Traditional Chinese medicine composition pill for treating diabetes and preparation method thereof

Abstract

The invention belongs to the field of traditional Chinese medicine preparations, and particularly relates to a traditional Chinese medicine composition pill for treating diabetes and a preparation method thereof. The traditional Chinese medicine composition pill is prepared from the following raw materials in parts by weight: 50 to 60 parts of traditional Chinese medicine composition, 20 to 30 parts of ethyl cellulose, 5 to 8 parts of polyethylene glycol, 15 to 20 parts of polylactic acid-glycolic acid copolymer, 8 to 12 parts of graft modified hydroxypropyl methyl cellulose, 25 to 30 parts of microcrystalline cellulose, 1 to 3 parts of silicon dioxide, 2 to 5 parts of magnesium stearate, 0.5 to 1 part of surfactant and 0.5 to 1 part of antioxidant. According to the preparation method, traditional Chinese medicine extracts such as radix astragali and fructus lycii are combined with materials such as ethyl cellulose, polylactic acid-glycolic acid copolymer and modified hydroxypropyl methyl fiber to form a multi-layer controlled release structure so as to delay drug release and protect drugs, microspheres are prepared through a spray drying technology, and uniform distribution, activity maintenance and rapid initial release of the drugs are ensured.

Description

Technical Field

[0001] The invention belongs to the field of traditional Chinese medicine preparations, and particularly relates to a traditional Chinese medicine composition pill for treating diabetes and a preparation method thereof. Background Art

[0002] Diabetes is a chronic disease characterized by high blood sugar. Long-term high blood sugar can lead to various complications, such as cardiovascular disease, retinopathy, and renal failure. According to the different causes, diabetes is mainly divided into type 1 diabetes caused by absolute insulin deficiency due to the destruction of pancreatic β cells and type 2 diabetes caused by the body's resistance to the action of insulin. In China, the number of diabetic patients is huge and has a trend of increasing year by year. From the perspective of traditional Chinese medicine, diabetes belongs to the category of "diabetes", which is mainly manifested as "upper consumption" (thirst and frequent drinking), "middle consumption" (frequent hunger due to frequent eating), and "lower consumption" (polyuria and weight loss), which are mostly caused by factors such as yin deficiency and dryness, qi and yin deficiency, and spleen and kidney deficiency. Its pathogenesis is mainly yin deficiency and dryness, or due to spleen and stomach weakness, spleen dysfunction, internal dampness and heat, dryness and heat generation, damage to body fluids, resulting in insufficient qi and yin, and then forming diabetes. Traditional Chinese medicine has a long history of treating diabetes, and many traditional prescriptions such as Liuwei Dihuang Pills and Yuquan Pills have certain hypoglycemic effects. In recent years, with the progress of modern medical research, more and more studies have proved the effectiveness of some Chinese medicine ingredients in improving blood sugar control, for example, bitter melon, astragalus, salvia miltiorrhiza, etc. Compared with Western medicine, Chinese medicine composition pills usually contain a variety of herbal extracts or their active ingredients, aiming to achieve therapeutic purposes through multi-target regulation. This preparation form is easy to take and easy to store, and can be personalized according to the patient's constitution and condition. In addition, Chinese medicine composition pills often have fewer side effects. After the pills enter the digestive tract, they can slowly release the drug ingredients and continue to exert therapeutic effects, which are suitable for long-term treatment of chronic diseases such as diabetes. Therefore, it is extremely necessary to develop a pill Chinese medicine with small toxic and side effects and long shelf life. Summary of the invention

[0003] In view of the defects of the prior art, the object of the present invention is to provide a Chinese medicine composition pill for treating diabetes and a preparation method thereof.

[0004] The technical effect described in the present invention is achieved through the following technical scheme: a Chinese medicine composition pill for treating diabetes, composed of the following raw materials in parts by weight: 50 to 60 parts of Chinese medicine composition, 20 to 30 parts of ethyl cellulose, 5 to 8 parts of polyethylene glycol, 15 to 20 parts of polylactic acid-glycolic acid copolymer, 8 to 12 parts of grafted modified hydroxypropyl methylcellulose, 25 to 30 parts of microcrystalline cellulose, 1 to 3 parts of silicon dioxide, 2 to 5 parts of magnesium stearate, 0.5 to 1 part of surfactant and 0.5 to 1 part of antioxidant.

[0005] Preferably, the Chinese medicine composition is composed of the following raw materials in parts by weight: 20-25 parts of astragalus extract, 10-15 parts of rehmannia extract, 10-15 parts of yam extract, 10-15 parts of kudzu root extract, 5-10 parts of salvia miltiorrhiza extract, 5-10 parts of mulberry leaf extract, 3-8 parts of coptis chinensis extract, 1-3 parts of pepper extract, 5-10 parts of ophiopogon extract and 5-10 parts of wolfberry extract.

[0006] Preferably, all the Chinese herbal extracts in the Chinese herbal composition are prepared by conventional technical means.

[0007] Preferably, the molecular weight of the polyethylene glycol is any one of PEG-4000 and PEG-6000.

[0008] Preferably, the surfactant is any one of Tween-80, lecithin and polyethylene glycol-stearate.

[0009] Preferably, the antioxidant is any one of vitamin E, butylated hydroxyanisole, tea polyphenols and propyl gallate.

[0010] Preferably, the specific preparation steps of the grafted modified hydroxypropyl methylcellulose are as follows: A1: Dissolve hydroxypropyl methylcellulose in dichloromethane, stir and mix evenly to obtain a hydroxypropyl methylcellulose solution with a concentration of 5-10%; add 1M NaOH solution dropwise to the hydroxypropyl methylcellulose solution, maintain the pH between 8 and 10, then slowly add sodium hexadecyl sulfate, continue stirring and react at 30-40°C for 2-6 hours, and after the reaction is completed, add 1M HCl solution to adjust the pH to neutral to obtain a reaction mixture; A2: Pour excess deionized water into the reaction mixture prepared in step A1, stir to form a precipitate, centrifuge at 5000 rpm for 10 min, take the precipitate, wash it three times with ethanol, and vacuum dry it at 40° C. for 12 to 24 h to obtain grafted modified hydroxypropyl methylcellulose.

[0011] Preferably, the amount of sodium cetyl sulfate used in step A1 is 1 to 5% of the mass amount of hydroxypropyl methylcellulose.

[0012] Preferably, another aspect of the present invention is to provide a method for preparing a Chinese medicine composition pill for treating diabetes, and the specific preparation steps are as follows: S1: dissolving ethyl cellulose in a solution prepared by ethanol and ethyl acetate in a volume ratio of 1:2, stirring and mixing, and obtaining a 5% ethyl cellulose solution; dissolving polylactic acid-glycolic acid copolymer in a 70wt% ethanol solution, stirring and mixing, and obtaining a 5% polylactic acid-glycolic acid copolymer solution; dissolving polyethylene glycol and grafted modified hydroxypropyl methylcellulose in a 70wt% ethanol solution, stirring and mixing, and obtaining a 2% hydrophilic solution; S2: adding the Chinese medicine composition to the hydrophilic solution prepared in step S1, stirring at a speed of 1000 rpm for 20 to 30 minutes to mix evenly, then gradually adding a surfactant and the ethyl cellulose solution and the polylactic acid-co-glycolic acid solution prepared in step S1, and continuing to stir at a speed of 1000 rpm for 30 to 60 minutes to mix evenly, to obtain a mixed solution; S3: adding the mixed solution prepared in step S2 to a spray drying device to obtain dry particles; mixing the dry particles with microcrystalline cellulose, silicon dioxide, magnesium stearate and antioxidants and stirring them evenly, adding them to a rotary tablet press, setting the tableting pressure to 12 to 20 kN, and controlling the pill weight to 200 to 300 mg. After the pressing is completed, the Chinese medicine composition pills are obtained.

[0013] Preferably, the spray drying setting parameters in step S3 are feed rate 5-8 mL / min, inlet air temperature 60-70° C., outlet air temperature 45-60° C., and atomization pressure 3-4 bar.

[0014] The beneficial effects of the present invention are as follows: The astragalus and wolfberry extracts used in the present invention have the effects of enhancing pancreatic islet function and improving sugar metabolism; the raw rehmannia, kudzu root and salvia miltiorrhiza extracts can regulate blood sugar levels and improve insulin resistance; the yam, mulberry leaf and ophiopogon extracts have the effects of protecting pancreatic islet cells, anti-oxidation and anti-inflammatory effects; the coptis and pepper extracts help regulate intestinal function by inhibiting sugar absorption, anti-inflammatory and antibacterial effects; these extracts work together to help comprehensively control blood sugar levels and relieve diabetes-related symptoms.

[0015] In the present invention, ethyl cellulose, as a hydrophobic polymer, can effectively delay the release of drugs in the body and form a barrier to protect drugs from moisture and oxygen erosion. By combining with polylactic acid-glycolic acid copolymer (PLGA) and long-chain alkyl grafted modified hydroxypropyl methylcellulose (HPMC), ethyl cellulose can further enhance the controlled release effect and ensure stable and continuous release of drugs in the body. This multilayer structure can gradually release drugs, thereby reducing the need for frequent medication. Polyethylene glycol (PEG) as a hydrophilic filler plays a role in forming micropores in hydrophobic materials (ethyl cellulose and polylactic acid-glycolic acid copolymer), promotes water penetration, and accelerates the initial release of drugs. A small amount of polyethylene glycol can significantly accelerate the initial release of drugs after contact with body fluids, while ensuring that the hydrophobicity of the overall material is not significantly affected, so as to achieve the purpose of rapid onset; combined with polyethylene glycol to accelerate the initial release, the active ingredients in Rehmannia glutinosa can take effect quickly, protect pancreatic islet cells, and at the same time, combined with the controlled release mechanism of polylactic acid-glycolic acid copolymer, maintain long-term drug effects. The combination of polylactic acid-co-glycolic acid and ethyl cellulose forms a hydrophobic barrier, which plays an important role in drug controlled release and ensures the stability and long-term effect of the drug. Long-chain modified hydroxypropyl methylcellulose also plays a key role in regulating the drug release rate. Its hydrophilicity promotes the initial release of the drug, while the hydrophobic modified structure ensures that the drug remains stable in different physiological environments and achieves subsequent controlled release. Microcrystalline cellulose ensures the physical stability of the preparation during production and storage by providing good structural strength, and its excellent fluidity contributes to the uniform distribution of the preparation. At the same time, the synergistic effect of microcrystalline cellulose with ethyl cellulose, polylactic acid-co-glycolic acid and silicon dioxide can further improve the moisture resistance of the pills and extend the shelf life of the drug. The lower proportion of microcrystalline cellulose and silicon dioxide will not affect the hydrophobic barrier. In addition, piperine in pepper extract can be combined with microcrystalline cellulose excipients to enhance the absorption efficiency of other ingredients and improve the bioavailability of the overall formulation. Silicon dioxide acts as a hygroscopic agent to ensure that the drug remains stable in a humid environment and prevent the active ingredients from becoming ineffective. Magnesium stearate improves the mechanical strength and lubricity of the pills, making the production process smoother and reducing pill breakage and molding defects.

[0016] The present invention forms stable microspheres with the active ingredients of the Chinese medicine extract and the above-mentioned auxiliary materials through spray drying technology, thereby ensuring uniform distribution of the drug and extending the shelf life. At the same time, this low-temperature rapid drying technology is suitable for heat-sensitive drugs, and can maintain the activity of the drug while avoiding degradation caused by high temperature. In addition, the rapid drying process of spray drying helps to form uniformly distributed polyethylene glycol and hydrophobic material composite particles, and utilizes the hydrophilicity of polyethylene glycol during the drying process to cause its distribution to be more dispersed. When the particles enter the water environment, the polyethylene glycol dissolves quickly to form pores, promote water entry and accelerate the initial release. Although the amount of polyethylene glycol used is small, its hydrophilicity and microporous structure are sufficient to significantly increase the rate of initial drug release without destroying the overall hydrophobic barrier structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings in the following description are only for the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0018] Figure 1 It is a dissolution test chart of the Chinese medicine composition pills prepared in Examples 2 to 3 of the present invention and Comparative Examples 1 to 4.

[0019] Figure 2 It is a pH result diagram of the stability test of the Chinese medicine composition pills prepared in Examples 2 to 3 of the present invention and Comparative Examples 1 to 4; Figure 3 It is a weight change diagram of the stability test of the Chinese medicine composition pills prepared in Examples 2 to 3 of the present invention and Comparative Examples 1 to 4; Figure 4 It is a graph showing the friability test results of the Chinese medicine composition pills prepared in Examples 2 to 3 of the present invention and Comparative Examples 1 to 4. DETAILED DESCRIPTION

[0020] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. It should be noted that, unless otherwise specified, the raw materials involved in the present invention are purchased through conventional commercial channels.

[0021] Example 1: A Chinese medicine composition pill for treating diabetes, composed of the following raw materials in parts by weight: 50 parts of Chinese medicine composition, 20 parts of ethyl cellulose, 5 parts of polyethylene glycol, 15 parts of polylactic acid-glycolic acid copolymer, 8 parts of grafted modified hydroxypropyl methylcellulose, 25 parts of microcrystalline cellulose, 1 part of silicon dioxide, 2 parts of magnesium stearate, 0.5 parts of surfactant and 0.5 parts of antioxidant; The Chinese medicine composition is composed of the following raw materials in parts by weight: 20 parts of astragalus extract, 10 parts of rehmannia extract, 10 parts of yam extract, 10 parts of kudzu root extract, 5 parts of salvia miltiorrhiza extract, 5 parts of mulberry leaf extract, 3 parts of coptis root extract, 1 part of pepper extract, 5 parts of ophiopogon extract and 5 parts of wolfberry extract; All the Chinese herbal extracts in the Chinese herbal composition are prepared by conventional technical means.

[0022] The specific preparation steps of grafted modified hydroxypropyl methylcellulose are as follows: A1: Dissolve 10 g of hydroxypropyl methylcellulose in 200 mL of dichloromethane, stir and mix well to obtain a 5% hydroxypropyl methylcellulose solution; add 1 M NaOH solution dropwise to the hydroxypropyl methylcellulose solution, maintain the pH at 8, then slowly add 0.1 g of sodium hexadecyl sulfate, stir and react for 6 h at 30°C, and after the reaction is completed, add 1 M HCl solution to adjust the pH to neutral to obtain a reaction mixture; A2: Pour 600 mL of excess deionized water into the reaction mixture prepared in step A1, stir to form a precipitate, centrifuge at 5000 rpm for 10 min, take the precipitate, wash it three times with ethanol, and vacuum dry it at 40° C. for 12 h to obtain grafted modified hydroxypropyl methylcellulose; This embodiment also provides a Chinese medicine composition pill for treating diabetes. The specific preparation steps are as follows: S1: dissolving ethyl cellulose in a solution prepared by ethanol and ethyl acetate in a volume ratio of 1:2, stirring and mixing, and obtaining a 5% ethyl cellulose solution; dissolving polylactic acid-glycolic acid copolymer in a 70wt% ethanol solution, stirring and mixing, and obtaining a 5% polylactic acid-glycolic acid copolymer solution; dissolving PEG-4000 and grafted modified hydroxypropyl methylcellulose in a 70wt% ethanol solution, stirring and mixing, and obtaining a 2% hydrophilic solution; S2: adding the Chinese medicine composition to the hydrophilic solution prepared in step S1, stirring at a speed of 1000 rpm for 20 minutes to mix evenly, then gradually adding Tween-80 and the ethyl cellulose solution and polylactic acid-co-glycolic acid solution prepared in step S1, and continuing to stir at a speed of 1000 rpm for 30 minutes to mix evenly, to obtain a mixed solution; S3: Add the mixed solution prepared in step S2 to a spray drying device, set the parameters as feed rate 5 mL / min, inlet temperature 60°C, outlet temperature 45°C, and atomization pressure 3 bar, to obtain dry particles; mix the dry particles with microcrystalline cellulose, silicon dioxide, magnesium stearate and butylated hydroxyanisole, stir them evenly, add them to a rotary tablet press, set the tableting pressure to 12 kN, and control the pill weight to 200 mg. After the pressing is completed, the Chinese medicine composition pills are obtained.

[0023] Example 2: A Chinese medicine composition pill for treating diabetes, composed of the following raw materials in parts by weight: 60 parts of Chinese medicine composition, 30 parts of ethyl cellulose, 6 parts of polyethylene glycol, 20 parts of polylactic acid-glycolic acid copolymer, 8 parts of grafted modified hydroxypropyl methylcellulose, 25 parts of microcrystalline cellulose, 2 parts of silicon dioxide, 5 parts of magnesium stearate, 0.5 parts of surfactant and 0.5 parts of antioxidant; The Chinese medicine composition is composed of the following raw materials in parts by weight: 25 parts of astragalus extract, 10 parts of rehmannia extract, 12 parts of yam extract, 12 parts of kudzu root extract, 8 parts of salvia miltiorrhiza extract, 6 parts of mulberry leaf extract, 5 parts of coptis root extract, 2 parts of pepper extract, 5 parts of ophiopogon extract and 5 parts of wolfberry extract; All the Chinese medicinal extracts in the Chinese medicinal composition are prepared by conventional technical means.

[0024] 1. The specific preparation steps of the grafted modified hydroxypropyl methylcellulose are as follows: A1: Dissolve 20 g of hydroxypropyl methylcellulose in 200 mL of dichloromethane, stir and mix well to obtain a 10% hydroxypropyl methylcellulose solution; add 1 M NaOH solution dropwise to the hydroxypropyl methylcellulose solution, maintain the pH at 9, then slowly add 1 g of sodium hexadecyl sulfate, stir and react for 4 h at 37°C, and after the reaction is completed, add 1 M HCl solution to adjust the pH to neutral to obtain a reaction mixture; A2: Pour excess deionized water into the reaction mixture prepared in step A1, stir to form a precipitate, centrifuge at 5000 rpm for 10 min, take the precipitate, wash it three times with ethanol, and vacuum dry it at 40° C. for 24 h to obtain grafted modified hydroxypropyl methylcellulose; 2. The specific preparation steps of the Chinese medicine composition pills for treating diabetes are as follows: S1: dissolving ethyl cellulose in a solution prepared by ethanol and ethyl acetate in a volume ratio of 1:2, stirring and mixing, and obtaining a 5% ethyl cellulose solution; dissolving polylactic acid-glycolic acid copolymer in a 70wt% ethanol solution, stirring and mixing, and obtaining a 5% polylactic acid-glycolic acid copolymer solution; dissolving PEG-4000 and grafted modified hydroxypropyl methylcellulose in a 70wt% ethanol solution, stirring and mixing, and obtaining a 2% hydrophilic solution; S2: adding the Chinese medicine composition to the hydrophilic solution prepared in step S1, stirring at a speed of 1000 rpm for 25 min to mix evenly, then gradually adding lecithin and the ethyl cellulose solution and polylactic acid-co-glycolic acid solution prepared in step S1, and continuing to stir at a speed of 1000 rpm for 40 min to mix evenly, to obtain a mixed solution; S3: Add the mixed solution prepared in step S2 to a spray drying device, set the parameters as feed rate 6 mL / min, inlet temperature 65°C, outlet temperature 50°C, and atomization pressure 4 bar, to obtain dry particles; mix the dry particles with microcrystalline cellulose, silicon dioxide, magnesium stearate and vitamin E, stir them evenly, add them to a rotary tablet press, set the tableting pressure to 15 kN, control the pill weight to 300 mg, and after the pressing is completed, obtain the Chinese medicine composition pills.

[0025] Example 3: A Chinese medicine composition pill for treating diabetes, composed of the following raw materials in parts by weight: 55 parts of Chinese medicine composition, 25 parts of ethyl cellulose, 6 parts of polyethylene glycol, 20 parts of polylactic acid-glycolic acid copolymer, 10 parts of grafted modified hydroxypropyl methylcellulose, 26 parts of microcrystalline cellulose, 2 parts of silicon dioxide, 4 parts of magnesium stearate, 01 parts of surfactant and 1 part of antioxidant; The Chinese medicine composition is composed of the following raw materials in parts by weight: 20 parts of astragalus extract, 15 parts of rehmannia extract, 15 parts of yam extract, 10 parts of kudzu root extract, 8 parts of salvia miltiorrhiza extract, 8 parts of mulberry leaf extract, 6 parts of coptis root extract, 2 parts of pepper extract, 8 parts of ophiopogon extract and 8 parts of wolfberry extract; All the Chinese medicinal extracts in the Chinese medicinal composition are prepared by conventional technical means.

[0026] 1. The specific preparation steps of the grafted modified hydroxypropyl methylcellulose are as follows: A1: Dissolve 16 g of hydroxypropyl methylcellulose in 200 mL of dichloromethane, stir and mix well to obtain a hydroxypropyl methylcellulose solution with a concentration of 8%; add 1 M NaOH solution dropwise to the hydroxypropyl methylcellulose solution, maintain the pH at 9.5, then slowly add 0.6 g of sodium hexadecyl sulfate, stir and react for 5 h at 35°C, and after the reaction is completed, add 1 M HCl solution to adjust the pH to neutral to obtain a reaction mixture; A2: Pour excess deionized water into the reaction mixture prepared in step A1, stir to form a precipitate, centrifuge at 5000 rpm for 10 min, take the precipitate, wash it three times with ethanol, and vacuum dry it at 40° C. for 18 h to obtain grafted modified hydroxypropyl methylcellulose; 2. The specific preparation steps of the Chinese medicine composition pills for treating diabetes are as follows: S1: dissolving ethyl cellulose in a solution prepared by ethanol and ethyl acetate in a volume ratio of 1:2, stirring and mixing, and obtaining a 5% ethyl cellulose solution; dissolving polylactic acid-glycolic acid copolymer in a 70wt% ethanol solution, stirring and mixing, and obtaining a 5% polylactic acid-glycolic acid copolymer solution; dissolving PEG-4000 and grafted modified hydroxypropyl methylcellulose in a 70wt% ethanol solution, stirring and mixing, and obtaining a 2% hydrophilic solution; S2: adding the Chinese medicine composition to the hydrophilic solution prepared in step S1, stirring at a speed of 1000 rpm for 25 minutes to mix evenly, then gradually adding Tween-80 and the ethyl cellulose solution and polylactic acid-co-glycolic acid solution prepared in step S1, and continuing to stir at a speed of 1000 rpm for 50 minutes to mix evenly, to obtain a mixed solution; S3: Add the mixed solution prepared in step S2 to a spray drying device, set the parameters as feed rate 7 mL / min, inlet temperature 60°C, outlet temperature 55°C, and atomization pressure 3.5 bar, to obtain dry particles; mix the dry particles with microcrystalline cellulose, silicon dioxide, magnesium stearate and tea polyphenols, stir them evenly, add them to a rotary tablet press, set the tableting pressure to 18 kN, control the pill weight to 300 mg, and after the pressing is completed, obtain the Chinese medicine composition pills.

[0027] Example 4: A Chinese medicine composition pill for treating diabetes, composed of the following raw materials in parts by weight: 60 parts of Chinese medicine composition, 30 parts of ethyl cellulose, 8 parts of polyethylene glycol, 20 parts of polylactic acid-glycolic acid copolymer, 12 parts of grafted modified hydroxypropyl methylcellulose, 30 parts of microcrystalline cellulose, 3 parts of silicon dioxide, 5 parts of magnesium stearate, 1 part of surfactant and 1 part of antioxidant; The Chinese medicine composition is composed of the following raw materials in parts by weight: 25 parts of astragalus extract, 15 parts of rehmannia extract, 15 parts of yam extract, 15 parts of kudzu root extract, 10 parts of salvia miltiorrhiza extract, 10 parts of mulberry leaf extract, 8 parts of coptis root extract, 3 parts of pepper extract, 10 parts of ophiopogon extract and 10 parts of wolfberry extract; All the Chinese medicinal extracts in the Chinese medicinal composition are prepared by conventional technical means.

[0028] 1. The specific preparation steps of the grafted modified hydroxypropyl methylcellulose are as follows: A1: Dissolve 20 g of hydroxypropyl methylcellulose in 200 mL of dichloromethane, stir and mix well to obtain a 10% hydroxypropyl methylcellulose solution; add 1 M NaOH solution dropwise to the hydroxypropyl methylcellulose solution, maintain the pH at 10, then slowly add 1 g of sodium hexadecyl sulfate, continue stirring and react at 40°C for 2 h, and after the reaction is completed, add 1 M HCl solution to adjust the pH to neutral to obtain a reaction mixture; A2: Pour excess deionized water into the reaction mixture prepared in step A1, stir to form a precipitate, centrifuge at 5000 rpm for 10 min, take the precipitate, wash it three times with ethanol, and vacuum dry it at 40° C. for 24 h to obtain grafted modified hydroxypropyl methylcellulose; 2. The specific preparation steps of the Chinese medicine composition pills for treating diabetes are as follows: S1: dissolving ethyl cellulose in a solution prepared by ethanol and ethyl acetate in a volume ratio of 1:2, stirring and mixing, and obtaining a 5% ethyl cellulose solution; dissolving polylactic acid-glycolic acid copolymer in a 70wt% ethanol solution, stirring and mixing, and obtaining a 5% polylactic acid-glycolic acid copolymer solution; dissolving PEG-6000 and grafted modified hydroxypropyl methylcellulose in a 70wt% ethanol solution, stirring and mixing, and obtaining a 2% hydrophilic solution; S2: adding the Chinese medicine composition to the hydrophilic solution prepared in step S1, stirring at a speed of 1000 rpm for 30 minutes to mix evenly, then gradually adding polyethylene glycol-stearate and the ethyl cellulose solution and polylactic acid-co-glycolic acid solution prepared in step S1, and continuing to stir at a speed of 1000 rpm for 60 minutes to mix evenly, to obtain a mixed solution; S3: Add the mixed solution prepared in step S2 to a spray drying device, set the parameters as feed rate 8 mL / min, inlet temperature 70°C, outlet temperature 60°C, and atomization pressure 4 bar, to obtain dry particles; mix the dry particles with microcrystalline cellulose, silicon dioxide, magnesium stearate and propyl gallate, stir them evenly, add them to a rotary tablet press, set the tableting pressure to 20 kN, control the pill weight to 300 mg, and after the pressing is completed, obtain the Chinese medicine composition pills.

[0029] Comparative Example 1: The operation of Comparative Example 1 is basically the same as that of Example 2, except that polyethylene glycol is not added in Comparative Example 1.

[0030] Comparative Example 2: The operation of Comparative Example 2 is basically the same as that of Example 2, except that hydroxypropyl methyl fiber is used in Comparative Example 2 instead of grafted modified hydroxypropyl methyl fiber.

[0031] Comparative Example 3: The operation of Comparative Example 3 is basically the same as that of Example 2, except that methyl cellulose is used instead of ethyl cellulose in Comparative Example 3.

[0032] Performance Test: Safety test: 50 mice weighing 25 g were selected and divided into 5 groups, one of which was not subjected to any test as a control group, and the other 4 groups were respectively administered with the Chinese medicine pills prepared in Examples 1 to 4, and the medication was administered orally. Each group was administered with a pill dose of 1 mg and 10 mg, respectively. After 14 days of administration, the behavioral changes, weight changes and deaths of the mice on the 1st, 3rd, 7th and 14th days were recorded. The results are shown in Tables 1 and 2.

[0033] Table 1. Safety test results of 1 mg in mice

[0034] Table 2. Safety test results of 10 mg in mice

[0035] It can be seen from the results in Tables 1 and 2 that the Chinese medicine pills prepared by the present invention have no obvious side effects and no toxicological damage to mice. It can be seen from the results of Example 4 that the loss of appetite of some mice from the first day to the third day may be due to the high proportion of active ingredients in the drug ingredients that stimulate the mouse intestines to a certain extent. In addition, individual differences in mice may also lead to changes in appetite.

[0036] Drug release rate test: Take 3 samples of the Chinese medicine composition pills prepared in Examples 2 to 3 of the present invention and Comparative Examples 1 to 3, respectively, for a total of 18 samples, each sample weighing 100 mg, and dissolve each sample in 500 mL of test solution (495 mL of pH 1.2 phosphate buffer + 5 mL Tween-80), and sample at 15 min, 30 min, 60 min, 90 min, 120 min, and 180 min, respectively. Sample 10 mL at each sampling point, and then replenish 10 mL of solution to determine the dissolution rate (Xn'=Xn+(X1+X2+…+Xn-1)V2 / V1; wherein Xn is the relative percentage dissolution measured after correction for the nth time, Xn' is the relative percentage dissolution actually measured for the nth time, V1 is the volume of the dissolution medium, and V2 is the volume number replenished after each sampling). The results are as follows: Figure 1 shown.

[0037] Depend on Figure 1 As can be seen from the results, the pills prepared by the present invention can quickly release part of the active substances in the early stage to exert their effects, and start to release slowly at the 60th minute, which has an excellent regulating effect on the absorption of the drug; from the results of Comparative Example 1 and Example 2, it can be seen that due to the absence of polyethylene glycol, the surface of the particles lacks a microporous structure, and the water penetration rate is significantly slowed down. At the same time, due to the hydrophobicity of ethyl cellulose and polylactic acid-glycolic acid copolymer, water cannot quickly enter the interior of the drug particles, and the drug release is relatively slow; from the results of Comparative Example 2 and Example 2, it can be seen that the unmodified hydroxypropyl methylcellulose has a strong hydrophilicity and can swell rapidly after contacting water, resulting in a faster initial drug release. Although ethyl cellulose and polylactic acid-glycolic acid copolymer still play a role in delayed release, the rapid swelling of unmodified hydroxypropyl methylcellulose weakens the protective effect of the hydrophobic shell, resulting in a rapid increase in the release rate in the initial stage. From the results of Comparative Example 3 and Example 2, it can be seen that methyl cellulose, as a more hydrophilic material, easily swells after contact with water, which accelerates the initial release rate of the drug. At the same time, methyl cellulose lacks the hydrophobic barrier effect of ethyl cellulose. After the initial release rate of the drug increases, the release control in the middle and late stages is greatly weakened.

[0038] Accelerated stability test: The Chinese medicine composition pill samples prepared in Examples 2 and 3 of the present invention and Comparative Examples 1 to 3 were sealed in commercial packaging and placed at a temperature of 35 ± 5°C and a relative humidity of 80 ± 5% for 6 months. Samples were taken once at the 1st, 2nd, 3rd and 6th month of the test period to test the pH value and calculate the weight change = (weight before test - weight after test) / weight before test × 100%. The results are as follows: Figure 2 and Figure 3 shown.

[0039] Depend on Figure 2 and Figure 3As can be seen from the results, the Chinese medicine pills prepared by the present invention have excellent storage stability, with minimal weight change in the accelerated test, and relatively stable pH change without significant change; as can be seen from the results of Comparative Example 1 and Example 2, the absence of polyethylene glycol has little effect on the hydrophobicity of the Chinese medicine pills, and the weight change is also minimal, and the pH change is also not significantly affected; as can be seen from the results of Comparative Example 2 and Example 2, the unmodified hydroxypropyl methylcellulose has higher hydrophilicity, which may cause it to absorb more water under high humidity conditions, resulting in a large weight change in the later stage of the storage test, and at the same time, the partial release of the drug due to the absorption of water may lead to a large fluctuation in the pH value; as can be seen from the results of Comparative Example 3 and Example 2, methylcellulose, as a hydrophilic material, cannot construct a hydrophobic system, and is easy to absorb water and swell under high humidity conditions, resulting in a more obvious weight change, and at the same time, the release of the drug causes a significant change in the pH value.

[0040] Contact angle test: 10 μL of deionized water was dripped onto the surface of the pills prepared in Example 2 and Comparative Example 1 using a syringe, and the droplet was kept on the surface of the pill for 5 seconds to ensure that the liquid was in full contact with the surface, and the multi-point contact angle (5 positions) was measured to obtain an average value, and the contact angle value of each group of samples was recorded; then the pills prepared in Example 2 and Comparative Example 1 were respectively placed in a disintegration tester to simulate the in vivo water environment (using PBS buffer at 37°C), and the time for the pills to completely disintegrate (disperse into particles) was recorded. All results were tested three times and the average value was taken. The contact angle results and the pill disintegration results are shown in Table 2.

[0041] Table 2. Contact angle test results

[0042] From the results in Table 2, it can be seen that the addition of polyethylene glycol does not have a significant effect on the overall hydrophobicity of the material. The pills still retain good hydrophobicity. At the same time, due to the presence of polyethylene glycol, micropores are formed after contact with the water environment, which accelerates the disintegration rate of the early pills. The disintegration time of the pills is relatively fast, which is also beneficial to the rapid release of some active ingredients in the early stage.

[0043] Friability test: 20 pills of each of the Chinese medicine composition pills prepared in Examples 2 to 3 and Comparative Examples 1 to 3 were placed in a friability tester. The rotation speed and rotation time of the friability tester were set according to the requirements of the pharmacopoeia. The percentage change in the weight of the pills before and after the test was calculated, i.e., friability = (weight before test - weight after test) / weight before test × 100%. The results are as follows: Figure 4 shown.

[0044] Depend on Figure 4As can be seen from the results, the Chinese medicine composition pills prepared by the present invention have excellent shock resistance and wear resistance, and the friability is far less than 1%; from the results of Comparative Example 1 and Example 2, it can be seen that the absence of polyethylene glycol has no obvious effect on the strength of the pills; from the results of Comparative Example 2 and Example 2, it can be seen that the mechanical strength and wear resistance of unmodified hydroxypropyl methylcellulose are lower than those of its modified product, and although ethyl cellulose and polylactic acid-glycolic acid copolymer can provide a certain protection, the overall resistance to crushing of the pills is reduced due to the poor synergy of the unmodified hydroxypropyl methylcellulose; from the results of Comparative Example 3 and Example 2, it can be seen that compared with ethyl cellulose, methyl cellulose is a hydrophilic material with lower mechanical strength and easy moisture absorption, which makes the pills more easily broken under friction and impact, and methyl cellulose replaces ethyl cellulose, and the synergy with polylactic acid-glycolic acid copolymer and modified hydroxypropyl methylcellulose is extremely poor, resulting in a decrease in overall hydrophobicity and mechanical properties.

[0045] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A Chinese medicine composition pill for treating diabetes, characterized in that: The invention is composed of the following raw materials in parts by weight: 50-60 parts of a traditional Chinese medicine composition, 20-30 parts of ethyl cellulose, 5-8 parts of polyethylene glycol, 15-20 parts of a polylactic acid-glycolic acid copolymer, 8-12 parts of grafted modified hydroxypropyl methylcellulose, 25-30 parts of microcrystalline cellulose, 1-3 parts of silicon dioxide, 2-5 parts of magnesium stearate, 0.5-1 part of a surfactant and 0.5-1 part of an antioxidant.

2. A Chinese medicine composition pill for treating diabetes according to claim 1, characterized in that: The Chinese medicine composition is composed of the following raw materials in parts by weight: 20 to 25 parts of astragalus extract, 10 to 15 parts of rehmannia root extract, 10 to 15 parts of yam extract, 10 to 15 parts of kudzu root extract, 5 to 10 parts of salvia miltiorrhiza extract, 5 to 10 parts of mulberry leaf extract, 3 to 8 parts of coptis root extract, 1 to 3 parts of pepper extract, 5 to 10 parts of ophiopogon japonicus extract and 5 to 10 parts of wolfberry extract.

3. A Chinese medicine composition pill for treating diabetes according to claim 2, characterized in that: The molecular weight of the polyethylene glycol is any one of PEG-4000 and PEG-6000.

4. A Chinese medicine composition pill for treating diabetes according to claim 3, characterized in that: The surfactant is any one of Tween-80, lecithin and polyethylene glycol-stearate.

5. A Chinese medicine composition pill for treating diabetes according to claim 4, characterized in that: The antioxidant is any one of vitamin E, butylated hydroxyanisole, tea polyphenols and propyl gallate.

6. A Chinese medicine composition pill for treating diabetes according to claim 5, characterized in that: The specific preparation steps of the grafted modified hydroxypropyl methylcellulose are as follows: A1: dissolving hydroxypropyl methylcellulose in dichloromethane, stirring and mixing to obtain a hydroxypropyl methylcellulose solution; dropping a NaOH solution into the hydroxypropyl methylcellulose solution to maintain the pH, then slowly adding sodium dodecyl sulfate, stirring and reacting continuously, and after the reaction is completed, adding an HCl solution to adjust the pH to neutral to obtain a reaction mixture; A2: Pour excess deionized water into the reaction mixture prepared in step A1, stir to form a precipitate, centrifuge, take the precipitate, wash it three times with ethanol, and vacuum dry it to obtain grafted modified hydroxypropyl methylcellulose; The amount of sodium lauryl sulfate used in step A1 is 1 to 5% of the mass amount of hydroxypropyl methylcellulose.

7. A method for preparing a Chinese medicine composition pill for treating diabetes according to any one of claims 1 to 6, characterized in that: The specific preparation steps are as follows: S1: dissolving ethyl cellulose in a solution prepared by ethanol and ethyl acetate in a volume ratio of 1:2, stirring and mixing uniformly to obtain an ethyl cellulose solution; dissolving polylactic acid-glycolic acid copolymer in an ethanol solution, stirring and mixing uniformly to obtain a polylactic acid-glycolic acid copolymer solution; dissolving polyethylene glycol and grafted modified hydroxypropyl methylcellulose in an ethanol solution, stirring and mixing uniformly to obtain a hydrophilic solution; S2: adding the Chinese medicine composition to the hydrophilic solution prepared in step S1, stirring and mixing evenly, then gradually adding a surfactant and the ethyl cellulose solution and the polylactic acid-co-glycolic acid solution prepared in step S1, and continuing to stir and mix evenly to obtain a mixed solution; S3: adding the mixed solution prepared in step S2 to a spray drying device to obtain dry particles; mixing the dry particles with microcrystalline cellulose, silicon dioxide, magnesium stearate and antioxidants and stirring them evenly, adding them to a rotary tablet press for tableting, and obtaining Chinese medicine composition pills after the compression is completed.

8. A method for preparing the Chinese medicine composition pills for treating diabetes according to claim 7, characterized in that: The spray drying setting parameters in step S3 are feed rate 5-8 mL / min, inlet temperature 60-70° C., outlet temperature 45-60° C., and atomization pressure 3-4 bar.

Images