Medicament for treating diabetes and preparation method thereof

Abstract

The invention discloses a medicament for treating diabetes and a preparation method thereof, and relates to the field of high polymer materials. When the medicament for treating diabetes is prepared, chitosan and thioglycollic acid react to prepare sulfydryl modified chitosan; reacting the sulfydryl modified chitosan with a mixed solution of zein and capsaicin to prepare capsaicin sustained-release microspheres; the preparation method comprises the following steps: reacting metformin hydrochloride, gelatin, hydroxyethyl cellulose and polyvinyl alcohol to prepare metformin hydrochloride microspheres; the capsaicin sustained-release microspheres, metformin hydrochloride microspheres, magnesium stearate, carboxymethyl starch sodium and adhesive particles are tableted to prepare tablets, and the tablets are coated with a coating solution to prepare the capsaicin sustained-release tablet. The medicament for treating diabetes mellitus prepared by the invention has good slow release performance and low irritation to stomach.

Description

Technical Field

[0001] The present invention relates to the field of medicaments, and particularly to a medicament for treating diabetes and a preparation method thereof. Background Art

[0002] Diabetes is a chronic, prevalent non-communicable disease with many characteristics, such as a long treatment period, easy occurrence of various complications (such as kidney disease, eye disease), and recurrence of the condition. It has now seriously endangered the health of people all over the world. Diabetes does not directly threaten human life safety, but due to the relatively low insulin secretion in patients, it can induce many other diseases, seriously reducing the living standards of patients, and even leading to death if not controlled.

[0003] Capsaicin is a pungent alkaloid present in chili peppers. It has attracted wide attention due to its bioactive effects such as cardiovascular protection, analgesia, anti-inflammation, antioxidant, anti-cancer, and weight loss. However, capsaicin is metabolized rapidly in the body, with a half-life in humans of only 25 minutes, which limits the exertion of its biological activity. In addition, due to the strong irritation of capsaicin, direct oral administration may cause oral inflammation, gastric ulcers, and gastrointestinal spasms, limiting its scope of application. Metformin hydrochloride is a commonly used drug for treating type 2 diabetes. In the present invention, capsaicin and metformin hydrochloride are made into a medicament, which has a good sustained-release effect and low irritation to the stomach, and has a good market prospect. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation method of a medicament for treating diabetes to solve the problems existing in the prior art.

[0005] To solve the above technical problems, the present invention provides the following technical solutions: A medicament for treating diabetes, wherein the medicament for treating diabetes is prepared by reacting chitosan and mercaptoacetic acid to obtain mercapto-modified chitosan; reacting the mercapto-modified chitosan with a mixed solution of zein and capsaicin to obtain capsaicin sustained-release microspheres; reacting metformin hydrochloride, gelatin, hydroxyethyl cellulose, and polyvinyl alcohol to obtain metformin hydrochloride microspheres; and tableting the capsaicin sustained-release microspheres, metformin hydrochloride microspheres, magnesium stearate, sodium carboxymethyl starch, and binder particles, and then coating the tablets with a coating solution.

[0006] A preparation method of a medicament for treating diabetes, comprising the following preparation steps: (1) Mix mercapto-modified chitosan and deionized water at a mass ratio of 0.3:100, and adjust the pH to 4 with 0.09 mol / L hydrochloric acid solution to obtain a chitosan solution; slowly add a mixed solution of zein and capsaicin that is 0.5 times the mass of the chitosan solution to the chitosan solution, with a rotation speed of 2800 - 3200 r / min, centrifuge to separate the precipitate, and freeze-dry the solid to obtain capsaicin sustained-release microspheres; (2) Mix polyvinyl alcohol and deionized water at a mass ratio of 1:(95 - 105), heat at 95 - 105 °C for 20 - 30 min to obtain the outer aqueous phase; use an emulsifier to disperse the primary emulsion in the outer aqueous phase to a homogeneous state, with a volume ratio of the primary emulsion to the outer aqueous phase of 1:(5 - 10), an emulsification time of 1 - 3 min, and a rotation speed of 5000 - 6000 r / min to obtain a multiple emulsion, rotary evaporate at 30 - 40 °C for 10 - 20 min, centrifuge to separate the solid after cooling to room temperature, and freeze-dry the solid to obtain metformin hydrochloride microspheres; pass the capsaicin sustained-release microspheres and metformin hydrochloride microspheres through an 80-mesh sieve, and pass magnesium stearate and sodium carboxymethyl starch through a 100-mesh sieve; granulate the 5% hydroxypropyl cellulose aqueous solution by extrusion through a 24-mesh sieve, and dry at 55 - 65 °C for 6 - 8 h to obtain binder granules; mix the capsaicin sustained-release microspheres, metformin hydrochloride microspheres, magnesium stearate, sodium carboxymethyl starch, and binder granules, and compress them into tablets with a diameter of 10 mm and a hardness of 50 - 60 N to obtain tablets; (3) Wipe off the fine powder from the tablets and preheat them in a coating pan at 35 - 45 °C for 6 - 8 min. Slowly increase the rotation speed of the coating pan to 25 r / min, with an air inlet temperature of 40 - 45 °C and a spraying pressure of 2 - 3 kg / cm 2 and perform coating with the coating solution until the film weight gain reaches 4%, then continue to dry with hot air for 10 - 20 min, cool to room temperature, and dry in an oven at 35 - 40 °C for 3 - 5 h to obtain the medicament for treating diabetes.

[0007] As an optimization, the preparation method of the mercapto-modified chitosan described in step (1) is: mix chitosan and 0.09 mol / L hydrochloric acid solution at a mass ratio of 1:100, stir at 200 - 300 r / min for 30 min, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride that is 2.2 - 2.6 times the mass of chitosan and mercaptoacetic acid with the same mass as chitosan, adjust the pH to 5 with 0.5 mol / L sodium hydroxide solution, continue to stir at room temperature for 3 - 5 h, dialyze with a cellulose membrane dialysis bag with a molecular weight cut-off of 12 kDa at 8 °C for 4 days, and the dialysis media are in turn: 5 mmol / L hydrochloric acid solution for 24 h; 5 mmol / L hydrochloric acid solution containing 1% sodium chloride for 48 h; 1 mmol / L hydrochloric acid solution for 24 h. After dialysis, freeze-dry to obtain.

[0008] As an optimization, the preparation method of the mixed solution of zein and capsaicin in step (1) is as follows: Mix zein, capsaicin, and an ethanol solution with a mass concentration of 80% in a mass ratio of 0.3:0.03:50 to obtain it.

[0009] As an optimization, the preparation method of the colostrum in step (2) is as follows: Mix metformin hydrochloride, gelatin, and deionized water in a mass ratio of 1:(1.5 - 2.5):(5 - 15) to obtain the inner aqueous phase; mix hydroxyethyl cellulose and dichloromethane in a mass ratio of 1:(85 - 95) to obtain the oil phase; mix the inner aqueous phase and the oil phase in a volume ratio of 1:(20 - 40), and ultrasonicate with an ultrasonic cell disruptor for 15 - 35 s, with an ultrasonic power of 100 W - 300 W and a pulse of 5 s to obtain it.

[0010] As an optimization, the preparation method of the coating solution in step (3) is as follows: Swell acrylic resin in an ethanol solution with a mass concentration of 95% at 100 times its mass for 22 - 26 h, and add triethyl citrate at 0.2 times the mass of the acrylic resin and mix well to obtain a resin solution; mix talc powder and an ethanol solution with a mass concentration of 95% in a mass ratio of 1:(8 - 12) to obtain a talc powder suspension, slowly pour the talc powder suspension into the resin solution, stir at 100 - 200 r / min for 10 - 20 min, and pass through a 40 - mesh sieve to obtain it.

[0011] Compared with the prior art, the beneficial effects achieved by the present invention are as follows: When preparing the medicament for treating diabetes, the present invention reacts chitosan and mercaptoacetic acid to obtain mercapto - modified chitosan; reacts the mercapto - modified chitosan with the mixed solution of zein and capsaicin to obtain capsaicin sustained - release microspheres; reacts metformin hydrochloride, gelatin, hydroxyethyl cellulose, and polyvinyl alcohol to obtain metformin hydrochloride microspheres; tablets are prepared by tabletting capsaicin sustained - release microspheres, metformin hydrochloride microspheres, magnesium stearate, carboxymethyl starch sodium, and binder particles, and the tablets are coated with a coating solution to obtain them.

[0012] The reaction of mercapto - modified chitosan with the mixed solution of zein and capsaicin to obtain capsaicin sustained - release microspheres. Zein has high hydrophobicity, and capsaicin is a hydrophobic alkaloid. Zein has a good coating effect on capsaicin, making the medicament for treating diabetes have a good sustained - release effect; the embedding of metformin hydrochloride by gelatin and hydroxyethyl cellulose effectively improves the sustained - release effect of the medicament for treating diabetes.

[0013] The coating solution prepared from acrylic resin, triethyl citrate, and talc powder has a good coating effect. The structural characteristics of acrylic resin make its structure stable when the pH is lower than 7 and start to dissolve when the pH is greater than 7, enabling the coated tablets to be released only in the intestinal solution and reducing the irritation of the drug to the stomach. Specific embodiments

[0014] The technical solutions in the embodiments 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 a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0015] Embodiment 1: A preparation method of a medicament for treating diabetes, comprising the following preparation steps: (1) Mix chitosan and 0.09 mol / L hydrochloric acid solution at a mass ratio of 1:100, stir at 200 r / min for 30 min, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride 2.2 times the mass of chitosan and mercaptoacetic acid equal to the mass of chitosan, adjust the pH to 5 with 0.5 mol / L sodium hydroxide solution, continue stirring at room temperature for 3 h, dialyze with a cellulose membrane dialysis bag with a cut-off molecular weight of 12 kDa at 8 °C for 4 days, and the dialysis media are successively: 5 mmol / L hydrochloric acid solution for 24 h; 5 mmol / L hydrochloric acid solution containing 1% sodium chloride for 48 h; 1 mmol / L hydrochloric acid solution for 24 h. After dialysis, freeze-dry to obtain mercapto-modified chitosan; mix mercapto-modified chitosan and deionized water at a mass ratio of 0.3:100, and adjust the pH to 4 with 0.09 mol / L hydrochloric acid solution to obtain a chitosan solution; mix zein, capsaicin, and 80% ethanol solution by mass ratio of 0.3:0.03:50 to obtain a mixed solution of zein and capsaicin; slowly add a mixed solution of zein and capsaicin 0.5 times the mass of the chitosan solution to the chitosan solution at a rotation speed of 2800 r / min, centrifuge to separate the precipitate, and freeze-dry the solid to obtain capsaicin sustained-release microspheres; (2) Mix metformin hydrochloride, gelatin, and deionized water at a mass ratio of 1:1.5:5 to obtain an internal aqueous phase; mix hydroxyethyl cellulose and dichloromethane at a mass ratio of 1:85 to obtain an oil phase; mix the internal aqueous phase and the oil phase at a volume ratio of 1:20, and ultrasonicate with an ultrasonic cell disruptor for 15 s, the ultrasonic power is 100 W, and the pulse is 5 s to obtain primary emulsion; mix polyvinyl alcohol and deionized water at a mass ratio of 1:95, heat at 95 °C for 20 min to obtain an external aqueous phase; disperse the primary emulsion in the external aqueous phase into a homogeneous state with an emulsifier, the volume ratio of the primary emulsion to the external aqueous phase is 1:5, the emulsification time is 1 min, and the rotation speed is 5000 r / min to obtain a multiple emulsion. Rotavapor at 30 °C for 10 min, cool to room temperature and then centrifuge to separate the solid, and freeze-dry the solid to obtain metformin hydrochloride microspheres; (3) Pass the capsaicin sustained-release microspheres and metformin hydrochloride microspheres through an 80-mesh sieve, and pass the magnesium stearate and sodium carboxymethyl starch through a 100-mesh sieve; Granulate the 5% (mass concentration) aqueous solution of hydroxypropyl cellulose by extrusion through a 24-mesh sieve and dry it at 55 °C for 6 h to obtain the binder granules; Mix the capsaicin sustained-release microspheres, metformin hydrochloride microspheres, magnesium stearate, sodium carboxymethyl starch, and binder granules evenly and press them into tablets with a diameter of 10 mm and a hardness of 50 N to obtain the tablets; Swell the acrylic resin in a 95% (mass concentration) ethanol solution 100 times its mass for 22 h, add 0.2 times the mass of the acrylic resin of triethyl citrate and mix evenly to obtain the resin solution; Mix talcum powder and a 95% (mass concentration) ethanol solution in a mass ratio of 1:8 to obtain a talcum powder suspension, slowly pour the talcum powder suspension into the resin solution, stir at 100 r / min for 10 min, and pass through a 40-mesh sieve to obtain the coating solution; Wipe off the fine powder from the tablets and preheat them in a coating pan at 35 °C for 6 min. Slowly increase the rotation speed of the coating pan to 25 r / min, with the inlet air temperature at 40 °C and the spraying pressure at 2 kg / cm 2 , coat with the coating solution until the film weight gain reaches 4%, continue to dry with hot air for 10 min, cool to room temperature, and dry in an oven at 35 °C for 3 h to obtain the medicament for treating diabetes.

[0016] Example 2: A preparation method of a medicament for treating diabetes, comprising the following preparation steps: (1) Mix chitosan and a 0.09 mol / L hydrochloric acid solution in a mass ratio of 1:100, stir at 250 r / min for 30 min, add 2.4 times the mass of chitosan of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and the same mass of mercaptoacetic acid as chitosan, adjust the pH to 5 with a 0.5 mol / L sodium hydroxide solution, continue to stir at room temperature for 4 h, dialyze with a cellulose membrane dialysis bag with a cut-off molecular weight of 12 kDa at 8 °C for 4 days, and the dialysis media are successively: 5 mmol / L hydrochloric acid solution for 24 h; 5 mmol / L hydrochloric acid solution containing 1% sodium chloride for 48 h; 1 mmol / L hydrochloric acid solution for 24 h. After dialysis, freeze-dry to obtain the mercapto-modified chitosan; Mix the mercapto-modified chitosan and deionized water in a mass ratio of 0.3:100 and adjust the pH to 4 with a 0.09 mol / L hydrochloric acid solution to obtain the chitosan solution; Mix zein, capsaicin, and an 80% (mass concentration) ethanol solution in a mass ratio of 0.3:0.03:50 to obtain a mixed solution of zein and capsaicin; Slowly add 0.5 times the mass of the chitosan solution of the mixed solution of zein and capsaicin to the chitosan solution at a rotation speed of 3000 r / min, centrifuge to separate the precipitate, and freeze-dry the solid to obtain the capsaicin sustained-release microspheres; (2) Mix metformin hydrochloride, gelatin, and deionized water in a mass ratio of 1:2:10 to obtain the internal aqueous phase; mix hydroxyethyl cellulose and dichloromethane in a mass ratio of 1:90 to obtain the oil phase; mix the internal aqueous phase and the oil phase in a volume ratio of 1:30, and ultrasonicate for 25 s using an ultrasonic cell disruptor with an ultrasonic power of 200 W and a pulse of 5 s to obtain the primary emulsion; mix polyvinyl alcohol and deionized water in a mass ratio of 1:100, heat at 100 °C for 25 min to obtain the external aqueous phase; disperse the primary emulsion in the external aqueous phase to a homogeneous state using an emulsifier, with a volume ratio of the primary emulsion to the external aqueous phase of 1:7.5, an emulsification time of 2 min, and a rotation speed of 5500 r / min to obtain the multiple emulsion, rotary evaporate at 35 °C for 15 min, centrifuge to separate the solid after cooling to room temperature, and freeze-dry the solid to obtain metformin hydrochloride microspheres; (3) Pass the capsaicin sustained-release microspheres and metformin hydrochloride microspheres through an 80-mesh sieve, and pass magnesium stearate and sodium carboxymethyl starch through a 100-mesh sieve; granulate the 5% (mass concentration) aqueous solution of hydroxypropyl cellulose by extrusion through a 24-mesh sieve and dry at 60 °C for 7 h to obtain the binder granules; mix the capsaicin sustained-release microspheres, metformin hydrochloride microspheres, magnesium stearate, sodium carboxymethyl starch, and binder granules and compress them into tablets with a diameter of 10 mm and a hardness of 55 N to obtain the tablets; swell the acrylic resin in a 95% (mass concentration) ethanol solution 100 times its mass for 24 h, add triethyl citrate 0.2 times the mass of the acrylic resin and mix well to obtain the resin solution; mix talc powder and the 95% (mass concentration) ethanol solution in a mass ratio of 1:10 to obtain the talc powder suspension, slowly pour the talc powder suspension into the resin solution, stir at 150 r / min for 15 min, and pass through a 40-mesh sieve to obtain the coating solution; wipe off the fine powder from the tablets, preheat in a coating pan at 40 °C for 7 min, gradually increase the rotation speed of the coating pan to 25 r / min, with an inlet air temperature of 42.5 °C and a spraying pressure of 2.5 kg / cm 2 , coat with the coating solution until the film weight gain reaches 4%, continue to dry with hot air for 15 min, cool to room temperature, and dry in an oven at 37.5 °C for 4 h to obtain the medicament for treating diabetes.

[0017] Example 3: A preparation method of a medicament for treating diabetes, comprising the following preparation steps: (1)Mix chitosan and 0.09 mol / L hydrochloric acid solution at a mass ratio of 1:100, stir at 300 r / min for 30 min, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride which is 2.6 times the mass of chitosan and mercaptoacetic acid with the same mass as chitosan, adjust the pH to 5 with 0.5 mol / L sodium hydroxide solution, continue to stir at room temperature for 5 h, dialyze with a cellulose membrane dialysis bag with a molecular weight cut-off of 12 kDa at 8 °C for 4 days, and the dialysis media are as follows: 5 mmol / L hydrochloric acid solution for 24 h; 5 mmol / L hydrochloric acid solution containing 1% sodium chloride for 48 h; 1 mmol / L hydrochloric acid solution for 24 h. After dialysis, freeze-dry to obtain thiol-modified chitosan; mix thiol-modified chitosan and deionized water at a mass ratio of 0.3:100, and adjust the pH to 4 with 0.09 mol / L hydrochloric acid solution to obtain a chitosan solution; mix zein, capsaicin, and 80% ethanol solution by mass ratio of 0.3:0.03:50 to obtain a mixed solution of zein and capsaicin; slowly add a mixed solution of zein and capsaicin which is 0.5 times the mass of the chitosan solution to the chitosan solution, with a rotation speed of 3200 r / min, centrifuge to separate the precipitate, and freeze-dry the solid to obtain capsaicin sustained-release microspheres; (2)Mix metformin hydrochloride, gelatin, and deionized water at a mass ratio of 1:2.5:15 to obtain the internal aqueous phase; mix hydroxyethyl cellulose and dichloromethane at a mass ratio of 1:95 to obtain the oil phase; mix the internal aqueous phase and the oil phase at a volume ratio of 1:40, and ultrasonicate with an ultrasonic cell disruptor for 35 s, with an ultrasonic power of 300 W and a pulse of 5 s to obtain the primary emulsion; mix polyvinyl alcohol and deionized water at a mass ratio of 1:105, heat at 105 °C for 30 min to obtain the external aqueous phase; disperse the primary emulsion in the external aqueous phase to a homogeneous state with an emulsifier, with a volume ratio of the primary emulsion to the external aqueous phase of 1:10, an emulsification time of 3 min, and a rotation speed of 6000 r / min to obtain the multiple emulsion, rotary evaporate at 40 °C for 20 min, centrifuge to separate the solid after cooling to room temperature, and freeze-dry the solid to obtain metformin hydrochloride microspheres; (3) Pass the capsaicin sustained-release microspheres and metformin hydrochloride microspheres through an 80-mesh sieve, and pass magnesium stearate and sodium carboxymethyl starch through a 100-mesh sieve; Granulate the 5% (mass concentration) aqueous solution of hydroxypropyl cellulose by extruding it through a 24-mesh sieve, and dry it at 65 °C for 8 h to obtain binder granules; Mix the capsaicin sustained-release microspheres, metformin hydrochloride microspheres, magnesium stearate, sodium carboxymethyl starch, and binder granules evenly, and press them into tablets with a diameter of 10 mm and a hardness of 60 N to obtain tablets; Swell the acrylic resin in a 95% (mass concentration) ethanol solution 100 times its mass for 26 h, add 0.2 times the mass of the acrylic resin of triethyl citrate and mix evenly to obtain a resin solution; Mix talc powder and a 95% (mass concentration) ethanol solution in a mass ratio of 1:12 to obtain a talc suspension, slowly pour the talc suspension into the resin solution, stir at 200 r / min for 20 min, and pass through a 40-mesh sieve to obtain a coating solution; Wipe off the fine powder from the tablets, preheat them in a coating pan at 45 °C for 8 min, gradually increase the rotation speed of the coating pan to 25 r / min, the inlet air temperature is 45 °C, and the spray pressure is 3 kg / cm 2 , coat with the coating solution, stop when the film weight gain reaches 4%, continue to dry with hot air for 20 min, cool to room temperature, and dry in an oven at 40 °C for 5 h to obtain a medicament for treating diabetes.

[0018] Comparative Example 1: The difference between Comparative Example 1 and Example 2 is that step (1) is not carried out, and step (3) is modified as follows: Pass the capsaicin and metformin hydrochloride microspheres through an 80-mesh sieve, and pass magnesium stearate and sodium carboxymethyl starch through a 100-mesh sieve; Granulate the 5% (mass concentration) aqueous solution of hydroxypropyl cellulose by extruding it through a 24-mesh sieve, and dry it at 60 °C for 7 h to obtain binder granules; Mix the capsaicin, metformin hydrochloride microspheres, magnesium stearate, sodium carboxymethyl starch, and binder granules evenly, and press them into tablets with a diameter of 10 mm and a hardness of 55 N to obtain tablets; Swell the acrylic resin in a 95% (mass concentration) ethanol solution 100 times its mass for 24 h, add 0.2 times the mass of the acrylic resin of triethyl citrate and mix evenly to obtain a resin solution; Mix talc powder and a 95% (mass concentration) ethanol solution in a mass ratio of 1:10 to obtain a talc suspension, slowly pour the talc suspension into the resin solution, stir at 150 r / min for 15 min, and pass through a 40-mesh sieve to obtain a coating solution; Wipe off the fine powder from the tablets, preheat them in a coating pan at 40 °C for 7 min, gradually increase the rotation speed of the coating pan to 25 r / min, the inlet air temperature is 42.5 °C, and the spray pressure is 2.5 kg / cm 2 , coat with the coating solution, stop when the film weight gain reaches 4%, continue to dry with hot air for 15 min, cool to room temperature, and dry in an oven at 37.5 °C for 4 h to obtain a medicament for treating diabetes. The remaining steps are the same as those in Example 2.

[0019] Comparative Example 2: The difference between Comparative Example 2 and Example 2 is that step (2) is not carried out, and step (3) is modified as follows: Capsaicin sustained-release microspheres and metformin hydrochloride are sieved through a 80-mesh sieve, and magnesium stearate and sodium carboxymethyl starch are sieved through a 100-mesh sieve; An aqueous solution of hydroxypropyl cellulose with a mass concentration of 5% is granulated by extrusion through a 24-mesh sieve and dried at 60 °C for 7 h to obtain binder granules; Capsaicin sustained-release microspheres, metformin hydrochloride, magnesium stearate, sodium carboxymethyl starch, and binder granules are mixed evenly and pressed into tablets with a diameter of 10 mm and a hardness of 55 N to obtain tablets; Acrylic resin is swollen in an ethanol solution with a mass concentration of 95% and 100 times its mass for 24 h, and triethyl citrate 0.2 times the mass of the acrylic resin is added and mixed evenly to obtain a resin solution; Talc powder and an ethanol solution with a mass concentration of 95% are mixed evenly according to a mass ratio of 1:10 to obtain a talc powder suspension, the talc powder suspension is slowly poured into the resin solution, stirred at 150 r / min for 15 min, and sieved through a 40-mesh sieve to obtain a coating solution; After wiping off the fine powder from the tablets, they are preheated in a coating pan at 40 °C for 7 min, the rotation speed of the coating pan is slowly increased to 25 r / min, the inlet air temperature is 42.5 °C, and the spray pressure is 2.5 kg / cm 2 , and coated with the coating solution until the film weight gain reaches 4%, then continue to dry with hot air for 15 min, cool to room temperature, and dry in an oven at 37.5 °C for 4 h to obtain a medicament for treating diabetes. The remaining steps are the same as those in Example 2.

[0020] Comparative Example 3: The difference between Comparative Example 3 and Example 2 is that step (3) is modified as follows: Capsaicin sustained-release microspheres and metformin hydrochloride microspheres are sieved through a 80-mesh sieve, and magnesium stearate and sodium carboxymethyl starch are sieved through a 100-mesh sieve; An aqueous solution of hydroxypropyl cellulose with a mass concentration of 5% is granulated by extrusion through a 24-mesh sieve and dried at 60 °C for 7 h to obtain binder granules; Capsaicin sustained-release microspheres, metformin hydrochloride microspheres, magnesium stearate, sodium carboxymethyl starch, and binder granules are mixed evenly and pressed into tablets to obtain a medicament for treating diabetes. The remaining steps are the same as those in Example 2.

[0021] Test Example 1: Sustained-release effect test: Prepare a simulated gastric digestive fluid containing 2000 U / mL pepsin and a simulated intestinal digestive fluid containing 100 U / mL pancreatin. Place the medicaments obtained in each example and comparative example in 10 mL of gastric digestive fluid, adjust the pH value to 3.0, and then digest at a rate of 100 r / min in a 37 °C water bath for 2 h. After the gastric digestion is completed, filter, place the solid in 5 mL of deionized water, adjust the pH value to 7.0, then add 20 mL of intestinal digestive fluid and mix evenly, and carry out 2 h of simulated intestinal digestion under the same water bath oscillation conditions.

[0022] (1) During the digestion process, 200 μL of samples were taken from the digestive juice every 30 min. The taken samples were quickly frozen with liquid nitrogen and then freeze-dried. 0.2 mL of anhydrous methanol was added to the obtained powder, and it was vortexed for 30 s to extract the capsaicin released from the medicament; after centrifugation (10,000 Xg, 10 min), the capsaicin content in the supernatant was determined by liquid chromatography method, and the release rate was calculated according to The results are shown in Table 1.

[0023] (2) During the digestion process, 200 μL of samples were taken from the digestive juice every 30 min. The taken samples were quickly frozen with liquid nitrogen and then freeze-dried. 0.2 mL of deionized water was added to the obtained powder, and it was vortexed for 30 s to extract the metformin hydrochloride released from the medicament; after centrifugation (10,000 Xg, 10 min), the metformin hydrochloride content in the supernatant was determined by liquid chromatography method, and the release rate was calculated according to The results are shown in Table 2.

[0024] Table 1 ; Table 2 ; From the comparison of the experimental data of Examples 1-3 and Comparative Examples 1-3 in Tables 1 and 2, it can be found that the medicament for treating diabetes prepared by the present invention has a good sustained-release effect.

[0025] The difference between Comparative Example 1 and Example 2 is that capsaicin was directly added without encapsulating capsaicin in the sustained-release microspheres. By comparison, the 4-h release rate and 8-h release rate of Comparative Example 1 in Table 1 are greater than those of Example 2, indicating that the capsaicin sustained-release microspheres were prepared by reacting a mixture solution of thiol-modified chitosan, zein and capsaicin. Zein has high hydrophobicity, and capsaicin is a hydrophobic alkaloid. Zein has a good coating effect on capsaicin, making the medicament for treating diabetes have a good sustained-release effect.

[0026] The difference between Comparative Example 2 and Example 2 is that metformin hydrochloride was directly added without encapsulating metformin hydrochloride in the microspheres prepared from gelatin and hydroxyethyl cellulose. By comparison, the 4-h release rate and 8-h release rate of Comparative Example 2 in Table 2 are greater than those of Example 2, indicating that encapsulating metformin hydrochloride with gelatin and hydroxyethyl cellulose effectively improves the sustained-release effect of the medicament for treating diabetes.

[0027] The difference between Comparative Example 3 and Example 2 is that the tablets were not coated with the coating solution. By comparison, the release rate at 2 h in Tables 1 and 2 is greater than that in Example 2, indicating that the coating solution prepared from acrylic resin, triethyl citrate, and talc has a good coating effect. The structural characteristics of acrylic resin make it structurally stable when the pH is lower than 7 and start to dissolve when the pH is greater than 7, enabling the coated tablets to be released only in the intestinal solution and reducing the irritation of the drug to the stomach.

[0028] The specific embodiments described above have further elaborated on the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only the specific embodiments of the present invention and does not limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A medicament for treating diabetes, characterized in that, The medicament for treating diabetes is prepared by tabletting capsaicin sustained-release microspheres, metformin hydrochloride microspheres, magnesium stearate, sodium carboxymethyl starch, and binder particles, and then coating the tablets with a coating solution; The capsaicin sustained-release microspheres are prepared by reacting chitosan with mercaptoacetic acid to obtain mercapto-modified chitosan; and then reacting the mercapto-modified chitosan with a mixed solution of zein and capsaicin; The metformin hydrochloride microspheres are prepared by reacting metformin hydrochloride, gelatin, hydroxyethyl cellulose, and polyvinyl alcohol; 2. A method for preparing a medicament for treating diabetes according to claim 1, characterized in that, It includes the following preparation steps: (1) Mix mercapto-modified chitosan and deionized water at a mass ratio of 0.3:100, and adjust the pH to 4 with a 0.09 mol / L hydrochloric acid solution to obtain a chitosan solution; Slowly add a mixed solution of zein and capsaicin, which is 0.5 times the mass of the chitosan solution, to the chitosan solution at a rotation speed of 2800-3200 r / min, centrifuge to separate the precipitate, and freeze-dry the solid to obtain capsaicin sustained-release microspheres; (2) Mix polyvinyl alcohol and deionized water at a mass ratio of 1:(95-105), heat at 95-105 °C for 20-30 min to obtain an outer aqueous phase; disperse the primary emulsion in the outer aqueous phase into a homogeneous state with an emulsifier, with the volume ratio of the primary emulsion to the outer aqueous phase being 1:(5-10), an emulsification time of 1-3 min, and a rotation speed of 5000-6000 r / min to obtain a multiple emulsion. Rotate and evaporate at 30-40 °C for 10-20 min, cool to room temperature, then centrifuge to separate the solid, and freeze-dry the solid to obtain metformin hydrochloride microspheres; Pass the capsaicin sustained-release microspheres and metformin hydrochloride microspheres through an 80-mesh sieve, and pass magnesium stearate and sodium carboxymethyl starch through a 100-mesh sieve; Granulate the 5% (mass concentration) aqueous solution of hydroxypropyl cellulose by extruding it through a 24-mesh sieve, and dry it at 55-65 °C for 6-8 h to obtain binder particles; Mix the capsaicin sustained-release microspheres, metformin hydrochloride microspheres, magnesium stearate, sodium carboxymethyl starch, and binder particles, and press them into tablets with a diameter of 10 mm and a hardness of 50-60 N to obtain tablets; (3)After wiping off the fine powder from the tablets, place them in a coating pan and preheat at 35 - 45°C for 6 - 8 min. Slowly increase the rotation speed of the coating pan to 25 r / min, with the inlet air temperature at 40 - 45°C and the spray pressure at 2 - 3 kg / cm 2 , coat with the coating solution until the film weight gain reaches 4%, continue to dry with hot air for 10 - 20 min, cool to room temperature, and dry in an oven at 35 - 40°C for 3 - 5 h to obtain the medicament for treating diabetes.

3. The preparation method of the medicament for treating diabetes according to claim 2, characterized in that, The preparation method of the mercapto-modified chitosan described in step (1) is as follows: Mix chitosan and a 0.09 mol / L hydrochloric acid solution at a mass ratio of 1:100, stir at 200-300 r / min for 30 min, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, which is 2.2-2.6 times the mass of chitosan, and mercaptoacetic acid with the same mass as chitosan, adjust the pH to 5 with a 0.5 mol / L sodium hydroxide solution, continue to stir at room temperature for 3-5 h, dialyze with a cellulose membrane dialysis bag with a cut-off molecular weight of 12 kDa at 8 °C for 4 days, and the dialysis media are in turn: 5 mmol / L hydrochloric acid solution for 24 h; 5 mmol / L hydrochloric acid solution containing 1% sodium chloride for 48 h; 1 mmol / L hydrochloric acid solution for 24 h. After dialysis, freeze-dry to obtain it.

4. The preparation method of the medicament for treating diabetes according to claim 2, characterized in that, The preparation method of the mixed solution of zein and capsaicin described in step (1) is as follows: Mix zein, capsaicin, and an 80% (mass concentration) ethanol solution at a mass ratio of 0.3:0.03:50 to obtain it.

5. The preparation method of the medicament for treating diabetes according to claim 2, characterized in that, The preparation method of the colostrum described in step (2) is as follows: Mix metformin hydrochloride, gelatin, and deionized water in a mass ratio of 1:(1.5 - 2.5):(5 - 15) to obtain the inner aqueous phase; Mix hydroxyethyl cellulose and dichloromethane in a mass ratio of 1:(85 - 95) to obtain the oil phase; Mix the inner aqueous phase and the oil phase in a volume ratio of 1:(20 - 40), and ultrasonicate with an ultrasonic cell disruptor for 15 - 35 s, with an ultrasonic power of 100 W - 300 W and a pulse of 5 s to obtain it.

6. The preparation method of the medicament for treating diabetes according to claim 2, characterized in that, The preparation method of the coating solution described in step (3) is as follows: Swell the acrylic resin in an ethanol solution with a mass concentration of 95% at 100 times its mass for 22 - 26 h, add triethyl citrate at 0.2 times the mass of the acrylic resin and mix well to obtain the resin solution; Mix talcum powder and an ethanol solution with a mass concentration of 95% in a mass ratio of 1:(8 - 12) to obtain the talcum powder suspension, slowly pour the talcum powder suspension into the resin solution, stir at 100 - 200 r / min for 10 - 20 min, and pass through a 40-mesh sieve to obtain it.