-660 parts of Polygonatum sibiricum, 620-660 parts of Rehmannia glutinosa, and 620-660 parts of Trichosanthes kirilowii. The specific conditions for decoction three times are as follows: the first time, add 8-12 times the amount of water and boil for 1.5-2.5 hours; the second time, add 7-9 times the amount of water and boil for 0.8-1.2 hours; the third time, add 5-7 times the amount of water and boil for 0.8-1.2 hours. After combining the decoctions, filter them while hot through a 200-300 mesh filter cloth.

4. The preparation process of a hypoglycemic capsule according to claim 1, characterized in that, Step S3 specifically includes: Concentrate the extract under reduced pressure to a concentration of 1.17-1.22 at 60°C. Slowly add 95% ethanol to the concentrate while stirring, adjusting the ethanol content to 45%-55%. Let it stand for 12-24 hours, then centrifuge to collect precipitate I and supernatant I. Continue adding 95% ethanol to supernatant I until the ethanol content reaches 70%-80%, stir, and let it stand for 40-56 hours. Centrifuge to collect precipitate II and supernatant II. Combine precipitate I and precipitate II, wash 1-2 times with 70%-80% ethanol, and add the washings to supernatant II. Recover the ethanol from supernatant II under reduced pressure and continue concentrating to a thick paste with a relative density of 1.25-1.30 at 50°C, thus obtaining thick paste A.

5. The preparation process of a hypoglycemic capsule according to claim 1, characterized in that, In step S4, 8-12 times the amount of purified water is added to the combined precipitate I and precipitate II, and the mixture is ultrasonically treated at 50-70℃ and 260-300W power for 30-60 minutes to fully dissolve the polysaccharides.

6. The preparation process of a hypoglycemic capsule according to claim 1, characterized in that, In step S4, the chitosan flocculation method is as follows: adjust the pH of the reconstituted solution to 5-6, slowly add a chitosan solution with a concentration of 0.1%-0.3% at 0.5%-1.0% of the volume of the reconstituted solution, stir for 15-30 minutes, and let it stand for flocculation for 1-2 hours.

7. The preparation process of a hypoglycemic capsule according to claim 1, characterized in that, In step S4, the method of graded ultrafiltration is as follows: first, ultrafiltration is performed through a 30,000-50,000 Da ultrafiltration membrane, and the permeate is collected; then, the permeate is ultrafiltered through a 5,000 Da ultrafiltration membrane, and the retentate is collected; the retentate is concentrated under reduced pressure to a thick paste with a relative density of 1.25-1.30 at 50°C, resulting in thick paste B of the effective polysaccharide fraction.

8. The preparation process of a hypoglycemic capsule according to claim 1, characterized in that, In step S5, the excipient is corn starch, and the mass ratio of the hypoglycemic capsule extract to corn starch is 220-330:2-5; First, combine thick paste A and thick paste B to obtain hypoglycemic capsule extract. Add the sterilized Codonopsis pilosula powder prepared in step S1 and mix evenly. Vacuum dry the mixture at a temperature of 65-75℃ and a vacuum degree of -0.06~-0.08MPa until the moisture content is ≤5%. After pulverizing, pass the extract through an 80-mesh sieve to obtain dry powder. Then, put the dry powder and corn starch into a two-dimensional motion mixer and set the speed to 25-35 rpm. Mix for 30-50 minutes to obtain a total mixture. Finally, fill the total mixture into enteric-coated capsules at a ratio of 0.4-0.5g / capsule to obtain hypoglycemic capsules.

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