Irbesartan and hydrochlorothiazide capsule as well as preparation method and application thereof

Abstract

The invention relates to the technical field of irbesartan and hydrochlorothiazide capsules, in particular to an irbesartan and hydrochlorothiazide capsule as well as a preparation method and application thereof. The irbesartan capsule is prepared from 150 parts of irbesartan, a sorbitol functionalized beta-cyclodextrin hydrochlorothiazide inclusion compound containing 12.5 parts of hydrochlorothiazide effective components, 38.5 parts of lactose, 27 parts of microcrystalline cellulose 101, 12 parts of croscarmellose sodium, 5 parts of hydroxypropyl methylcellulose, 2.5 parts of silicon dioxide and 2.5 parts of magnesium stearate. Natural beta-cyclodextrin is subjected to hydrophilic function modification, diethylene glycol anhydride serves as a connecting agent, sorbitol serves as a hydrophilic function raw material, sorbitol functionalized beta-cyclodextrin is prepared through an esterification reaction, hydrochlorothiazide is included through the sorbitol functionalized beta-cyclodextrin, and the sorbitol functionalized beta-cyclodextrin hydrochlorothiazide inclusion compound is formed. The water solubility and the stability of hydrochlorothiazide are obviously improved.

Description

Technical Field

[0001] The present invention relates to the technical field of irbesartan hydrochlorothiazide capsules, and in particular to irbesartan hydrochlorothiazide capsules, a preparation method and application thereof. Background Art

[0002] Hypertension is a common chronic cardiovascular disease, a clinical syndrome characterized by elevated systemic arterial pressure. It is categorized as either primary or secondary. Irbesartan is a drug that lowers blood pressure by improving the dilation and constriction of arterioles. However, clinical studies have shown that irbesartan alone is insufficient to maintain normal blood pressure in patients with essential hypertension, requiring a combination of multiple medications. Hydrochlorothiazide is a diuretic that lowers blood pressure by accelerating the excretion of sodium, potassium, phosphorus, and chloride, improving circulatory capacity, and thereby reducing blood pressure. These two drugs can synergistically lower blood pressure, complementing each other's deficiencies, reducing potential adverse reactions associated with long-term monotherapy, enhancing patient compliance, and improving safety and therapeutic efficacy. Developed by Sanofi, the irbesartan and hydrochlorothiazide combination tablets are marketed under the trade name COAPROVEL. The FDA approved the combination tablets for marketing in the United States in 1997, the European Union in 1999, and China in 2004.

[0003] Currently, the production of irbesartan-hydrochlorothiazide combination formulations includes capsules, standard tablets, and dispersible tablets. Hydrochlorothiazide contains a thiazine ring, which is unstable under light and heat conditions and easily oxidized and decomposed. Furthermore, hydrochlorothiazide has poor water solubility, a slightly bitter taste, and a gastrointestinal irritant effect. To improve the stability and water solubility of hydrochlorothiazide and enhance its clinical application, existing technologies generally use cyclodextrin as a carrier material to prepare it into an inclusion compound.

[0004] Cyclodextrin is a natural material. It is a cyclic oligomer formed by a series of D-pyranose glucose units connected by α-1,4 glycosidic bonds. It is usually composed of 6-12 glucose units. The most common cyclodextrins are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. Cyclodextrin has a hydrophobic cavity and a hydrophilic exterior. The cavity structure can embed molecules of suitable shape and size to form non-covalent bonds. Considering factors such as cost, cavity size, and availability, β-cyclodextrin is the most widely used and relatively suitable. β-cyclodextrin has good biocompatibility and can be used to prepare drug-carrying materials, but the solubility of natural β-cyclodextrin is poor, which limits its application in the pharmaceutical field.

[0005] Therefore, the present invention improves the hydrophilicity of β-cyclodextrin by hydrophilic modification, and uses the hydrophilic β-cyclodextrin to coat hydrochlorothiazide to form an inclusion compound, which is used to improve the water solubility and stability of hydrochlorothiazide, and then prepares irbesartan hydrochlorothiazide capsules to further improve the stability of the finished drug. Summary of the Invention

[0006] The present invention provides an irbesartan hydrochlorothiazide capsule, a preparation method and an application thereof, which are used to solve the problems of poor stability and water solubility of hydrochlorothiazide.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] An irbesartan-hydrochlorothiazide capsule, comprising 150 parts by weight of irbesartan and a sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex containing 12.5 parts by weight of a hydrochlorothiazide active ingredient;

[0009] The sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is obtained by including hydrochlorothiazide in sorbitol functionalized β-cyclodextrin.

[0010] Preferably, the mass ratio of β-cyclodextrin, diglycolic anhydride, and sorbitol in the sorbitol-functionalized β-cyclodextrin is 1:0.8-1.5:1.6-2.5.

[0011] Preferably, the irbesartan hydrochlorothiazide capsules comprise the following raw materials in parts by weight: 150 parts of irbesartan, sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex containing 12.5 parts of hydrochlorothiazide pharmacological components, 38.5 parts of lactose, 27 parts of microcrystalline cellulose 101, 12 parts of cross-linked sodium carboxymethyl cellulose, 5 parts of hypromellose, 2.5 parts of silicon dioxide, and 2.5 parts of magnesium stearate.

[0012] A method for preparing irbesartan hydrochlorothiazide capsules comprises the following steps:

[0013] Sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is stirred and mixed with lactose, microcrystalline cellulose 101, cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, and silicon dioxide, and then irbesartan is added and mixed to form a mixture. The mixture is crushed, and the crushed mixture is mixed again, granulated, wet-granulated, dried, granulated, magnesium stearate is added for total mixing, and finally capsule shells are used for filling to obtain irbesartan hydrochlorothiazide capsules.

[0014] Preferably, the preparation method of the sorbitol functionalized β-cyclodextrin is:

[0015] Under the action of activator and catalyst, β-cyclodextrin undergoes esterification reaction with diglycolic anhydride to obtain carboxylated β-cyclodextrin;

[0016] Carboxylated β-cyclodextrin undergoes esterification reaction with sorbitol to obtain sorbitol-functionalized β-cyclodextrin.

[0017] Preferably, the activator is dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0018] Preferably, the catalyst is 4-dimethylaminopyridine or 1-hydroxybenzotriazole.

[0019] Preferably, the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is prepared by an ultrasonic method or a coprecipitation method.

[0020] The invention relates to an application of irbesartan hydrochlorothiazide capsules and an application of a sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex in the preparation of a drug for treating essential hypertension.

[0021] The beneficial effects of the present invention are as follows:

[0022] The present invention modifies natural β-cyclodextrin into a hydrophilic functionalized form, uses diglycolic anhydride as a linker, and sorbitol as a hydrophilic functional raw material, and obtains sorbitol-functionalized β-cyclodextrin through a two-step esterification reaction. The sorbitol-functionalized β-cyclodextrin is then used to include hydrochlorothiazide to form a sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex, thereby significantly improving the water solubility and stability of hydrochlorothiazide. The present invention adopts a coprecipitation method and an ultrasonic method to prepare the sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex. Experimental test results show that the sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex prepared by the ultrasonic method has the best water solubility. Cytotoxicity tests show that the sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex has high safety. DETAILED DESCRIPTION

[0023] By improving the hydrophilicity of natural β-cyclodextrin and increasing the water solubility of cyclodextrin, sorbitol-functionalized β-cyclodextrin is prepared. Hydrochlorothiazide is included with the hydrophilic β-cyclodextrin to form a sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex, which significantly improves the water solubility and stability of hydrochlorothiazide.

[0024] Experimental Example 1:

[0025] The method for preparing sorbitol functionalized β-cyclodextrin is:

[0026] Under the action of 4-dimethylaminopyridine and dicyclohexylcarbodiimide, β-cyclodextrin and diglycolic anhydride undergo an esterification reaction to obtain carboxylated β-cyclodextrin, and the carboxylated β-cyclodextrin undergoes an esterification reaction with sorbitol. The mass ratio of β-cyclodextrin, diglycolic anhydride, and sorbitol participating in the reaction is 1:(0.8-1.5):(1.6-2.5) to obtain sorbitol-functionalized β-cyclodextrin.

[0027] Experimental Example 2:

[0028] The specific steps for preparing sorbitol functionalized β-cyclodextrin are:

[0029] 2.2 g of β-cyclodextrin was added to 40 mL of N,N-dimethylformamide, nitrogen was introduced, and the solution was heated and stirred to form a clear and transparent solution. After cooling slightly, 0.8 g of 4-dimethylaminopyridine and 1.4 g of dicyclohexylcarbodiimide were added. After mixing evenly, 2.3 g of diglycolic anhydride was slowly added. The temperature was raised to 50°C and stirred for 8 hours. After cooling to room temperature, 4 g of sorbitol was added. After reacting at 40°C for 10 hours, anhydrous ethanol was added for precipitation, filtered, washed with acetone, and dried in vacuo at 80°C for 5 hours to obtain sorbitol-functionalized β-cyclodextrin.

[0030] Example 1:

[0031] An irbesartan hydrochlorothiazide capsule comprises the following raw materials in parts by weight:

[0032] 150 units of irbesartan: batch number 80321122513, purchased from Zhuhai Rundu Pharmaceutical Co., Ltd.

[0033] 45 parts of sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex: The batch number of hydrochlorothiazide is H210705, which was purchased from Changzhou Pharmaceutical Factory Co., Ltd., wherein the drug content of the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is 27.78%, that is, the amount of hydrochlorothiazide in the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is 12.5 parts;

[0034] 38.5 parts of lactose: batch number 2210005, purchased from Jiangsu Daoning Pharmaceutical Co., Ltd.;

[0035] 27 parts of microcrystalline cellulose 101: batch number 211211, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0036] 12 parts of cross-linked sodium carboxymethyl cellulose: batch number 220704, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0037] 5 parts of Hydroxypropyl Methylcellulose: Batch No. 220915, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0038] 2.5 parts of silicon dioxide: batch number 151112014, purchased from Evonik Specialty Chemicals (Shanghai) Co., Ltd.

[0039] 2.5 parts of magnesium stearate: batch number 220619, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0040] A preparation method of irbesartan hydrochlorothiazide capsules comprises the following steps:

[0041] Step 1: Prepare a sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex by ultrasonication: accurately weigh 216 parts by weight of sorbitol-functionalized β-cyclodextrin, dissolve it in distilled water, heat it to 40°C, and ultrasonicate it to form a sorbitol-functionalized β-cyclodextrin saturated solution, accurately weigh 54 parts by weight of hydrochlorothiazide, dissolve it in ethanol, and slowly add it to the sorbitol-functionalized β-cyclodextrin saturated solution, ultrasonicate it for 30 minutes, cool it to room temperature, put it in a refrigerator for 24 hours, filter it, wash it with ethanol, then wash it with distilled water, and dry it to obtain a sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex;

[0042] Step 2, premixing: sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex, lactose, microcrystalline cellulose 101, croscarmellose sodium, hydroxypropyl cellulose and silicon dioxide were stirred and mixed uniformly by weight at a stirring speed of 300 rpm, a cutting speed of 1500 rpm, and a mixing time of 300 s. Irbesartan was then added and mixed together at a stirring speed of 300 rpm, a cutting speed of 1500 rpm, and a mixing time of 300 s. The mixture was collected and set aside;

[0043] Step 3, crushing: crushing the prepared mixture;

[0044] Step 4: Mixing: Mix the crushed mixture again with a stirring speed of 150 rpm and a cutting speed of 1500 rpm for 400 s.

[0045] Step 5, granulation: spray 95% ethanol as a binder into the material in step 3, and prepare a soft material under the conditions of a stirring speed of 150 rpm and a shear speed of 1500 rpm;

[0046] Step 6: Wet granulation: Use a 2.0 aperture sieve to wet granulate the soft material;

[0047] Step 7: Drying: Dry the prepared wet granulated soft material at a temperature of 60°C with a moisture content of less than 2%-3%.

[0048] Step 8: Granulation: Use a 1.0 aperture sieve to granulate the dried granules;

[0049] Step 9: Total mixing: Add magnesium stearate to the granules after granulation and mix for 5 minutes;

[0050] Step 10: Filling: Use capsule shells for filling, with a filling amount of 250 mg / capsule.

[0051] Determination of the hydrochlorothiazide content in sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex:

[0052] Accurately weigh 50 mg of the prepared sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex, add it to a 25 mL volumetric flask, make up to volume with dilute hydrochloric acid, set the dilute hydrochloric acid as the blank group, and measure the absorbance at a wavelength of 274 nm with an ultraviolet spectrophotometer. The percentage of hydrochlorothiazide is calculated to be 27.78%.

[0053] Example 2:

[0054] An irbesartan hydrochlorothiazide capsule comprises the following raw materials in parts by weight:

[0055] 150 units of irbesartan: batch number 80321122513, purchased from Zhuhai Rundu Pharmaceutical Co., Ltd.

[0056] 48 parts of sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex: The batch number of hydrochlorothiazide is H210705, which was purchased from Changzhou Pharmaceutical Factory Co., Ltd., wherein the drug content of the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is 26.03%, that is, the amount of hydrochlorothiazide in the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is 12.5 parts;

[0057] 38.5 parts of lactose: batch number 2210005, purchased from Jiangsu Daoning Pharmaceutical Co., Ltd.;

[0058] 27 parts of microcrystalline cellulose 101: batch number 211211, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0059] 12 parts of cross-linked sodium carboxymethyl cellulose: batch number 220704, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0060] 5 parts of Hydroxypropyl Methylcellulose: Batch No. 220915, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0061] 2.5 parts of silicon dioxide: batch number 151112014, purchased from Evonik Specialty Chemicals (Shanghai) Co., Ltd.

[0062] 2.5 parts of magnesium stearate: batch number 220619, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0063] A preparation method of irbesartan hydrochlorothiazide capsules comprises the following steps:

[0064] Step 1: Prepare a sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex by coprecipitation: accurately weigh 216 parts by weight of sorbitol-functionalized β-cyclodextrin, dissolve it in distilled water, heat it to 40°C, and stir it at a constant temperature at a rate of 100 r / min to form a sorbitol-functionalized β-cyclodextrin saturated solution, accurately weigh 54 parts by weight of hydrochlorothiazide, dissolve it in ethanol, and slowly add it to the sorbitol-functionalized β-cyclodextrin saturated solution, stir for 3 hours, cool to room temperature, refrigerate for 24 hours, filter, wash with ethanol, then wash with distilled water, and dry to obtain a sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex;

[0065] Step 2, premixing: sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex, lactose, microcrystalline cellulose 101, croscarmellose sodium, hydroxypropyl cellulose and silicon dioxide were stirred and mixed uniformly by weight at a stirring speed of 300 rpm, a cutting speed of 1500 rpm, and a mixing time of 300 s. Irbesartan was then added and mixed together at a stirring speed of 300 rpm, a cutting speed of 1500 rpm, and a mixing time of 300 s. The mixture was collected and set aside;

[0066] Step 3, crushing: crushing the prepared mixture;

[0067] Step 4: Mixing: Mix the crushed mixture again with a stirring speed of 150 rpm and a cutting speed of 1500 rpm for 400 s.

[0068] Step 5, granulation: spray 95% ethanol as a binder into the material in step 3, and prepare a soft material under the conditions of a stirring speed of 150 rpm and a shear speed of 1500 rpm;

[0069] Step 6: Wet granulation: Use a 2.0 aperture sieve to wet granulate the soft material;

[0070] Step 7: Drying: Dry the prepared wet granulated soft material at a temperature of 60°C with a moisture content of less than 2%-3%.

[0071] Step 8: Granulation: Use a 1.0 aperture sieve to granulate the dried granules;

[0072] Step 9: Total mixing: Add magnesium stearate to the granules after granulation and mix for 5 minutes;

[0073] Step 10: Filling: Use capsule shells for filling, with a filling amount of 250 mg / capsule.

[0074] Determination of the hydrochlorothiazide content in sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex:

[0075] Accurately weigh 50 mg of the prepared sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex, add it to a 25 mL volumetric flask, make up to volume with dilute hydrochloric acid, set the dilute hydrochloric acid as the blank group, and measure the absorbance at a wavelength of 274 nm with an ultraviolet spectrophotometer. The percentage of hydrochlorothiazide is calculated to be 26.03%.

[0076] Example 3:

[0077] An irbesartan hydrochlorothiazide capsule comprises the following raw materials in parts by weight:

[0078] 150 units of irbesartan: batch number 80321122513, purchased from Zhuhai Rundu Pharmaceutical Co., Ltd.

[0079] 41 parts of sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex: The batch number of hydrochlorothiazide is H210705, which was purchased from Changzhou Pharmaceutical Factory Co., Ltd., wherein the drug content of the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is 30.48%, that is, the amount of hydrochlorothiazide in the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is 12.5 parts;

[0080] 38.5 parts of lactose: batch number 2210005, purchased from Jiangsu Daoning Pharmaceutical Co., Ltd.;

[0081] 27 parts of microcrystalline cellulose 101: batch number 211211, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0082] 12 parts of cross-linked sodium carboxymethyl cellulose: batch number 220704, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0083] 5 parts of Hydroxypropyl Methylcellulose: Batch No. 220915, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0084] 2.5 parts of silicon dioxide: batch number 151112014, purchased from Evonik Specialty Chemicals (Shanghai) Co., Ltd.

[0085] 2.5 parts of magnesium stearate: batch number 220619, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0086] A preparation method of irbesartan hydrochlorothiazide capsules comprises the following steps:

[0087] Step 1: Prepare a sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex by ultrasonication: accurately weigh 243 parts by weight of sorbitol-functionalized β-cyclodextrin, dissolve it in distilled water, heat it to 40°C, and ultrasonicate it to form a sorbitol-functionalized β-cyclodextrin saturated solution, accurately weigh 54 parts by weight of hydrochlorothiazide, dissolve it in ethanol, and slowly add it to the sorbitol-functionalized β-cyclodextrin saturated solution, ultrasonicate it for 30 minutes, cool it to room temperature, put it in a refrigerator for 24 hours, filter it, wash it with ethanol, then wash it with distilled water, and dry it to obtain a sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex;

[0088] Step 2, premixing: sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex, lactose, microcrystalline cellulose 101, croscarmellose sodium, hydroxypropyl cellulose and silicon dioxide were stirred and mixed uniformly by weight at a stirring speed of 300 rpm, a cutting speed of 1500 rpm, and a mixing time of 300 s. Irbesartan was then added and mixed together at a stirring speed of 300 rpm, a cutting speed of 1500 rpm, and a mixing time of 300 s. The mixture was collected and set aside;

[0089] Step 3, crushing: crushing the prepared mixture;

[0090] Step 4: Mixing: Mix the crushed mixture again with a stirring speed of 150 rpm and a cutting speed of 1500 rpm for 400 s.

[0091] Step 5, granulation: spray 95% ethanol as a binder into the material in step 3, and prepare a soft material under the conditions of a stirring speed of 150 rpm and a shear speed of 1500 rpm;

[0092] Step 6: Wet granulation: Use a 2.0 aperture sieve to wet granulate the soft material;

[0093] Step 7: Drying: Dry the prepared wet granulated soft material at a temperature of 60°C with a moisture content of less than 2%-3%.

[0094] Step 8: Granulation: Use a 1.0 aperture sieve to granulate the dried granules;

[0095] Step 9: Total mixing: Add magnesium stearate to the granules after granulation and mix for 5 minutes;

[0096] Step 10: Filling: Use capsule shells for filling, with a filling amount of 250 mg / capsule.

[0097] Determination of the hydrochlorothiazide content in sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex:

[0098] Accurately weigh 50 mg of the prepared sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex, add it to a 25 mL volumetric flask, make up to volume with dilute hydrochloric acid, set the dilute hydrochloric acid as the blank group, and measure the absorbance at a wavelength of 274 nm with an ultraviolet spectrophotometer. The percentage of hydrochlorothiazide is calculated to be 30.48%.

[0099] Example 4:

[0100] An irbesartan hydrochlorothiazide capsule comprises the following raw materials in parts by weight:

[0101] 150 units of irbesartan: batch number 80321122513, purchased from Zhuhai Rundu Pharmaceutical Co., Ltd.

[0102] 41.5 parts of sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex: The batch number of hydrochlorothiazide is H210705, which was purchased from Changzhou Pharmaceutical Factory Co., Ltd., wherein the drug content of the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is 30.11%, that is, the amount of hydrochlorothiazide in the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is 12.5 parts;

[0103] 38.5 parts of lactose: batch number 2210005, purchased from Jiangsu Daoning Pharmaceutical Co., Ltd.;

[0104] 27 parts of microcrystalline cellulose 101: batch number 211211, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0105] 12 parts of cross-linked sodium carboxymethyl cellulose: batch number 220704, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0106] 5 parts of Hydroxypropyl Methylcellulose: Batch No. 220915, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0107] 2.5 parts of silicon dioxide: batch number 151112014, purchased from Evonik Specialty Chemicals (Shanghai) Co., Ltd.

[0108] 2.5 parts of magnesium stearate: batch number 220619, purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0109] A preparation method of irbesartan hydrochlorothiazide capsules comprises the following steps:

[0110] Step 1: Prepare a sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex by ultrasonication: accurately weigh 270 parts by weight of sorbitol-functionalized β-cyclodextrin, dissolve it in distilled water, heat it to 40°C, and ultrasonicate it to form a sorbitol-functionalized β-cyclodextrin saturated solution, accurately weigh 54 parts by weight of hydrochlorothiazide, dissolve it in ethanol, and slowly add it to the sorbitol-functionalized β-cyclodextrin saturated solution, ultrasonicate it for 30 minutes, cool it to room temperature, put it in a refrigerator for 24 hours, filter it, wash it with ethanol, then wash it with distilled water, and dry it to obtain a sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex;

[0111] Step 2, premixing: sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex, lactose, microcrystalline cellulose 101, croscarmellose sodium, hydroxypropyl cellulose and silicon dioxide were stirred and mixed uniformly by weight at a stirring speed of 300 rpm, a cutting speed of 1500 rpm, and a mixing time of 300 s. Irbesartan was then added and mixed together at a stirring speed of 300 rpm, a cutting speed of 1500 rpm, and a mixing time of 300 s. The mixture was collected and set aside;

[0112] Step 3, crushing: crushing the prepared mixture;

[0113] Step 4: Mixing: Mix the crushed mixture again with a stirring speed of 150 rpm and a cutting speed of 1500 rpm for 400 s.

[0114] Step 5, granulation: spray 95% ethanol as a binder into the material in step 3, and prepare a soft material under the conditions of a stirring speed of 150 rpm and a shear speed of 1500 rpm;

[0115] Step 6: Wet granulation: Use a 2.0 aperture sieve to wet granulate the soft material;

[0116] Step 7: Drying: Dry the prepared wet granulated soft material at a temperature of 60°C with a moisture content of less than 2%-3%.

[0117] Step 8: Granulation: Use a 1.0 aperture sieve to granulate the dried granules;

[0118] Step 9: Total mixing: Add magnesium stearate to the granules after granulation and mix for 5 minutes;

[0119] Step 10: Filling: Use capsule shells for filling, with a filling amount of 250 mg / capsule.

[0120] Determination of the hydrochlorothiazide content in sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex:

[0121] Accurately weigh 50 mg of the prepared sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex, add it to a 25 mL volumetric flask, make up to volume with dilute hydrochloric acid, set the dilute hydrochloric acid as the blank group, and measure the absorbance at a wavelength of 274 nm with an ultraviolet spectrophotometer. The percentage of hydrochlorothiazide is calculated to be 30.11%.

[0122] Example 5:

[0123] 1. Determination of solubility:

[0124] An excess of hydrochlorothiazide and the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex prepared in Examples 1 to 4 containing an equal amount of hydrochlorothiazide were weighed separately and added to a 200 mL stoppered conical flask. Distilled water was added to form a supersaturated solution. After shaking in a constant temperature water bath shaker at room temperature for one day, the solution was filtered through a 0.45 μm microporous filter membrane. 10 mL of each filtrate was accurately measured and the absorbance at a wavelength of 273 nm was measured. The solubility of the sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex and hydrochlorothiazide in water was calculated. The results are shown in Table 1:

[0125] Table 1 Solubility determination results of sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex

[0126] serial number Solubility (g / L) Solubilization multiple Example 1 172.35 239.38 Example 2 161.02 223.64 Example 3 176.85 245.63 Example 4 176.48 245.11 Hydrochlorothiazide 0.72 /

[0127] As shown in Table 1, the sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex prepared in the examples of the present invention has good water solubility.

[0128] 2. Cytotoxicity test of sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex:

[0129] HUVEC cells (human umbilical vein endothelial cells) were cultured in a DMEM medium containing 10% fetal bovine serum in an incubator at 37°C, saturated humidity, and 5% carbon dioxide. They were seeded in a 96-well plate, with 7,000 cells seeded per well. The sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex prepared in Examples 1 to 4 was added to each group at a concentration of 200 μmol / L. Untreated cells were used as the control group. The cells were divided into 12 groups and cultured continuously. The sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex prepared in each Example was added to each group at a concentration of 200 μmol / L. The alcohol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex was subjected to three repeated experiments. After 2 days of treatment, CCK8 was used for detection. 10 μL of CCK8 solution was added to each well of each group of cells, and the cells were cultured in an incubator at 37°C with 5% carbon dioxide for 5 h. The absorbance at 490 nm was measured with a microplate reader, and the cell viability was calculated using the formula: cell viability = (B1 / B0) × 100%, where B1 is the average absorbance of the sample and B0 is the average absorbance of the control group. The results are recorded in Table 2.

[0130] Table 2 Cytotoxicity test results of sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex

[0131] serial number Cell survival rate (%) Example 1 >95 Example 2 >95 Example 3 >95 Example 4 >95

[0132] As shown in Table 2, the survival rates of HUVEC cells were all greater than 95%, which basically indicates that the sorbitol-functionalized β-cyclodextrin-hydrochlorothiazide inclusion complex has a high safety for HUVEC cells.

Claims

1. An irbesartan hydrochlorothiazide capsule, characterized in that: The capsule comprises 150 parts by weight of irbesartan and a sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex containing 12.5 parts by weight of a hydrochlorothiazide medicinal component; The sorbitol functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is obtained by including hydrochlorothiazide in sorbitol functionalized β-cyclodextrin.

2. The irbesartan hydrochlorothiazide capsule according to claim 1, characterized in that: The mass ratio of beta-cyclodextrin, diglycolic anhydride and sorbitol in the sorbitol functionalized beta-cyclodextrin is 1:0.8-1.5:1.6-2.

5.

3. The irbesartan hydrochlorothiazide capsule according to claim 2, characterized in that: The invention comprises the following raw materials in parts by weight: 150 parts of irbesartan, a sorbitol-functionalized beta-cyclodextrin hydrochlorothiazide inclusion complex containing 12.5 parts of hydrochlorothiazide active ingredient, 38.5 parts of lactose, 27 parts of microcrystalline cellulose 101, 12 parts of cross-linked sodium carboxymethyl cellulose, 5 parts of hypromellose, 2.5 parts of silicon dioxide, and 2.5 parts of magnesium stearate.

4. The method for preparing irbesartan hydrochlorothiazide capsules according to claim 3, wherein: The following steps are involved: Sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex is stirred and mixed with lactose, microcrystalline cellulose 101, cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, and silicon dioxide, and then irbesartan is added and mixed to form a mixture. The mixture is crushed, and the crushed mixture is mixed again, granulated, wet-granulated, dried, granulated, magnesium stearate is added for total mixing, and finally capsule shells are used for filling to obtain irbesartan hydrochlorothiazide capsules.

5. The method for preparing irbesartan hydrochlorothiazide capsules according to claim 4, wherein: The preparation method of the sorbitol functionalized β-cyclodextrin is: Under the action of activator and catalyst, β-cyclodextrin undergoes esterification reaction with diglycolic anhydride to obtain carboxylated β-cyclodextrin; Carboxylated β-cyclodextrin undergoes esterification reaction with sorbitol to obtain sorbitol-functionalized β-cyclodextrin.

6. The method for preparing irbesartan hydrochlorothiazide capsules according to claim 5, characterized in that: The activator is dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

7. The method for preparing irbesartan hydrochlorothiazide capsules according to claim 5, characterized in that: The catalyst is 4-dimethylaminopyridine or 1-hydroxybenzotriazole.

8. The method for preparing irbesartan hydrochlorothiazide capsules according to any one of claims 4 to 7, characterized in that: The sorbitol functionalized beta-cyclodextrin hydrochlorothiazide inclusion complex is prepared by an ultrasonic method or a coprecipitation method.

9. The use of irbesartan hydrochlorothiazide capsules according to claim 3, characterized in that: Use of sorbitol-functionalized β-cyclodextrin hydrochlorothiazide inclusion complex in the preparation of drugs for treating essential hypertension.