A method for preparing a metformin compound hypoglycemic oral solution

Abstract

This invention provides a method for preparing a metformin compound hypoglycemic oral solution, relating to the pharmaceutical field, comprising: step S1, pretreatment of traditional Chinese medicine components; step S2, enzymatic hydrolysis of the first group of traditional Chinese medicine components; step S3, supercritical extraction; step S4, preparation of mixed traditional Chinese medicines; step S5, preparation of inclusion complex; step S6, compound formulation; and step S7, post-processing. This method synergistically combines extracts from seven traditional Chinese medicines—bitter melon, phellodendron bark, astragalus root, kudzu root, rehmannia root, ginseng, and privet fruit—with metformin hydrochloride to form a metformin compound hypoglycemic oral solution, balancing the synergy, safety, and stability of traditional Chinese and Western medicines, thereby improving hypoglycemic effects while reducing the incidence of gastrointestinal adverse reactions to metformin.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing a metformin compound hypoglycemic oral solution. Background Technology

[0002] Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, accounting for 90%–95% of all diabetes cases. It is a prevalent chronic metabolic disease characterized by insulin resistance and impaired pancreatic β-cell function. Clinical manifestations include elevated blood glucose, excessive thirst, increased appetite, fatigue, and weakness in the lower back and knees. Poor long-term control can easily lead to various complications affecting the cardiovascular system, kidneys, and eyes, severely impacting patients' quality of life. Metformin hydrochloride, a foundational medication for treating type 2 diabetes, lowers blood glucose by inhibiting hepatic gluconeogenesis and gluconeogenesis, increasing peripheral tissue sensitivity to insulin, and reducing intestinal glucose absorption. It does not cause hypoglycemia and has minimal impact on weight, making it the first-line drug recommended by clinical guidelines.

[0003] However, metformin hydrochloride monotherapy has several limitations: First, the incidence of gastrointestinal adverse reactions is high, with up to 30% of patients experiencing symptoms such as nausea, bloating, diarrhea, and stomach discomfort after taking the medication. Some patients discontinue the medication due to intolerance, leading to decreased medication adherence. Second, it is not effective in improving symptoms such as thirst, fatigue, and weakness in the lower back and knees caused by qi and yin deficiency and internal heat in patients with type II diabetes. It can only lower blood sugar and cannot address the overall health of the body. Third, after long-term monotherapy, some patients experience further decline in pancreatic function, leading to fluctuations in blood sugar levels. This necessitates increasing the dosage or combining the medication with other drugs, increasing the risk of adverse reactions. Fourth, although metformin hydrochloride is highly water-soluble, its stability in oral formulations is easily affected by factors such as pH and temperature.

[0004] Traditional Chinese medicine (TCM) has unique advantages in the treatment of diabetes, including multiple targets, multiple pathways, fewer side effects, and comprehensive conditioning. Currently, there are some studies and reports on compound hypoglycemic agents combining TCM and Western medicine. For example, Chinese patent document CN103110815A discloses a TCM composition for treating type II diabetes and its preparation method. It is mainly composed of Astragalus membranaceus, Codonopsis pilosula, Rehmannia glutinosa, Dioscorea opposita, Polygonatum odoratum, Lycium barbarum, Asparagus cochinchinensis, Scrophularia ningpoensis, Ligustrum lucidum, Pueraria lobata, bitter melon powder, Lindera strychnifolia, Morus alba, and Lycium chinense root bark. It can relieve thirst caused by type II diabetes, regulate blood sugar, and treat various complications caused by diabetes, showing significant effects on type II diabetes. However, it does not use metformin hydrochloride in combination, and does not form a compound TCM and Western medicine formula, so its hypoglycemic effect is limited. Chinese patent document CN112641869A discloses a method for preparing a compound medicine for diabetes, which includes Codonopsis pilosula, Astragalus membranaceus, Gypsum, Scutellaria baicalensis, Atractylodes lancea, Lycium chinense root bark, Pueraria lobata, Schisandra chinensis, Salvia miltiorrhiza, Ligusticum chuanxiong, Anemarrhena asphodeloides, Phellodendron chinense, Trichosanthes kirilowii, Rehmannia glutinosa, Os draconis, metformin, and glibenclamide. This combination of drugs, with traditional Chinese medicine as the main raw material, is used to treat diabetic patients, achieving good efficacy and few side effects. However, the formula lacks traditional Chinese medicines that clear heat and nourish yin. Furthermore, the existing compound preparations for traditional Chinese medicine extraction mostly involve simple water decoction, resulting in low retention of effective components and high impurity content. Metformin hydrochloride is also prone to complexation and adsorption with traditional Chinese medicine extracts (metformin hydrochloride is a basic guanidine compound, and some traditional Chinese medicine extracts contain a large amount of organic acids, flavonoids, tannins, etc., and direct mixing of the two easily leads to acid-base complexation and hydrogen bond adsorption), forming insoluble complexes. This not only causes a decrease in the content of metformin hydrochloride during storage but also hinders dissolution in vivo, making it impossible to achieve synergistic effects and even potentially causing component antagonism, thus reducing bioavailability. Summary of the Invention

[0005] To address the problems existing in the prior art, the present invention aims to provide a method for preparing metformin compound hypoglycemic oral solution. This method involves synergistically combining a mixed extract of traditional Chinese medicine decoction pieces with metformin hydrochloride to form a metformin compound hypoglycemic oral solution. This effectively solves the problems of high incidence of gastrointestinal adverse reactions, insufficient improvement of accompanying symptoms, easy fluctuation of blood glucose with long-term use, and inaccurate formulation, low retention rate of active ingredients, and poor stability of existing compound hypoglycemic preparations of traditional Chinese and Western medicine. This method achieves both improved hypoglycemic effect and reduced incidence of gastrointestinal adverse reactions of metformin, taking into account the synergy, safety, and stability of traditional Chinese and Western medicine.

[0006] The objective of this invention is achieved through the following technical solution:

[0007] A method for preparing a metformin compound hypoglycemic oral solution includes: Step S1: Pretreatment of Chinese herbal components: Bitter melon, astragalus, kudzu root, rehmannia root and ginseng were used as the first group of Chinese herbal components (water-soluble heat-sensitive components group), and phellodendron bark and privet fruit were used as the second group of Chinese herbal components (lipid-soluble weakly polar components group), and were pretreated separately. Step S2, Compound enzymatic hydrolysis of the first Chinese herbal medicine group: The first Chinese herbal medicine group is subjected to compound enzymatic hydrolysis using a compound enzyme. After enzymatic hydrolysis, the enzyme is inactivated by instantaneous inactivation, solid-liquid separation, ultrafiltration to remove impurities and vacuum concentration to obtain the first concentrate. Step S3, Supercritical Extraction: First, mix the residue of the first Chinese herbal medicine group after enzymatic hydrolysis in step S2 with the second Chinese herbal medicine group after pretreatment in step S1, and then perform supercritical gradient extraction to obtain the second concentrate. Step S4, Preparation of Traditional Chinese Medicine Mixture: First, mix the first concentrate and the second concentrate, then add them dropwise to an mPEG-PLGA (methoxy polyethylene glycol-poly(D,L-lactic acid-co-hydroxyacetic acid) copolymer) organic solution, then magnetically stir with purified water and filter through a filter membrane to obtain a solution of active ingredients of traditional Chinese medicine. Step S5, Inclusion Complex Preparation: First, prepare the inclusion system base solution, then add metformin hydrochloride aqueous solution dropwise to the inclusion system base solution, and carry out the inclusion reaction, cold storage and standing, and filter membrane filtration in sequence to obtain the metformin hydrochloride supramolecular inclusion complex solution. Step S6, Compound Preparation: First, mix the solution of active ingredients of traditional Chinese medicine in step S4 with the supramolecular inclusion complex solution of metformin hydrochloride in step S5, then add the excipients in sequence, adjust the pH to 5.0-5.5, make up the volume and homogenize to obtain the compound solution. Step S7, Post-processing: The compound drug solution is sequentially filtered, sterilized, and filled to obtain metformin compound hypoglycemic oral solution.

[0008] Based on further optimization of the above scheme, in the first group of traditional Chinese medicine, the dosages of bitter melon, astragalus, kudzu root, rehmannia root, and ginseng are 10-20g, 15-30g, 10-20g, 8-16g, and 3-8g, respectively; in the second group of traditional Chinese medicine, the dosages of phellodendron bark and privet fruit are 6-12g and 6-15g, respectively.

[0009] Based on further optimization of the above scheme, the pretreatment in step S1 is as follows: For the first group of Chinese medicines, the impurities and non-medicinal parts are removed by cleaning, and after crushing, the mixture is passed through a 30-40 mesh sieve. The material passing through the sieve is collected and sealed for later use. For the second group of Chinese medicines, after cleaning, the Phellodendron bark is crushed to 40 mesh and soaked in a 0.5% sodium carbonate solution for 28-32 minutes. The ratio of Phellodendron bark to sodium carbonate solution is 1:1.4-1.6. After soaking, the mixture is dried at 38-42℃ (dried until the moisture content is no more than 8%) and evenly mixed with the Ligustrum lucidum that has passed through a 40 mesh sieve. The mixture is then sealed for later use.

[0010] Based on further optimization of the above scheme, in step S2, the compound enzyme is a pharmaceutical-grade single enzyme, including cellulase, hemicellulase, pectinase and neutral protease, with proportions of 34%–36%, 19%–21%, 24%–26% and 19%–21%, respectively. Among them, the enzyme activity of cellulase is 10,000 U / g, the enzyme activity of hemicellulase is 8,000 U / g, the enzyme activity of pectinase is 15,000 U / g and the enzyme activity of neutral protease is 50,000 U / g. The specific steps of the compound enzymatic hydrolysis are as follows: The pretreated first herbal medicine group is placed in a sealed enzymatic hydrolysis vessel, and then 10 times the volume of purified water is added. The mixture is stirred at 95–105 rpm for 5–10 minutes. The pH is then adjusted to 4.8 ± 0.2 using a citrate-sodium citrate buffer solution (the citrate-sodium citrate buffer solution is prepared by mixing citrate monohydrate, sodium citrate dihydrate, and purified water, with a mass ratio of 21.01 g:29.41 g, and then brought to a final volume of 1000 mL with purified water). Next, 1% of the dry weight of the first herbal medicine group of the compound enzyme is added. The mixture is kept at a constant temperature of 43–47°C and a stirring speed of 95–105 rpm for 2.3–2.7 hours to complete the enzymatic hydrolysis (the pH of the calibration system is monitored every 30 minutes during the hydrolysis process to ensure that the fluctuation range does not exceed 4.6–5.0).

[0011] Based on further optimization of the above scheme, in step S2, the instantaneous enzyme inactivation specifically involves: immediately after enzymatic hydrolysis, using a tubular instantaneous high-temperature inactivation method at 84–86℃ for 9–11 seconds, followed by rapid cooling to 23–27℃ within 10 minutes after enzyme inactivation; the solid-liquid separation specifically involves: the enzyme hydrolysate after enzyme inactivation is first coarsely filtered through a 100-mesh stainless steel filter (to remove coarse particles of the drug residue), and then cross-flow filtered through a 0.8μm ceramic membrane (to remove small drug residues and insoluble impurities), and the clear filtrate is collected; the ultrafiltration removal specifically involves: the clear filtrate is filtered through a 5000D ultrafiltration system. Ultrafiltration using a spiral wound ultrafiltration membrane with molecular weight cutoff is performed at a pressure of 0.11–0.13 MPa and a temperature of 23–27 °C (to remove ineffective large molecular impurities such as tannins, resins, and mucilage that easily cause precipitation), yielding a purified enzymatic hydrolysate. The purified enzymatic hydrolysate is then transferred to a falling film vacuum concentration tank and concentrated under reduced pressure at a temperature of 58–62 °C and a vacuum of -0.08–-0.10 MPa (concentrated to a dry extract content of 18% (w / v)), yielding the first concentrate. This concentrate is then naturally cooled to 23–27 °C and sealed for later use.

[0012] Based on further optimization of the above scheme, in step S3, the supercritical gradient extraction specifically involves: adding the mixture of the first herbal residue after enzymatic hydrolysis and the second herbal pretreatment group into a supercritical CO2 extraction vessel, compacting and sealing it, using pharmaceutical-grade anhydrous ethanol as an entrainer, and sequentially performing the first and second stage extractions, then combining the two stage extracts; then transferring the combined extract into a vacuum concentration tank, and concentrating it under reduced pressure at a temperature of 38–42°C and a vacuum degree of -0.07–-0.09 MPa (recovering anhydrous ethanol and concentrating until no alcohol odor is detected); then adding PEG400 and stirring to dissolve it, with a PEG400 to Phellodendron bark mass ratio of 0.1:3, to obtain the second concentrate, which is then naturally cooled to 23–27°C and sealed for later use.

[0013] The first stage of extraction is as follows: at 38–42℃, the pressure of the extraction vessel is adjusted to 19.5–20.5 MPa, the CO2 flow rate is 19.5–20.5 L / h (CO2 purity ≥99.9%), the entrainer is 5% of the CO2 volume, and extraction is carried out at constant temperature and pressure for 58–62 min. The pressure of the separation vessel is 5.5–6.5 MPa, and the temperature is 33–37℃. The first stage extract is then collected. The second stage of extraction is as follows: at 38–42℃, the pressure of the extraction vessel is adjusted to 29.5–30.5 MPa, the CO2 flow rate is 19.5–20.5 L / h (CO2 purity ≥99.9%), the entrainer is 10% of the CO2 volume, and extraction is carried out at constant temperature and pressure for 88–92 min. The pressure of the separation vessel is 5.5–6.5 MPa, and the temperature is 33–37℃. The second stage extract is then collected.

[0014] Based on further optimization of the above scheme, step S4 specifically involves: first, mixing the first concentrate and the second concentrate at 23–27°C and a speed of 180–220 rpm for 15–20 min to obtain a premix; then, adding the premix dropwise to the mPEG-PLGA organic solution at a rate of 0.3–0.5 mL / min and stirring at a speed of 230–270 rpm for 28–32 min to form a homogeneous and transparent organic phase for later use. The total weight of mPEG-PLGA and the traditional Chinese medicine (i.e., the total weight of the first and second traditional Chinese medicine groups) is used as a reference. The mass ratio of the purified water to the organic phase was 6:43. Then, the container containing purified water was placed on a magnetic stirrer and stirred at a constant speed of 380–420 rpm. The mass ratio of purified water to organic phase was 1:3.8–4. The organic phase was added dropwise to the purified water at a rate of 0.45–0.55 mL / min, all in the dark, at a constant temperature of 23–27°C. After the addition was complete, stirring was continued for 3.8–4.2 h. After stirring, the solution was filtered through a 0.22 μm microporous membrane (to remove unencapsulated free components and large particle aggregates) to obtain a solution of the active ingredients of the traditional Chinese medicine for later use.

[0015] Specifically, the mPEG-PLGA organic solution is prepared by adding mPEG-PLGA to anhydrous ethanol and stirring at 230-270 rpm for 30-40 minutes at 28-32°C, resulting in a concentration of 0.2-0.3 g / mL. mPEG-PLGA is a pharmaceutical-grade biodegradable amphiphilic block copolymer approved by the FDA and China NMPA for oral / injectable formulations. It comprises a hydrophilic block mPEG (methoxy-terminated polyethylene glycol) and a hydrophobic block PLGA (polylactic acid-glycolic acid copolymer). In this invention, the molecular weight of mPEG is 5 kDa, the molecular weight of PLGA is 10 kDa (LA / GA monomer ratio is 50:50), and the total molecular weight is 15 kDa.

[0016] Based on further optimization of the above scheme, the specific preparation method of the inclusion system base liquid in step S5 is as follows: First, add hydroxypropyl-β-cyclodextrin to purified water and stir at 200-250 rpm for 20-30 min at 48-52℃ to obtain a saturated aqueous solution; then add chitosan oligosaccharide and stir at 180-220 rpm for 28-32 min, adjust the pH to 5-5.4, and keep warm at 48-52℃ for later use; wherein, the mass-volume ratio of hydroxypropyl-β-cyclodextrin, chitosan oligosaccharide and purified water is 12g:1g:60-62mL.

[0017] Based on further optimization of the above scheme, in step S5, the inclusion reaction is specifically as follows: First, an aqueous solution of metformin hydrochloride with a mass-volume concentration of 8%–10% (w / v) is added dropwise to the inclusion system base solution at a rate of 3.5–4 mL / min, while stirring at a speed of 280–320 rpm. The volume ratio of the metformin hydrochloride aqueous solution to the inclusion system base solution is 1:3. After the addition is completed, the mixture is stirred continuously at 280–320 rpm at 48–52°C for 1.8–2.2 h. After the reaction is completed, the temperature is rapidly reduced to 23–27°C, and then refrigerated at 3.5–4.5°C for 11–13 h to obtain the inclusion solution. Then, the refrigerated inclusion solution is filtered through a 0.45 μm microporous membrane (to remove unencapsulated free drug and excipients) to obtain a metformin hydrochloride supramolecular inclusion complex solution.

[0018] Based on further optimization of the above scheme, step S6 specifically involves: First, under constant temperature of 23–27°C and stirring speed of 230–270 rpm, adding metformin hydrochloride supramolecular inclusion complex solution to purified water and stirring for 13–17 minutes; then adding the traditional Chinese medicine active ingredient solution and continuing to stir for 23–27 minutes, with the amounts of metformin hydrochloride supramolecular inclusion complex solution, traditional Chinese medicine active ingredient solution, and purified water being 400 mL, 200 mL, and 300 mL respectively, to obtain the initial compound preparation solution; subsequently, adding preservatives and sweeteners to the initial compound preparation solution sequentially, with each addition of one type of preservative... After stirring and dissolving the ingredients for 5 minutes, add the next ingredient. After adding the first ingredient, the preservative concentration should be 0.1%–0.3% (w / v) and the sweetener concentration should be 5%–10% (w / v). Stir until all excipients are completely dissolved, then adjust the pH of the system to 5–5.5 using sodium citrate or citric acid. Next, add purified water to make up to 1000 mL and stir at 230–270 rpm for 13–17 minutes to ensure homogeneity of the solution. Finally, homogenize at a low speed of 950–1050 rpm for 4–6 minutes (to eliminate microbubbles) to obtain the compound solution.

[0019] The preservative is either ethylparaben or potassium sorbate (ethylparaben is preferred because it has a broad antibacterial spectrum and good compatibility with other ingredients); the sweetener is either xylitol or steviol glycosides (both are sugar-free sweeteners that do not raise blood sugar).

[0020] Based on further optimization of the above scheme, in step S7, the fine filtration specifically involves: first, pre-filtration of the compound drug solution through a 0.45μm microporous membrane (to remove small particulate impurities), and then fine filtration through a 0.22μm polyethersulfone (PES) microporous membrane at a filtration pressure of 0.11–0.13 MPa and a flow rate of 5.5–6.5 L / min (to remove microorganisms and pyrogens). The clarified drug solution after fine filtration is collected and transferred to an aseptic sterilization tank. The sterilization specifically involves: sterilizing the clarified drug solution after fine filtration at a low temperature using flowing steam at 95–105℃ for 9–11 minutes, while controlling the pressure inside the tank at 0 during the sterilization process. The pressure is 0.1-0.12 MPa (to avoid damage to supramolecular inclusion complexes and micelle structures due to high temperature and high pressure). After sterilization, the temperature is gradually reduced to 23-27℃ (to avoid sudden cooling that could cause turbidity of the drug solution and damage to the nanostructure). The filling process is as follows: In a Class A laminar flow aseptic filling production line under the background of a Class C clean area, the sterilized drug solution is filled into 10ml brown oral liquid bottles (the oral liquid bottles and rubber stoppers are sterilized in advance and pretreated by moist heat sterilization at 121℃ for 30min). The filling accuracy is controlled at ±0.1ml. Immediately after filling, the stoppers (pharmaceutical butyl rubber stoppers, which are sterilized in advance) are pressed and capped (aluminum-plastic combination caps) to ensure a tight seal and no leakage.

[0021] The following are the technical effects of this solution: This invention provides a precisely formulated oral liquid combining traditional Chinese and Western medicines, achieving a synergistic effect between seven traditional Chinese medicines and metformin hydrochloride. The combination of seven traditional Chinese medicines—bitter melon, phellodendron bark, astragalus root, kudzu root, rehmannia root, ginseng, and privet fruit—with metformin hydrochloride achieves complementary mechanisms of action: metformin hydrochloride directly inhibits hepatic glycogen output and enhances insulin sensitivity, while the traditional Chinese medicines regulate glucose metabolism at multiple targets (improving insulin resistance, protecting pancreatic β-cells, and promoting glucose utilization), resulting in a more stable hypoglycemic effect without the risk of hypoglycemia. Simultaneously, the traditional Chinese medicine components can neutralize the gastrointestinal irritation caused by metformin; astragalus strengthens the spleen and stomach, ginseng invigorates qi and strengthens the spleen, and rehmannia nourishes yin and the stomach, alleviating gastrointestinal mucosal irritation caused by metformin, significantly improving patient medication adherence.

[0022] In the extraction of traditional Chinese medicine (TCM), this invention combines enzymatic hydrolysis with supercritical CO2 extraction. This not only improves the dissolution and retention of water-soluble, heat-sensitive components in TCM, but also solves the problem of low water extraction rates for fat-soluble components. It enhances the extraction rate of key active ingredients while avoiding the destruction of effective components by high temperatures. Through the targeted decomposition of plant cell wall barriers by enzymatic hydrolysis, it prevents the large-scale dissolution of ineffective macromolecular impurities such as mucilage, tannins, and resins. Combined with the selective extraction of supercritical CO2, it effectively removes impurities such as tannins and large organic acid molecules that form acid-base complexes with metformin. This prevents direct mixing of TCM extracts and metformin hydrochloride, which can lead to acid-base complexes, hydrogen bond adsorption, and the formation of poorly soluble complexes (which not only reduce the content of metformin hydrochloride during storage but also hinder dissolution in vivo, reducing bioavailability). This improves the storage stability and in vivo bioavailability of the combined TCM and Western medicine. Meanwhile, by copolymerizing the effective components of traditional Chinese medicine with mPEG-PLGA, the water-soluble and fat-soluble active ingredients of traditional Chinese medicine are encapsulated in micelles, thereby resisting gastrointestinal enzyme degradation and the first-pass effect of the liver, significantly improving bioavailability. At the same time, it can achieve synchronous release in the small intestine with the subsequent metformin inclusion complex, synergistically enhancing the effect. Furthermore, a complex supramolecular inclusion system was constructed using hydroxypropyl-β-cyclodextrin, chitosan oligosaccharide, and metformin hydrochloride to selectively include metformin hydrochloride at specific sites. This not only completely blocked the complexation reaction between metformin hydrochloride and the traditional Chinese medicine components (the inclusion system completely embeds metformin into the hydrophobic cavity of hydroxypropyl-β-cyclodextrin, while chitosan oligosaccharide forms a stable protective layer on the outside, achieving dual protection of physical isolation and chemical shielding), but also significantly reduced gastrointestinal adverse reactions and improved patient compliance (the hydroxypropyl-β-cyclodextrin cavity is structurally stable in the gastric juice environment at pH 1.2–3.0 and does not release the drug; upon entering the weakly alkaline environment of the small intestine at pH 6.5–7.5, the inclusion complex rapidly dissociates, releasing metformin at specific sites). Moreover, the inclusion system can significantly improve the formulation stability of metformin hydrochloride and extend the product's shelf life.

[0023] The metformin compound hypoglycemic oral solution prepared by this invention has a scientific formulation, significant synergistic hypoglycemic effect, few side effects, good stability, and suitable taste, meeting the needs of clinical medication and having important clinical, social, and market value. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly described below. Obviously, the described embodiments are some embodiments of the present invention, but not all embodiments.

[0025] Example 1: A method for preparing a metformin compound hypoglycemic oral solution includes: Step S1: Pretreatment of Chinese herbal ingredients: Bitter melon, astragalus, kudzu root, rehmannia root, and ginseng were designated as the first group of Chinese herbal ingredients (water-soluble heat-sensitive ingredients group), and phellodendron bark and privet fruit were designated as the second group of Chinese herbal ingredients (lipid-soluble weakly polar ingredients group). In the first group of Chinese herbal ingredients, the dosages of bitter melon, astragalus, kudzu root, rehmannia root, and ginseng were 10g, 15g, 10g, 8g, and 3g, respectively; in the second group of Chinese herbal ingredients, the dosages of phellodendron bark and privet fruit were 6g and 6g, respectively.

[0026] Pretreatment was carried out separately: For the first group of Chinese herbal medicines, impurities and non-medicinal parts were removed by cleaning, pulverizing, and passing through a 30-mesh sieve. The sieve-passing material was collected and sealed for later use. For the second group of Chinese herbal medicines, after cleaning, the Phellodendron bark was pulverized to 40 mesh and soaked in a 0.5% sodium carbonate solution for 28 minutes. The ratio of Phellodendron bark to sodium carbonate solution was 1:1.4. After soaking, it was dried at 38℃ (dried until the moisture content was no more than 8%) and evenly mixed with Ligustrum lucidum that had passed through a 40-mesh sieve. The mixture was then sealed for later use.

[0027] Step S2, Compound Enzymatic Hydrolysis of the First Traditional Chinese Medicine Group: The first traditional Chinese medicine group is subjected to compound enzymatic hydrolysis using a compound enzyme. The compound enzyme is a combination of pharmaceutical-grade single enzymes, including cellulase, hemicellulase, pectinase and neutral protease, with proportions of 34%, 21%, 24% and 21%, respectively. Among them, the enzyme activity of cellulase is 10000 U / g, the enzyme activity of hemicellulase is 8000 U / g, the enzyme activity of pectinase is 15000 U / g, and the enzyme activity of neutral protease is 50000 U / g. The specific steps of the compound enzymatic hydrolysis are as follows: The pretreated first herbal medicine group is placed in a sealed enzymatic hydrolysis vessel, and then 10 times the volume of purified water is added. The mixture is stirred at 95 rpm for 10 minutes. The pH is then adjusted to 4.8 ± 0.2 using a citrate-sodium citrate buffer solution (the citrate-sodium citrate buffer solution is prepared by mixing citrate monohydrate, sodium citrate dihydrate, and purified water, with a mass ratio of 21.01 g: 29.41 g, and then brought to a final volume of 1000 mL with purified water). Next, 1% of the dry weight of the first herbal medicine group (i.e., 0.46 g) of the compound enzyme is added. The mixture is kept at a constant temperature of 43℃ and 95 rpm for 2.7 hours to complete the enzymatic hydrolysis (the pH of the calibration system is monitored every 30 minutes during the hydrolysis process to ensure that the fluctuation range does not exceed 4.6–5.0).

[0028] After enzymatic hydrolysis, the solution underwent instantaneous enzyme inactivation, solid-liquid separation, ultrafiltration for impurity removal, and vacuum concentration to obtain the first concentrate. Instantaneous enzyme inactivation specifically involved immediately inactivating the enzyme at 84℃ for 11 seconds using a tubular instantaneous high-temperature filter after hydrolysis, followed by rapid cooling to 23℃ within 10 minutes. Solid-liquid separation involved first coarse filtration through a 100-mesh stainless steel filter (to remove coarse particles of the residue), then cross-flow filtration through a 0.8μm ceramic membrane (to remove small residues and insoluble impurities), collecting the clear filtrate. Ultrafiltration for impurity removal involved… The clarified filtrate was ultrafiltered through a spiral wound ultrafiltration membrane with a molecular weight cutoff of 5000 Da at a pressure of 0.11 MPa and a temperature of 23°C (to remove ineffective large molecular impurities such as tannins, resins, and mucilage that easily cause precipitation), to obtain a purified enzymatic hydrolysate. The vacuum concentration was carried out by transferring the purified enzymatic hydrolysate to a falling film vacuum concentration tank and concentrating it under vacuum at a temperature of 58°C and a vacuum degree of -0.08 MPa (concentrated to a dry extract content of 18% (w / v)) to obtain the first concentrate, which was then naturally cooled to 23°C and sealed for later use.

[0029] Step S3, Supercritical Extraction: First, mix the residue of the first herbal medicine group after enzymatic hydrolysis in Step S2 with the second herbal medicine group after pretreatment in Step S1, and then perform supercritical gradient extraction. That is, put the mixture of the first herbal medicine group residue after enzymatic hydrolysis and the second herbal medicine group after pretreatment into a supercritical CO2 extraction vessel, compact and seal it, and use pharmaceutical-grade anhydrous ethanol as an entrainer. Perform the first stage extraction and the second stage extraction sequentially, and combine the extracts from both stages. Specifically, the first stage extraction is performed at 38℃, adjusting the pressure of the extraction vessel to 19.5 MPa and the CO2 flow rate to 19.5 L / min. The first stage of extraction is as follows: at 38°C, the extraction vessel pressure is adjusted to 29.5 MPa, the CO2 flow rate is 19.5 L / h (CO2 purity ≥ 99.9%), the entrainer is used at 10% of the CO2 volume, the extraction is carried out at constant temperature and pressure for 92 minutes, the separation vessel pressure is 5.5 MPa, and the temperature is 33°C. The second stage of extraction is as follows: at 38°C, the extraction vessel pressure is adjusted to 29.5 MPa, the CO2 flow rate is 19.5 L / h (CO2 purity ≥ 99.9%), the entrainer is used at 10% of the CO2 volume, the extraction is carried out at constant temperature and pressure for 92 minutes, the separation vessel pressure is 5.5 MPa, and the temperature is 33°C. The second stage of extraction is collected.

[0030] The combined extracts were then transferred to a vacuum concentration tank and concentrated under reduced pressure at 38°C and -0.07 MPa (to recover anhydrous ethanol and concentrate until no alcohol odor was detected). PEG400 was then added and stirred to dissolve the extract. The mass ratio of PEG400 to Phellodendron bark was 0.1:3. The second concentrate was obtained and naturally cooled to 23°C before being sealed for later use.

[0031] Step S4, Preparation of Traditional Chinese Medicine Mixture: First, mix the first concentrate and the second concentrate at 23°C and 180 rpm for 20 min to obtain a premix; then, add the premix dropwise to an mPEG-PLGA (methoxy polyethylene glycol-poly(D,L-lactic acid-co-hydroxyacetic acid) copolymer) organic solution at a rate of 0.3 mL / min, and stir at 230 rpm for 32 min to form a homogeneous and transparent organic phase for later use. The mass ratio of mPEG-PLGA (i.e., the mPEG-PLGA content in the organic solution) to the total weight of the traditional Chinese medicine (i.e., the total weight of the first and second traditional Chinese medicine groups) is 6:43; wherein, the mPEG-PLGA organic solution is specifically prepared by: mixing mPEG-PLGA... GA was added to anhydrous ethanol and stirred at 230 rpm for 40 min at 28°C to obtain mPEG-PLGA with a concentration of 0.2 g / mL (i.e., the mass-to-volume ratio of mPEG-PLGA to anhydrous ethanol is 2 g: 10 mL). mPEG-PLGA is a pharmaceutical-grade biodegradable amphiphilic block copolymer approved by the FDA and China NMPA for oral / injectable formulations. It includes the hydrophilic block mPEG (methoxy-terminated polyethylene glycol) and the hydrophobic block PLGA (polylactic acid-glycolic acid copolymer). In this invention, the molecular weight of mPEG is 5 kDa, the molecular weight of PLGA is 10 kDa (LA / GA monomer ratio is 50:50), and the total molecular weight is 15 kDa.

[0032] Next, the container containing purified water was placed on a magnetic stirrer and stirred at a constant speed of 380 rpm. The mass ratio of purified water to organic phase was 1:3.8. The organic phase was added dropwise to the purified water at a rate of 0.45 mL / min. The entire process was carried out in the dark and at a constant temperature of 23°C. After the addition was completed, the mixture was stirred continuously for 4.2 h. After stirring, the mixture was filtered through a 0.22 μm microporous membrane (to remove unencapsulated free components and large particle aggregates) to obtain a solution of the active ingredients of traditional Chinese medicine for later use.

[0033] Step S5, Inclusion Complex Preparation: First, prepare the inclusion system base solution. Specifically, add hydroxypropyl-β-cyclodextrin to purified water and stir at 200 rpm for 30 min at 48°C to obtain a saturated aqueous solution. Then add chitosan oligosaccharide and stir at 180 rpm for 32 min. Adjust the pH to 5 and keep warm at 48°C for later use. The mass-volume ratio of hydroxypropyl-β-cyclodextrin, chitosan oligosaccharide, and purified water is 12 g: 1 g: 60 mL.

[0034] First, an 8% (w / v) metformin hydrochloride aqueous solution (i.e., the mass-to-volume ratio of metformin hydrochloride to purified water) was added dropwise to the inclusion system base solution at 48℃ at a rate of 3.5 mL / min, while stirring at 280 rpm. The volume ratio of metformin hydrochloride aqueous solution to the inclusion system base solution was 1:3 (i.e., the volumes used were 100 mL and 300 mL, respectively). After the addition was completed, the mixture was stirred continuously at 280 rpm for 2.2 h at 48℃. After the reaction was completed, the temperature was rapidly reduced to 23℃, and then refrigerated at 3.5℃ for 13 h to obtain the inclusion solution. Then, the refrigerated inclusion solution was filtered through a 0.45 μm microporous membrane (to remove unencapsulated free drug and excipients) to obtain the metformin hydrochloride supramolecular inclusion complex solution.

[0035] Step S6, Compound Preparation: First, under constant temperature of 23℃ and stirring speed of 230 rpm, add metformin hydrochloride supramolecular inclusion complex solution to purified water and stir for 17 min; then add the traditional Chinese medicine active ingredient solution and continue stirring for 27 min. The volumes of metformin hydrochloride supramolecular inclusion complex solution, traditional Chinese medicine active ingredient solution, and purified water are 400 mL, 200 mL, and 300 mL, respectively, to obtain the initial compound preparation solution; then, add ethylparaben and xylitol excipients sequentially to the initial compound preparation solution, stirring and dissolving for 5 min after each addition before adding the next. After addition, the mass-volume concentration of ethylparaben is 0.1% (w / v) and the mass-volume concentration of xylitol is 5%. (w / v); after stirring until all excipients are completely dissolved, adjust the pH of the system to 5 using sodium citrate or citric acid; then, add purified water to make up to 1000 mL, and stir at 230 rpm for 17 min to make the solution homogeneous; finally, homogenize at 950 rpm for 6 min (to eliminate microbubbles) to obtain the compound solution.

[0036] Step S7, Post-processing: The compound drug solution is sequentially subjected to fine filtration, sterilization, and filling to obtain metformin compound hypoglycemic oral solution. The fine filtration specifically involves: first, pre-filtration of the compound drug solution through a 0.45μm microporous membrane (to remove small particulate impurities), followed by fine filtration through a 0.22μm polyethersulfone (PES) microporous membrane at a filtration pressure of 0.11MPa and a flow rate of 5.5L / min (to remove microorganisms and pyrogens). The clarified drug solution after fine filtration is collected and transferred to a sterile sterilization tank. The sterilization specifically involves: sterilizing the clarified drug solution after fine filtration with flowing steam at 95℃ for 11 minutes. During the sterilization process, the contents of the tank are sterilized. The pressure is controlled at 0.1 MPa (to avoid damage to the supramolecular inclusion complex and micelle structure due to high temperature and high pressure). After sterilization, the temperature is gradually reduced to 23-27℃ (to avoid sudden cooling that could cause turbidity of the drug solution and damage to the nanostructure). The filling process is as follows: In a Class A laminar flow aseptic filling production line under the background of a Class C clean area, the sterilized drug solution is filled into 10ml brown oral liquid bottles (the oral liquid bottles and rubber stoppers are sterilized in advance and pretreated by moist heat sterilization at 121℃ for 30min). The filling accuracy is controlled at ±0.1ml. Immediately after filling, the stoppers (pharmaceutical butyl rubber stoppers, which are sterilized in advance) are pressed and capped (aluminum-plastic combination caps) to ensure a tight seal and no leakage.

[0037] Example 2: A method for preparing a metformin compound hypoglycemic oral solution includes: Step S1: Pretreatment of Chinese herbal ingredients: Bitter melon, astragalus, kudzu root, rehmannia root, and ginseng were designated as the first group of Chinese herbal ingredients (water-soluble heat-sensitive ingredients group), and phellodendron bark and privet fruit were designated as the second group of Chinese herbal ingredients (lipid-soluble weakly polar ingredients group). In the first group of Chinese herbal ingredients, the dosages of bitter melon, astragalus, kudzu root, rehmannia root, and ginseng were 15g, 20g, 15g, 12g, and 5g, respectively; in the second group of Chinese herbal ingredients, the dosages of phellodendron bark and privet fruit were 9g and 10g, respectively.

[0038] Pretreatment was carried out separately: For the first group of Chinese herbal medicines, impurities and non-medicinal parts were removed by cleaning, pulverizing, and passing through a 35-mesh sieve. The sieve-passing material was collected and sealed for later use. For the second group of Chinese herbal medicines, after cleaning, the Phellodendron bark was pulverized to 40 mesh and soaked in a 0.5% sodium carbonate solution for 30 minutes. The ratio of Phellodendron bark to sodium carbonate solution was 1:1.5. After soaking, it was dried at 40℃ (dried until the moisture content was no more than 8%) and evenly mixed with the Ligustrum lucidum that had passed through a 40-mesh sieve. The mixture was then sealed for later use.

[0039] Step S2, Compound Enzymatic Hydrolysis of the First Traditional Chinese Medicine Group: The first traditional Chinese medicine group is subjected to compound enzymatic hydrolysis using a compound enzyme. The compound enzyme is a combination of pharmaceutical-grade single enzymes, including cellulase, hemicellulase, pectinase and neutral protease, with proportions of 35%, 20%, 25% and 20%, respectively. Among them, the enzyme activity of cellulase is 10000 U / g, the enzyme activity of hemicellulase is 8000 U / g, the enzyme activity of pectinase is 15000 U / g, and the enzyme activity of neutral protease is 50000 U / g. The specific steps of the compound enzymatic hydrolysis are as follows: The pretreated first herbal medicine group is placed in a sealed enzymatic hydrolysis vessel, and then 10 times the volume of purified water is added. The mixture is stirred at 100 rpm for 7.5 min. The pH is then adjusted to 4.8 ± 0.2 using a citrate-sodium citrate buffer solution (the citrate-sodium citrate buffer solution is prepared by mixing citrate monohydrate, sodium citrate dihydrate, and purified water, with a mass ratio of 21.01 g: 29.41 g, and then brought to a final volume of 1000 mL with purified water). Next, 1% of the dry weight of the first herbal medicine group (i.e., 0.67 g) of the compound enzyme is added. The mixture is kept at a constant temperature of 45℃ and a stirring speed of 100 rpm for 2.5 h to complete the enzymatic hydrolysis (the pH of the calibration system is monitored every 30 min during the hydrolysis process to ensure that the fluctuation range does not exceed 4.6–5.0).

[0040] After enzymatic hydrolysis, the solution underwent instantaneous enzyme inactivation, solid-liquid separation, ultrafiltration for impurity removal, and vacuum concentration to obtain the first concentrate. Instantaneous enzyme inactivation specifically involved immediately inactivating the enzyme at 85°C for 10 seconds using a tubular instantaneous high-temperature filter after hydrolysis, followed by rapid cooling to 25°C within 10 minutes. Solid-liquid separation involved first coarsely filtering the enzyme hydrolysate through a 100-mesh stainless steel filter (to remove coarse particles of the residue), then cross-flow filtration through a 0.8μm ceramic membrane (to remove small residues and insoluble impurities), collecting the clear filtrate. Ultrafiltration for impurity removal involved… The clarified filtrate was ultrafiltered through a spiral wound ultrafiltration membrane with a molecular weight cutoff of 5000 Da at a pressure of 0.12 MPa and a temperature of 25°C (to remove ineffective large molecular impurities such as tannins, resins, and mucilage that easily cause precipitation), to obtain a purified enzymatic hydrolysate. The vacuum concentration was carried out by transferring the purified enzymatic hydrolysate to a falling film vacuum concentration tank and concentrating it under vacuum at a temperature of 60°C and a vacuum degree of -0.09 MPa (concentrated to a dry extract content of 18% (w / v)) to obtain the first concentrate, which was then naturally cooled to 25°C and sealed for later use.

[0041] Step S3, Supercritical Extraction: First, mix the residue of the first herbal medicine group after enzymatic hydrolysis in Step S2 with the second herbal medicine group after pretreatment in Step S1, and then perform supercritical gradient extraction. That is, put the mixture of the first herbal medicine group residue after enzymatic hydrolysis and the second herbal medicine group after pretreatment into a supercritical CO2 extraction vessel, compact and seal it, and use pharmaceutical-grade anhydrous ethanol as an entrainer to perform the first stage extraction and the second stage extraction sequentially, combining the two stage extracts. Specifically, the first stage extraction is performed at 40℃, adjusting the pressure of the extraction vessel to 20 MPa and the CO2 flow rate to 20... The first stage of extraction is as follows: at 40℃, the extraction vessel pressure is adjusted to 30MPa, the CO2 flow rate is 20L / h (CO2 purity ≥99.9%), the entrainer (per hour) is 10% of the CO2 volume, the extraction is carried out at constant temperature and pressure for 90min, the separation vessel pressure is 6MPa, and the temperature is 35℃, and the first stage of extraction is collected.

[0042] The combined extracts were then transferred to a vacuum concentration tank and concentrated under reduced pressure at 40°C and -0.08 MPa (to recover anhydrous ethanol and concentrate until no alcohol odor was detected). PEG400 was then added and stirred to dissolve the extract. The mass ratio of PEG400 to Phellodendron bark was 0.1:3. The second concentrate was obtained and cooled naturally to 25°C. The concentrate was then sealed for later use.

[0043] Step S4, Preparation of Traditional Chinese Medicine Mixture: First, mix the first concentrate and the second concentrate (mixing volume ratio approximately 1:1.09) at 25℃ and 200 rpm for 17.5 min to obtain a premix; then, add the premix dropwise to an mPEG-PLGA (methoxy polyethylene glycol-poly(D,L-lactic acid-co-hydroxyacetic acid) copolymer) organic solution at a rate of 0.4 mL / min, and stir at 250 rpm for 30 min to form a homogeneous and transparent organic phase for later use. The mass ratio of mPEG-PLGA (i.e., the mPEG-PLGA content in the organic solution) to the total weight of the traditional Chinese medicine (i.e., the total weight of the first and second traditional Chinese medicine groups) is 6:43; wherein, the mPEG-PLGA organic solution is specifically prepared by: mPEG-PLGA was added to anhydrous ethanol and stirred at 250 rpm for 35 min at 30°C to obtain mPEG-PLGA with a concentration of 0.25 g / mL (i.e., the mass-to-volume ratio of mPEG-PLGA to anhydrous ethanol is 2.5 g: 10 mL). mPEG-PLGA is a pharmaceutical-grade biodegradable amphiphilic block copolymer approved by the FDA and China NMPA for oral / injectable formulations. It includes the hydrophilic block mPEG (methoxy-terminated polyethylene glycol) and the hydrophobic block PLGA (polylactic acid-glycolic acid copolymer). In this invention, the molecular weight of mPEG is 5 kDa, the molecular weight of PLGA is 10 kDa (LA / GA monomer ratio is 50:50), and the total molecular weight is 15 kDa.

[0044] Next, the container containing purified water was placed on a magnetic stirrer and stirred at a constant speed of 400 rpm. The mass ratio of purified water to organic phase was 1:3.9. The organic phase was added dropwise to the purified water at a rate of 0.5 mL / min. The process was carried out in the dark and at a constant temperature of 25°C. After the addition was completed, the mixture was stirred continuously for 4 hours. After stirring, the mixture was filtered through a 0.22 μm microporous membrane (to remove unencapsulated free components and large particle aggregates) to obtain a solution of the active ingredients of traditional Chinese medicine for later use.

[0045] Step S5, Inclusion Complex Preparation: First, prepare the inclusion complex base solution. Specifically, add hydroxypropyl-β-cyclodextrin to purified water and stir at 225 rpm for 25 min at 50°C to obtain a saturated aqueous solution. Then add chitosan oligosaccharide and stir at 200 rpm for 30 min. Adjust the pH to 5.2 and keep warm at 50°C for later use. The mass-volume ratio of hydroxypropyl-β-cyclodextrin, chitosan oligosaccharide, and purified water is 12 g: 1 g: 61 mL.

[0046] First, a 9% (w / v) metformin hydrochloride aqueous solution (i.e., the mass-to-volume ratio of metformin hydrochloride to purified water) was added dropwise to the inclusion system base solution at 50°C at a rate of 3.7 mL / min, while stirring at 300 rpm. The volume ratio of the metformin hydrochloride aqueous solution to the inclusion system base solution was 1:3 (i.e., 100 mL and 300 mL respectively). After the addition was completed, the mixture was stirred continuously at 300 rpm at 50°C for 2 hours. After the reaction was completed, the temperature was rapidly reduced to 25°C, and then refrigerated at 4°C for 12 hours to obtain the inclusion solution. Then, the refrigerated inclusion solution was filtered through a 0.45 μm microporous membrane (to remove unencapsulated free drug and excipients) to obtain the metformin hydrochloride supramolecular inclusion complex solution.

[0047] Step S6, Compound Preparation: First, under constant temperature of 25℃ and stirring speed of 250 rpm, add metformin hydrochloride supramolecular inclusion complex solution to purified water and stir for 15 min; then add the traditional Chinese medicine active ingredient solution and continue stirring for 25 min. The volumes of metformin hydrochloride supramolecular inclusion complex solution, traditional Chinese medicine active ingredient solution, and purified water are 400 mL, 200 mL, and 300 mL, respectively, to obtain the initial compound preparation solution; then, add ethylparaben and xylitol excipients sequentially to the initial compound preparation solution, stirring after each excipient is added. After stirring and dissolving for 5 minutes, the next ingredient is added. After adding, the mass-volume concentration of ethylparaben is 0.2% (w / v) and the mass-volume concentration of xylitol is 7.5% (w / v). After stirring until all excipients are completely dissolved, the pH of the system is adjusted to 5.2 using sodium citrate or citric acid. Then, purified water is added to make up to 1000 mL, and the mixture is stirred at 250 rpm for 15 minutes to make the solution homogeneous. Finally, the mixture is homogenized at 1000 rpm for 5 minutes (to eliminate microbubbles) to obtain the compound solution.

[0048] Step S7, Post-processing: The compound drug solution is sequentially subjected to fine filtration, sterilization, and filling to obtain metformin compound hypoglycemic oral solution. The fine filtration specifically involves: first, pre-filtration of the compound drug solution through a 0.45μm microporous membrane (to remove small particulate impurities), followed by fine filtration through a 0.22μm polyethersulfone (PES) microporous membrane at a filtration pressure of 0.12MPa and a flow rate of 6L / min (to remove microorganisms and pyrogens). The clarified drug solution after fine filtration is collected and transferred to an aseptic sterilization tank. The sterilization specifically involves: sterilizing the clarified drug solution after fine filtration with flowing steam at 100℃ for 10 minutes. During the sterilization process, the tank... The internal pressure is controlled at 0.11 MPa (to avoid damage to the supramolecular inclusion complex and micelle structure due to high temperature and high pressure). After sterilization, the temperature is gradually reduced to 25℃ (to avoid sudden cooling that could cause turbidity of the drug solution and damage to the nanostructure). The filling process is as follows: In a Class A laminar flow aseptic filling production line under the background of a Class C clean area, the sterilized drug solution is filled into 10ml brown oral liquid bottles (the oral liquid bottles and rubber stoppers are sterilized in advance and pretreated by moist heat sterilization at 121℃ for 30min). The filling accuracy is controlled at ±0.1ml. Immediately after filling, the stoppers (pharmaceutical butyl rubber stoppers, which are sterilized in advance) are pressed and capped (aluminum-plastic combination caps) to ensure a tight seal and no leakage.

[0049] Example 3: A method for preparing a metformin compound hypoglycemic oral solution includes: Step S1: Pretreatment of Chinese herbal ingredients: Bitter melon, astragalus, kudzu root, rehmannia root, and ginseng were designated as the first group of Chinese herbal ingredients (water-soluble heat-sensitive ingredients group), and phellodendron bark and privet fruit were designated as the second group of Chinese herbal ingredients (lipid-soluble weakly polar ingredients group). In the first group of Chinese herbal ingredients, the dosages of bitter melon, astragalus, kudzu root, rehmannia root, and ginseng were 20g, 30g, 20g, 16g, and 8g, respectively; in the second group of Chinese herbal ingredients, the dosages of phellodendron bark and privet fruit were 12g and 15g, respectively.

[0050] Pretreatment was carried out separately: For the first group of Chinese herbal medicines, impurities and non-medicinal parts were removed by cleaning, pulverizing, and passing through a 40-mesh sieve. The sieve-passing material was collected and sealed for later use. For the second group of Chinese herbal medicines, after cleaning, the Phellodendron bark was pulverized to 40 mesh and soaked in a 0.5% sodium carbonate solution for 32 minutes. The ratio of Phellodendron bark to sodium carbonate solution was 1:1.6. After soaking, it was dried at 42℃ (dried until the moisture content was no more than 8%) and evenly mixed with the Ligustrum lucidum that had passed through a 40-mesh sieve. The mixture was then sealed for later use.

[0051] Step S2, Compound Enzymatic Hydrolysis of the First Traditional Chinese Medicine Group: The first traditional Chinese medicine group is subjected to compound enzymatic hydrolysis using a compound enzyme. The compound enzyme is a combination of pharmaceutical-grade single enzymes, including cellulase, hemicellulase, pectinase and neutral protease, with proportions of 36%, 19%, 26% and 19%, respectively. Among them, the enzyme activity of cellulase is 10000 U / g, the enzyme activity of hemicellulase is 8000 U / g, the enzyme activity of pectinase is 15000 U / g, and the enzyme activity of neutral protease is 50000 U / g. The specific steps of the compound enzymatic hydrolysis are as follows: The pretreated first herbal medicine group is placed in a sealed enzymatic hydrolysis vessel, and then 10 times the volume of purified water is added. The mixture is stirred at 105 rpm for 5 minutes. The pH is then adjusted to 4.8 ± 0.2 using a citrate-sodium citrate buffer solution (the citrate-sodium citrate buffer solution is prepared by mixing citrate monohydrate, sodium citrate dihydrate, and purified water, with a mass ratio of 21.01 g: 29.41 g, and then brought to a final volume of 1000 mL with purified water). Next, 1% of the dry weight of the first herbal medicine group (i.e., 0.94 g) of the compound enzyme is added. The mixture is kept at a constant temperature of 47℃ and a stirring speed of 105 rpm for 2.3 hours to complete the enzymatic hydrolysis (the pH of the calibration system is monitored every 30 minutes during the hydrolysis process to ensure that the fluctuation range does not exceed 4.6–5.0).

[0052] After enzymatic hydrolysis, the solution underwent instantaneous enzyme inactivation, solid-liquid separation, ultrafiltration for impurity removal, and vacuum concentration to obtain the first concentrate. Instantaneous enzyme inactivation specifically involved immediately inactivating the enzyme at 86℃ for 9 seconds using a tubular instantaneous high-temperature filter after hydrolysis, followed by rapid cooling to 27℃ within 10 minutes. Solid-liquid separation involved first coarsely filtering the enzyme-inactivated hydrolysate through a 100-mesh stainless steel filter (to remove coarse particles of the residue), then cross-flow filtration through a 0.8μm ceramic membrane (to remove small residues and insoluble impurities), collecting the clear filtrate. Ultrafiltration for impurity removal involved… The clarified filtrate was ultrafiltered through a spiral wound ultrafiltration membrane with a molecular weight cutoff of 5000 Da at a pressure of 0.13 MPa and a temperature of 27°C (to remove ineffective large molecular impurities such as tannins, resins, and mucilage that are prone to precipitation), to obtain a purified enzymatic hydrolysate. The vacuum concentration was carried out by transferring the purified enzymatic hydrolysate to a falling film vacuum concentration tank and concentrating it under vacuum at a temperature of 62°C and a vacuum degree of -0.10 MPa (concentrated to a dry extract content of 18% (w / v)) to obtain the first concentrate, which was then naturally cooled to 27°C and sealed for later use.

[0053] Step S3, Supercritical Extraction: First, mix the residue of the first herbal medicine group after enzymatic hydrolysis in Step S2 with the second herbal medicine group after pretreatment in Step S1, and then perform supercritical gradient extraction. That is, put the mixture of the first herbal medicine group residue after enzymatic hydrolysis and the second herbal medicine group after pretreatment into a supercritical CO2 extraction vessel, compact and seal it, and use pharmaceutical-grade anhydrous ethanol as an entrainer. Perform the first stage extraction and the second stage extraction sequentially, and combine the extracts from both stages. Specifically, the first stage extraction is performed at 42℃, adjusting the pressure of the extraction vessel to 20.5 MPa and the CO2 flow rate to 20.5 L / min. The first stage of extraction is as follows: at 42°C, the extraction vessel pressure is adjusted to 30.5 MPa, the CO2 flow rate is 20.5 L / h (CO2 purity ≥ 99.9%), the entrainer is 10% of the CO2 volume, the extraction vessel pressure is 6.5 MPa, and the temperature is 37°C. The second stage of extraction is as follows: at 42°C, the extraction vessel pressure is adjusted to 30.5 MPa, the CO2 flow rate is 20.5 L / h (CO2 purity ≥ 99.9%), the entrainer is 10% of the CO2 volume, the extraction vessel pressure is 6.5 MPa, and the temperature is 37°C. The second stage of extraction is collected.

[0054] The combined extracts were then transferred to a vacuum concentration tank and concentrated under reduced pressure at 42°C and -0.09 MPa (to recover anhydrous ethanol and concentrate until no alcohol odor was detected). PEG400 was then added and stirred to dissolve the extract. The mass ratio of PEG400 to Phellodendron bark was 0.1:3. The second concentrate was obtained and naturally cooled to 27°C and then sealed for later use.

[0055] Step S4, Preparation of Traditional Chinese Medicine Mixture: First, mix the first concentrate and the second concentrate at 27°C and 220 rpm for 15 min to obtain a premix; then, add the premix dropwise to an mPEG-PLGA (methoxy polyethylene glycol-poly(D,L-lactic acid-co-hydroxyacetic acid) copolymer) organic solution at a rate of 0.5 mL / min, and stir at 270 rpm for 28 min to form a homogeneous and transparent organic phase for later use. The mass ratio of mPEG-PLGA (i.e., the mPEG-PLGA content in the organic solution) to the total weight of the traditional Chinese medicine (i.e., the total weight of the first and second traditional Chinese medicine groups) is 6:43; wherein, the mPEG-PLGA organic solution is specifically prepared by: mixing mPEG-PLGA... GA was added to anhydrous ethanol and stirred at 270 rpm for 30 min at 32°C to obtain mPEG-PLGA with a concentration of 0.3 g / mL (i.e., the mass-to-volume ratio of mPEG-PLGA to anhydrous ethanol is 3 g: 10 mL). mPEG-PLGA is a pharmaceutical-grade biodegradable amphiphilic block copolymer approved by the FDA and China NMPA for oral / injectable formulations. It includes the hydrophilic block mPEG (methoxy-terminated polyethylene glycol) and the hydrophobic block PLGA (polylactic acid-glycolic acid copolymer). In this invention, the molecular weight of mPEG is 5 kDa, the molecular weight of PLGA is 10 kDa (LA / GA monomer ratio is 50:50), and the total molecular weight is 15 kDa.

[0056] Next, the container containing purified water was placed on a magnetic stirrer and stirred at a constant speed of 420 rpm. The mass ratio of purified water to organic phase was 1:4. The organic phase was added dropwise to the purified water at a rate of 0.55 mL / min. The process was carried out in the dark and at a constant temperature of 27°C. After the addition was completed, the mixture was stirred continuously for 4.2 h. After stirring, the mixture was filtered through a 0.22 μm microporous membrane (to remove unencapsulated free components and large particle aggregates) to obtain a solution of the active ingredients of traditional Chinese medicine for later use.

[0057] Step S5, Inclusion Complex Preparation: First, prepare the inclusion system base solution. Specifically, add hydroxypropyl-β-cyclodextrin to purified water and stir at 250 rpm for 20 min at 52°C to obtain a saturated aqueous solution. Then add chitosan oligosaccharide and stir at 220 rpm for 28 min. Adjust the pH to 5.4 and keep warm at 52°C for later use. The mass-volume ratio of hydroxypropyl-β-cyclodextrin, chitosan oligosaccharide, and purified water is 12 g: 1 g: 62 mL.

[0058] First, a 10% (w / v) metformin hydrochloride aqueous solution (i.e., the mass-to-volume ratio of metformin hydrochloride to purified water) was added dropwise to the inclusion system base solution at 52℃ at a rate of 4 mL / min, while stirring at 320 rpm. The volume ratio of metformin hydrochloride aqueous solution to the inclusion system base solution was 1:3 (i.e., 100 mL and 300 mL, respectively). After the addition was completed, the mixture was stirred continuously at 320 rpm at 52℃ for 1.8 h. After the reaction was completed, the temperature was rapidly reduced to 27℃, and then refrigerated at 4.5℃ for 11 h to obtain the inclusion solution. Then, the refrigerated inclusion solution was filtered through a 0.45 μm microporous membrane (to remove unencapsulated free drug and excipients) to obtain the metformin hydrochloride supramolecular inclusion complex solution.

[0059] Step S6, Compound Preparation: First, under constant temperature of 27℃ and stirring speed of 270 rpm, add metformin hydrochloride supramolecular inclusion complex solution to purified water and stir for 13 min; then add the traditional Chinese medicine active ingredient solution and continue stirring for 23 min. The volumes of metformin hydrochloride supramolecular inclusion complex solution, traditional Chinese medicine active ingredient solution, and purified water are 400 mL, 200 mL, and 300 mL, respectively, to obtain the initial compound preparation solution; then, add potassium sorbate and steviol glycoside excipients sequentially to the initial compound preparation solution, adding each excipient as needed. After stirring and dissolving for 5 minutes, the next ingredient is added. The mass volume concentration of potassium sorbate after addition is 0.3% (w / v), and the mass volume concentration of steviol glycoside is 10% (w / v). After stirring until all excipients are completely dissolved, the pH of the system is adjusted to 5.5 using sodium citrate or citric acid. Then, purified water is added to make up to 1000 mL, and the mixture is stirred at 270 rpm for 13 minutes to make the solution homogeneous. Finally, the mixture is homogenized at a low speed of 1050 rpm for 4 minutes (to eliminate microbubbles) to obtain the compound solution.

[0060] Step S7, Post-processing: The compound drug solution is sequentially subjected to fine filtration, sterilization, and filling to obtain metformin compound hypoglycemic oral solution. The fine filtration specifically involves: first, pre-filtration of the compound drug solution through a 0.45μm microporous membrane (to remove small particulate impurities), followed by fine filtration through a 0.22μm polyethersulfone (PES) microporous membrane at a filtration pressure of 0.13MPa and a flow rate of 6.5L / min (to remove microorganisms and pyrogens). The clarified drug solution after fine filtration is collected and transferred to an aseptic sterilization tank. The sterilization specifically involves: sterilizing the clarified drug solution after fine filtration with flowing steam at 105℃ for 9 minutes. During the sterilization process, the tank... The internal pressure is controlled at 0.12 MPa (to avoid damage to the supramolecular inclusion complex and micelle structure due to high temperature and high pressure). After sterilization, the temperature is gradually reduced to 27℃ (to avoid sudden cooling that could cause turbidity of the drug solution and damage to the nanostructure). The filling process is as follows: In a Class A laminar flow aseptic filling production line under the background of a Class C clean area, the sterilized drug solution is filled into 10ml brown oral liquid bottles (the oral liquid bottles and rubber stoppers are sterilized in advance and pretreated by moist heat sterilization at 121℃ for 30min). The filling accuracy is controlled at ±0.1ml. Immediately after filling, the stoppers (pharmaceutical butyl rubber stoppers, which are sterilized in advance) are pressed and capped (aluminum-plastic combination caps) to ensure a tight seal and no leakage.

[0061] Comparative Example 1: A method for preparing a compound oral liquid, comprising: Step S1, Pretreatment of Chinese medicine components: Same as step S1 in Example 2.

[0062] Step S2, Chinese medicine extraction: Put the first Chinese medicine group and the second Chinese medicine group into the multi-functional extraction tank respectively, and add 10 times the amount of purified water. Stir at 200 rpm, heat to 95℃ to reflux state, and maintain a slight boiling reflux for extraction twice. The first extraction is 2 hours and the second extraction is 1.5 hours. Maintain the pressure inside the tank at 0.03 MPa during the extraction process. After extraction, the residue particles were removed by coarse filtration through a 100-mesh filter and then finely filtered using a 0.8μm plate and frame filter press. The clear filtrate was collected and the filter residue was discarded. The clear filtrate was then transferred to a vacuum concentration tank for concentration under reduced pressure. The concentration was carried out at 62℃ and a vacuum of -0.10MPa (concentrated to a dry extract content of 18% (w / v)). The first concentrate and the second concentrate (corresponding to the first and second Chinese medicine groups) were obtained. PEG400 was added to the second concentrate after vacuum concentration and stirred to dissolve it. The mass ratio of PEG400 to Phellodendron bark was 0.1:3. The concentrate was then naturally cooled to 25℃ and sealed for later use.

[0063] Step S3, Preparation of the Chinese herbal medicine mixture: Same as step S4 in Example 2.

[0064] Step S4, preparation of inclusion complex: consistent with step S5 in Example 2.

[0065] Step S5, compound preparation: consistent with step S6 in Example 2.

[0066] Step S6, Post-processing: Same as step S7 in Example 2.

[0067] Comparative Example 2: A method for preparing a compound oral liquid, comprising: Step S1, Pretreatment of Chinese medicine components: Same as step S1 in Example 2.

[0068] Step S2, Enzymatic hydrolysis of the first group of traditional Chinese medicine: consistent with step S2 in Example 2.

[0069] Step S3, Extraction of the Second Herbal Group: First, mix the residue of the first herbal group after enzymatic hydrolysis in Step S2 with the second herbal group after pretreatment in Step S1, add 10 times the amount of purified water, stir at 200 rpm, heat to 95℃ and reflux, maintain a slight boiling reflux for extraction twice, the first extraction for 2 hours and the second extraction for 1.5 hours, maintaining a pressure of 0.03 MPa in the tank during the extraction process. After extraction, coarsely filter through a 100-mesh filter to remove the residue particles, and then finely filter using a 0.8 μm plate and frame filter press, collect the clear filtrate and discard the filter residue; then, transfer the clear filtrate to a vacuum concentration tank for vacuum concentration, specifically: vacuum concentration at 62℃ and a vacuum degree of -0.10 MPa (concentrated to a dry extract content of 18% (w / v)), then add PEG400 and stir to dissolve, the mass ratio of PEG400 to Phellodendron bark is 0.1:3, to obtain the second concentrate, naturally cool to 25℃, and seal for later use.

[0070] Step S4, Preparation of Chinese herbal medicine mixture: Same as step S4 in Example 2.

[0071] Step S5, preparation of inclusion complex: consistent with step S5 in Example 2.

[0072] Step S6, Compound Preparation: Same as step S6 in Example 2.

[0073] Step S7, Post-processing: Same as step S7 in Example 2.

[0074] Comparative Example 3: A method for preparing a compound oral liquid, comprising: Step S1, Pretreatment of Chinese medicine components: Same as step S1 in Example 2.

[0075] Step S2, Extraction of the First Herbal Extract: The first herbal extract was placed in a multi-functional extraction tank, and 10 times the amount of purified water was added. The mixture was stirred at 200 rpm and heated to 95°C until reflux. It was then extracted twice under gentle boiling reflux conditions, for 2 hours the first time and 1.5 hours the second time, maintaining a tank pressure of 0.03 MPa throughout the extraction process. After extraction, the extract was coarsely filtered through a 100-mesh screen to remove the herbal residue particles, followed by fine filtration using a 0.8 μm plate and frame filter press. The clarified filtrate was collected, and the filter residue was discarded. The clarified filtrate was then transferred to a vacuum concentration tank for concentration under reduced pressure. Specifically, the concentration was carried out at 62°C and a vacuum of -0.10 MPa (concentrated to a dry extract content of 18% (w / v)) to obtain the first concentrate. This concentrate was then naturally cooled to 25°C and sealed for later use.

[0076] Step S3, supercritical extraction: consistent with step S3 in Example 2.

[0077] Step S4, Preparation of Chinese herbal medicine mixture: Same as step S4 in Example 2.

[0078] Step S5, preparation of inclusion complex: consistent with step S5 in Example 2.

[0079] Step S6, Compound Preparation: Same as step S6 in Example 2.

[0080] Step S7, Post-processing: Same as step S7 in Example 2.

[0081] Comparative Example 4: A method for preparing a compound oral liquid, comprising: Step S1, Pretreatment of Chinese medicine components: Same as step S1 in Example 2.

[0082] Step S2, Enzymatic hydrolysis of the first group of traditional Chinese medicine: consistent with step S2 in Example 2.

[0083] Step S3, supercritical extraction: consistent with step S3 in Example 2.

[0084] Step S4, Preparation of Traditional Chinese Medicine Mixture: First, mix the first concentrate and the second concentrate (mixing volume ratio of approximately 1:1.09) at 25°C and 200 rpm for 17.5 min to directly form a solution of active ingredients of traditional Chinese medicine for later use.

[0085] Step S5, preparation of inclusion complex: consistent with step S5 in Example 2.

[0086] Step S6, Compound Preparation: Same as step S6 in Example 2.

[0087] Step S7, Post-processing: Same as step S7 in Example 2.

[0088] Comparative Example 5: A method for preparing a compound oral liquid, comprising: Step S1, Pretreatment of Chinese medicine components: Same as step S1 in Example 2.

[0089] Step S2, Enzymatic hydrolysis of the first group of traditional Chinese medicine: consistent with step S2 in Example 2.

[0090] Step S3, supercritical extraction: consistent with step S3 in Example 2.

[0091] Step S4, Preparation of Chinese herbal medicine mixture: Same as step S4 in Example 2.

[0092] Step S5, Preparation of Compound Solution: First, under constant temperature of 25℃ and stirring speed of 250 rpm, add a 9% (w / v) metformin hydrochloride aqueous solution (i.e., the mass-to-volume ratio of metformin hydrochloride to purified water) to purified water and stir for 15 min; then add the active ingredient solution of traditional Chinese medicine and continue stirring for 25 min. The volumes of metformin hydrochloride aqueous solution, active ingredient solution of traditional Chinese medicine, and purified water are 400 mL, 200 mL, and 300 mL, respectively, to obtain the initial compound solution; then, add ethylparaben and xylitol sequentially to the initial compound solution. For the excipients, each excipient was added and stirred for 5 minutes to dissolve before adding the next. After each addition, the mass-volume concentration of ethylparaben was 0.2% (w / v) and the mass-volume concentration of xylitol was 7.5% (w / v). After all excipients were completely dissolved, the pH of the system was adjusted to 5.2 using sodium citrate or citric acid. Then, purified water was added to bring the volume to 1000 mL, and the mixture was stirred at 250 rpm for 15 minutes to ensure homogeneity. Finally, the mixture was homogenized at 1000 rpm for 5 minutes (to eliminate microbubbles) to obtain the compound drug solution.

[0093] Step S6 and post-processing are the same as step S7 in Example 2.

[0094] Experimental testing: Hypoglycemic effect experiment: SPF-grade SD rats, weighing 210±10g, were used to establish a type II diabetes model (high-fat diet for 4 weeks + intraperitoneal injection of streptozotocin 35mg / kg). 200 rats with fasting blood glucose ≥11.1mmol / L were randomly divided into 10 groups of 20 rats each. Eight groups were fed oral solutions of Examples 1-3 and Comparative Examples 1-5, respectively. Group 9 was the blank group, fed with physiological saline. Group 10 was the control group, fed commercially available metformin oral solution (containing 10g / 1000ml metformin, without traditional Chinese medicine), administered by gavage at 10mL / kg body weight, once daily for 4 weeks. The reduction in fasting blood glucose (FBG), 2-hour postprandial blood glucose (2h-PBG), and glycated hemoglobin (HbA1c) was recorded before and after 4 weeks of administration (average value of 20 rats per group). The results are shown in the table below.

[0095] As can be clearly seen from the table above, the compound oral liquid prepared by the specific method of this invention has excellent hypoglycemic effect and clear synergistic effect.

[0096] Gastrointestinal adverse reaction test: Within four weeks of administration, observe the rats daily for gastrointestinal reactions such as nausea, abdominal distension, diarrhea, and loss of appetite, and record the incidence of adverse reactions (if gastrointestinal reactions such as nausea, abdominal distension, diarrhea, and loss of appetite occur on a given day, record it once; otherwise, do not record it).

[0097] As can be clearly seen from the table above, the compound oral liquid prepared by the specific method of this invention can significantly reduce gastrointestinal adverse reactions caused by metformin and has higher safety.

[0098] Stability test: 100 vials of the oral liquid prepared in Examples 1 to 3 were subjected to accelerated and long-term storage tests (storage environment and storage time points were consistent for each group). Accelerated test (first 6 months): 40±2℃, relative humidity 75±5%RH; Long-term test: 25±2℃, relative humidity 60±5%RH. The properties, pH, and content of active ingredients (metformin hydrochloride, astragaloside IV, puerarin, etc.) were recorded at 0, 1, 3, 6, 12, and 18 months. Within 18 months, the oral liquid samples prepared in Examples 1 to 3 were clear brown liquids with no precipitation or off-odor; the pH was maintained at 5.3 to 5.7 with a pH fluctuation ≤0.3; the relative density was maintained at 1.08 to 1.12; the decrease in metformin hydrochloride content was ≤4%, and the decrease in astragaloside IV and puerarin content was ≤3%, indicating that the oral liquids had excellent stability.

Claims

1. A preparation method of a metformin compound antidiabetic oral liquid, characterized in that: The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. ​ The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid.

2. The preparation method of the metformin compound oral antidiabetic solution according to claim 1, characterized in that: The application relates to a preparation method of a metformin compound hypoglycemic oral liquid.

3. The preparation method of the metformin compound antidiabetic oral liquid according to claim 1 or 2, characterized in that: The application relates to a preparation method of a metformin compound hypoglycemic oral liquid.

4. The preparation method of the metformin compound antidiabetic oral liquid according to claim 2 or 3, characterized in that: The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates to a preparation method of a metformin compound hypoglycemic oral liquid. The application relates a preparation method of a metformin compound hypoglycemic oral liquid. The application discloses a preparation method of a metformin compound hypoglycemic oral liquid. The application provides a preparation method of a metformin compound hypoglycemic oral liquid.

5. The preparation method of the metformin compound oral antidiabetic solution according to claim 4, characterized in that: The step S2, the instant enzyme inactivation is specifically: after the enzymolysis, immediately using 84-86 ℃, 9-11 s of tubular instant high temperature enzyme inactivation, the enzyme inactivation after 10 min rapid cooling to 23-27 ℃;Solid-liquid separation is specifically: the enzyme inactivation after the enzymolysis liquid is first filtered through 100 mesh stainless steel filter screen, then through 0.8 μm ceramic membrane cross flow filtration, and the clear filtrate is collected;Ultrafiltration impurity removal is specifically: the clear filtrate is ultrafiltered through the 5000 Da molecular weight cut-off spiral ultrafiltration membrane, the pressure is 0.11-0.13 MPa, and the temperature is 23-27 ℃, to obtain the purified enzymolysis liquid;The vacuum concentration is specifically: the purified enzymolysis liquid is transferred into a falling film vacuum concentration tank, and the vacuum concentration is carried out at a temperature of 58-62 ℃ and a vacuum degree of-0.08 to-0.10 MPa, to obtain a first concentrate, and the first concentrate is naturally cooled to 23-27 ℃ and sealed for standby.

6. The preparation method of the metformin compound oral antidiabetic solution according to claim 5, characterized in that: The step S3, the supercritical gradient extraction is specifically: the mixture composed of the first traditional Chinese medicine group residue after enzymolysis treatment and the second traditional Chinese medicine group after pretreatment is put into a supercritical CO2 extraction kettle, and is compacted and sealed, medicinal grade anhydrous ethanol is used as a carrier, and first stage extraction and second stage extraction are carried out in turn, and the two stage extraction liquids are combined;Then the combined extraction liquid is transferred into a vacuum concentration tank, and vacuum concentration is carried out at a temperature of 38-42 ℃ and a vacuum degree of-0.07 to-0.09 MPa, then PEG400 is added for stirring and dissolution, the mass ratio of PEG400 to Huangbai is 0.1:3, to obtain a second concentrate, and the second concentrate is naturally cooled to 23-27 ℃ and sealed for standby.

7. The preparation method of the metformin compound oral antidiabetic solution according to claim 6, characterized in that: The step S4 is specifically: first, the first concentrate and the second concentrate are stirred and mixed at 23-27 ℃ and a speed of 180-220 rpm for 15-20 min to obtain a premix;Then the premix is added to the mPEG-PLGA organic solution at a rate of 0.3-0.5 mL / min, and stirred at a speed of 230-270 rpm for 28-32 min to form a uniform and transparent organic phase for standby, the mass ratio of mPEG-PLGA to total traditional Chinese medicine is 6:43;Then, a container containing purified water is placed on a magnetic stirrer and stirred at 380-420 rpm, the mass ratio of purified water to organic phase is 1:3.8-4, the organic phase is added to the purified water at a rate of 0.45-0.55 mL / min, the whole process is carried out in the dark at 23-27 ℃, and after the addition is completed, the stirring is continued for 3.8-4.2 h;After stirring, a 0.22 μm microporous filter membrane is used for filtration to obtain a traditional Chinese medicine active ingredient solution for standby.

8. The preparation method of the metformin compound oral antidiabetic solution according to claim 7, characterized in that: In step S5, the specific preparation method of the inclusion system base solution is as follows: First, add hydroxypropyl-β-cyclodextrin to purified water and stir at 200-250 rpm for 20-30 min at 48-52℃ to obtain a saturated aqueous solution; then add chitosan oligosaccharide and stir at 180-220 rpm for 28-32 min, adjust the pH to 5-5.4, and keep warm at 48-52℃ for later use; wherein, the mass-volume ratio of hydroxypropyl-β-cyclodextrin, chitosan oligosaccharide and purified water is 12g:1g:60-62mL.

9. The preparation method of the metformin compound oral antidiabetic solution according to claim 8, characterized in that: In step S5, the inclusion reaction specifically involves: first, adding an 8%–10% (w / v) metformin hydrochloride aqueous solution at a rate of 3.5–4 mL / min to the inclusion system base solution at 48–52°C, while stirring at 280–320 rpm. The volume ratio of the metformin hydrochloride aqueous solution to the inclusion system base solution is 1:

3. After the addition is complete, stirring is continued at 280–320 rpm for 1.8–2.2 h at 48–52°C. After the reaction is complete, the temperature is rapidly lowered to 23–27°C, and then refrigerated at 3.5–4.5°C for 11–13 h to obtain the inclusion solution. Then, the refrigerated inclusion solution is filtered through a 0.45 μm microporous membrane to obtain the metformin hydrochloride supramolecular inclusion complex solution.

10. The preparation method of the metformin compound oral antidiabetic solution according to claim 9, characterized in that: Step S6 specifically involves: First, under constant temperature (23-27℃) and stirring speed (230-270 rpm), adding metformin hydrochloride supramolecular inclusion complex solution to purified water and stirring for 13-17 minutes; then adding the traditional Chinese medicine active ingredient solution and continuing stirring for 23-27 minutes, with the amounts of metformin hydrochloride supramolecular inclusion complex solution, traditional Chinese medicine active ingredient solution, and purified water being 400 mL, 200 mL, and 300 mL respectively, to obtain the initial compound preparation solution; subsequently, adding preservatives and sweeteners to the initial compound preparation solution sequentially, stirring after each addition. After dissolving for 5 minutes, add the next ingredient. The preservative concentration after addition should be 0.1%–0.3% (w / v) and the sweetener concentration should be 5%–10% (w / v). Stir until all excipients are completely dissolved, then adjust the pH of the system to 5–5.5 using sodium citrate or citric acid. Next, add purified water to bring the volume to 1000 mL and stir at 230–270 rpm for 13–17 minutes to ensure homogeneity. Finally, homogenize at a low speed of 950–1050 rpm for 4–6 minutes to obtain the compound drug solution.

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