Irbesartan solid dispersion and preparation method of irbesartan solid dispersion preparation

Abstract

The invention provides an irbesartan solid dispersion and a preparation method of a preparation thereof, and belongs to the technical field of pharmaceutical preparations, the irbesartan solid dispersion is prepared from 10-30% by weight of irbesartan, 60-90% by weight of copovidone and 5-15% by weight of a plasticizer by adopting a twin-screw hot melt extrusion process, and the irbesartan solid dispersion is prepared from the preparation method of the irbesartan solid dispersion and the preparation of the irbesartan solid dispersion. And mixing the solid dispersion with a filling agent, a disintegrating agent and a lubricating agent which are conventional in pharmaceutics to prepare irbesartan unilateral tablets, or additionally adding hydrochlorothiazide and mixing to prepare irbesartan compound tablets. According to the irbesartan tablet and the preparation method thereof, irbesartan is prepared into the solid dispersion and then prepared into the tablet, so that the electrostatic agglomeration of irbesartan is improved to improve the mixing uniformity of the preparation, the dissolution performance of irbesartan is remarkably improved, and the bioavailability of the medicine is improved; therefore, the problems of insufficient subsequent mixing uniformity caused by electrostatic agglomeration in irbesartan preparation preparation and poor dissolution performance and low bioavailability caused by low solubility are effectively solved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a method for preparing an irbesartan solid dispersion and its formulation. Background Technology

[0002] In the field of antihypertensive drugs, irbesartan, an angiotensin II antagonist, has become a commonly used drug for treating essential hypertension and related complications due to its clear antihypertensive effect and wide clinical application. With the increasing demands for drug efficacy stability and bioavailability in clinical practice, the optimization of formulation technology for poorly soluble drugs has become an industry trend. Irbesartan belongs to the BCS Class II drug category and has low water solubility. Currently, the industry commonly uses micronization technology and solid dispersion technology to improve the dissolution performance of poorly soluble drugs. Among these, solid dispersion technology, because it can combine the drug with water-soluble carrier materials, significantly reduces drug crystallinity and improves solubility, is considered an important direction for solving the bioavailability problem of BCS Class II drugs. Related technologies are increasingly widely used in the formulation development of poorly soluble drugs in the fields of antihypertensive and lipid-lowering drugs.

[0003] Currently, the production of irbesartan monotherapy or combination formulations still primarily relies on traditional high-speed shear wet granulation. To mitigate the electrostatic aggregation tendency of irbesartan, the industry has undertaken some technological improvements. For example, CN201610523597.7 discloses a method using novel excipients such as trehalose and nano-mica powder to improve the electrostatic problem of irbesartan through wet granulation. Other existing technologies disclose a scheme using inulin lauryl carbamate melted at 80°C, followed by the addition of irbesartan and hydrochlorothiazide, and then stirring, solidifying, and pulverizing to improve the electrostatic aggregation of the active pharmaceutical ingredient. However, while these existing methods using specific excipients offer some improvement, they cannot simultaneously improve the dissolution rate of irbesartan. This limitation increases fluctuations in blood drug concentration during clinical use and reduces bioavailability.

[0004] Furthermore, existing technologies still have significant drawbacks: First, traditional high-speed shear wet granulation processes and publicly available improvements, such as the addition of trehalose and inulin lauryl carbamate, can only specifically address the electrostatic aggregation problem of irbesartan, but cannot simultaneously solve the problem of insufficient dissolution caused by its low solubility, thus leading to fluctuations in blood drug concentration during clinical use and ultimately reducing drug bioavailability; Second, although micronization technology can theoretically increase the dissolution rate by increasing the specific surface area of ​​irbesartan, this technology exacerbates the spontaneous aggregation tendency of irbesartan, which in turn increases the difficulty of drug dispersion in subsequent formulation processes and is not conducive to controlling the uniformity of formulation content; Third, irbesartan itself has high viscosity, which makes it prone to poor powder flowability and sticking during tableting, affecting production efficiency and potentially causing excessive tablet weight variation, thus reducing the stability of formulation quality. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, the purpose of this invention is to provide a method for preparing irbesartan solid dispersion and its formulation. By preparing irbesartan into a solid dispersion and then into tablets, the electrostatic aggregation of irbesartan is improved to enhance the uniformity of the formulation mixing, and the dissolution performance of irbesartan is significantly improved, thereby increasing the bioavailability of the drug. This effectively solves the problems of insufficient uniformity of subsequent mixing due to electrostatic aggregation, poor dissolution performance due to low solubility, and low bioavailability of irbesartan in formulation preparation.

[0006] To achieve the above objectives, the present invention provides the following solution: On one hand, the present invention provides an irbesartan solid dispersion, which is composed of the following components in weight percentage: 10-30% irbesartan, 60-90% copovidone, and 5-15% plasticizer; the irbesartan solid dispersion is prepared by hot melt extrusion process and is used to improve the electrostatic aggregation of irbesartan to enhance the mixing uniformity in subsequent formulations, and to improve the dissolution performance of irbesartan to improve its bioavailability, and is also used as a raw material to prepare irbesartan monoparticle tablets or irbesartan compound tablets.

[0007] Preferably, the plasticizer is a nonionic surfactant selected from one or more of glycerol polyoxyethylene ether hydroxy stearate and stearoyl polyoxyethylene glycerate.

[0008] Preferably, the copovidone is selected from one or more of PVP / VA 64 and PVP / VA 55, and the K value of the copovidone is in the range of 22 to 36.

[0009] Secondly, the present invention also provides a method for preparing the above-mentioned irbesartan solid dispersion, comprising the following steps: S1. According to the preset ratio, mix irbesartan, copovidone and plasticizer evenly to obtain a mixture; S2. Set the temperature of different heating sections of the twin-screw extruder to 50~200℃ and the screw speed to 50~1000rpm. After the temperature reaches the set temperature, start the screw and extrude the mixture after melting and shearing. S3. Cool the extrudate into a solid and then mechanically crush it to a suitable particle size to obtain irbesartan solid dispersion.

[0010] Preferably, in S2, the temperature of the heating section of the twin-screw extruder is set in a gradient from the feed port to the die.

[0011] Thirdly, the present invention also provides an irbesartan formulation comprising the above-mentioned irbesartan solid dispersion and pharmaceutically conventional excipients; the formulation is a tablet, and the excipients include fillers, disintegrants, and lubricants; the formulation is a single-ingredient formulation or a combination formulation.

[0012] Preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, starch, and mannitol; the disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, and low-substituted hydroxypropyl cellulose; and the lubricant is magnesium stearate.

[0013] Preferably, when the preparation is a compound preparation, it further contains hydrochlorothiazide.

[0014] Preferably, the irbesartan solid dispersion has a dissolution rate of not less than 90% within 20 minutes in a pH 4.5 or pH 6.8 medium, and the tablets have a dissolution rate of not less than 90% within 30 minutes in a pH 4.5 or pH 6.8 medium.

[0015] Fourthly, the present invention also provides a method for preparing the above-mentioned irbesartan formulation, comprising the following steps: mixing irbesartan solid dispersion with filler and disintegrant evenly, then adding lubricant and mixing evenly, and finally compressing into tablets.

[0016] According to specific embodiments provided by the present invention, the present invention discloses the following technical effects: (1) This invention significantly improves the dissolution performance and bioavailability of irbesartan by combining a component ratio of 10-30% irbesartan, 60-90% copovidone, and 5-15% plasticizer with a twin-screw hot-melt extrusion process. Irbesartan, as a BCSII drug, suffers from pH-dependent dissolution defects under traditional processes. In this invention, copovidone provides a water-soluble carrier environment, plasticizer improves drug wettability, and hot-melt extrusion ensures uniform dispersion of the drug in the carrier. The final solid dispersion achieves a dissolution rate of over 90% within 20 minutes in media with pH 4.5 and pH 6.8. The tablets prepared in this way also achieve a dissolution rate of over 90% within 30 minutes, solving the problem of drug absorption in vivo being affected by gastrointestinal pH, greatly improving bioavailability and reducing fluctuations in blood drug concentration.

[0017] (2) This invention introduces glycerol polyoxyethylene ether hydroxy stearate or stearoyl polyoxyethylene glycerate as a plasticizer, which effectively reduces the glass transition temperature (Tg) of irbesartan, making hot melt extrusion technology easier to implement. The plasticizer can adjust the physical properties of irbesartan, reducing its Tg to a suitable melting range. This eliminates the need to set excessively high heating temperatures to achieve full melting and shear mixing of the drug and copovidone, avoiding the risk of drug degradation due to high temperatures. At the same time, the reduced Tg also optimizes the flexibility of the extrudate, reducing the problems of material brittleness and adhesion to equipment during extrusion. This makes screw speed adjustment more flexible, process stability stronger, and eliminates the dependence on special high-temperature equipment, providing easily controllable technical conditions for industrial continuous production.

[0018] (3) This invention uses a hot melt extrusion process to form a solid dispersion of irbesartan, copovidone, and plasticizer, which effectively solves the problem of electrostatic agglomeration of irbesartan and improves its high viscosity physical properties, greatly facilitating the preparation of irbesartan monotherapy and compound formulations. In traditional processes, irbesartan is prone to uneven mixing due to electrostatic agglomeration, and its high viscosity can also cause problems such as poor flowability and sticking during tableting, especially in compound formulations where the uniformity of mixing with hydrochlorothiazide is more difficult to control; while the solid dispersion of this invention can encapsulate drug particles to neutralize static electricity and reduce viscosity. When mixed with fillers (microcrystalline cellulose, lactose, etc.), disintegrants (crosslinked carboxymethyl cellulose sodium, etc.), and lubricants (magnesium stearate), it can maintain uniform dispersion. The preparation of monotherapy or compound tablets can ensure the uniformity of content, and there are no problems of poor flow or sticking to the mold during the tableting process, which significantly improves the preparation efficiency and quality stability of formulations. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0020] Figure 1 This is a flowchart of a method for preparing an irbesartan solid dispersion according to the present invention; Figure 2 Dissolution curves of irbesartan solid dispersion with PVP / VA 64 as carrier in different media provided for embodiments of the present invention; Figure 3 The dissolution curve of irbesartan in tablets prepared using irbesartan solid dispersion is provided for embodiments of the present invention. Detailed Implementation

[0021] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0023] This invention prepares irbesartan into an amorphous solid dispersion to increase its solubility. Irbesartan is pretreated by hot-melt extrusion, and nonionic surfactants, such as glyceryl polyoxyethylene ether hydroxystearate and stearoyl polyoxyethylene glycerol ester, are introduced as plasticizers to lower the glass transition temperature (Tg) of irbesartan and adjust its electrostatic properties. Therefore, the specific technical solution of this invention includes: This invention provides an irbesartan solid dispersion and its preparation method. The irbesartan solid dispersion is composed of the following components by weight percentage: irbesartan 10-30%, copovidone 60-90%, and plasticizer 5-15%. In the above, the plasticizer is a nonionic surfactant selected from one or more of glycerol polyoxyethylene ether hydroxystearate and stearoyl polyoxyethylene glycerol ester. As nonionic surfactants, glycerol polyoxyethylene ether hydroxystearate and stearoyl polyoxyethylene glycerol ester can reduce the Tg of irbesartan, lower the melting temperature, and improve the wettability of the drug. They can also act as plasticizers to optimize the flexibility and processability of extrudates. Their balance of hydrophilicity and hydrophobicity helps to improve the dissolution rate of the poorly soluble drug irbesartan.

[0024] Copolyvinylpyrrolidone (PVP / VA) is a nonionic, water-soluble polymer obtained by copolymerization of N-vinylpyrrolidone (NVP) and vinyl acetate (VA) in a certain proportion. PVP / VA comes in various types with glass transition temperatures ranging from 55°C to 109°C. In the technical solution of this invention, PVP / VA 64 and PVP / VA 55 are preferred as carriers, with K values ​​in the range of 22 to 36.

[0025] like Figure 1 As shown, the method for preparing the above-mentioned irbesartan solid dispersion includes the following steps: S1. According to the preset ratio, mix irbesartan, copovidone and plasticizer evenly to obtain a mixture; S2. Set the temperature of different heating sections of the twin-screw extruder to 50~200℃ and the screw speed to 50~1000rpm. After the temperature reaches the set temperature, start the screw and extrude the mixture after melting and shearing. S3. Cool the extrudate into a solid and then mechanically crush it to a suitable particle size to obtain irbesartan solid dispersion.

[0026] In addition, the present invention also provides an irbesartan formulation comprising the above-mentioned irbesartan solid dispersion and pharmaceutically conventional excipients; wherein the formulation is a tablet, and the excipients include fillers, disintegrants, and lubricants; the formulation prepared may be a single-component formulation or a combination formulation. The specific method includes: uniformly mixing the irbesartan solid dispersion with fillers and disintegrants, then adding lubricants and mixing uniformly, and finally compressing into tablets.

[0027] The filler is selected from one or more of microcrystalline cellulose, lactose, starch, and mannitol; the disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, and low-substituted hydroxypropyl cellulose; and the lubricant is magnesium stearate. In addition, when the formulation is a compound preparation, it also contains hydrochlorothiazide.

[0028] The above content will be further elaborated below through specific embodiments, and the described embodiments are only some embodiments of the present invention. Furthermore, the irbesartan used in this invention is manufactured by Zhejiang Tianyu Pharmaceutical Co., Ltd., and the twin-screw hot melt extruder is a Thermo Fisher Scientific Pharma 16 twin-screw hot melt extruder. The dissolution curve was studied using a paddle method at 50 rpm and 1000 ml, with 0.1 mol / L hydrochloric acid, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer as the dissolution media. Samples of 1.5 ml were taken at 5, 10, 15, 20, 30, 45, and 60 minutes, filtered through a 0.45 μm PVDF membrane, and analyzed by high-performance liquid chromatography (HPLC).

[0029] Example 1 In this embodiment, PVP / VA 64 was used as a carrier to prepare irbesartan solid dispersion. The weight percentages of each component were: 20% irbesartan, 75% PVP / VA 64, and 5% glycerol polyoxyethylene ether hydroxy stearate.

[0030] The specific preparation process is as follows: Irbesartan, PVP / VA 64, and glycerol polyoxyethylene ether hydroxy stearate, as specified in the above ratio, are passed through a 60-mesh sieve and mixed in a mixer at 10 rpm for 15 minutes. The extrusion parameters of a twin-screw hot-melt extruder are set as follows: the temperature gradient from the feed port to the die is set to 50℃-80℃-120℃-170℃-190℃-190℃-190℃-190℃-170℃-160℃, and the screw speed is 50 rpm. The material is extruded and cooled into a solid. A hammer mill with a 1.0mm sieve is used for granulation at 400 rpm to prepare an irbesartan solid dispersion.

[0031] Subsequently, an appropriate amount of irbesartan solid dispersion (equivalent to 150 mg of irbesartan) was weighed and added to a dissolution vessel, and the dissolution rate of irbesartan in 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer was determined according to the above dissolution test method.

[0032] Example 2 In this embodiment, PVP / VA 64 was used as a carrier to prepare irbesartan solid dispersion. The weight percentages of each component were: 30% irbesartan, 60% PVP / VA 64, and 10% glycerol polyoxyethylene ether hydroxy stearate.

[0033] The specific preparation process is as follows: Irbesartan, PVP / VA 64, and glycerol polyoxyethylene ether hydroxystearate, as specified in the above ratio, are passed through a 60-mesh sieve and mixed in a mixer at 10 rpm for 15 minutes. The extrusion parameters of a twin-screw hot-melt extruder are set as follows: the temperature gradient from the feed inlet to the die is set to 50℃-80℃-120℃-160℃-180℃-180℃-180℃-180℃-160℃, and the screw speed is 80 rpm. The material is extruded and cooled into a solid. A hammer mill with a 1.0mm sieve is used for granulation at 400 rpm to obtain an irbesartan solid dispersion.

[0034] Subsequently, an appropriate amount of irbesartan solid dispersion (equivalent to 150 mg of irbesartan) was weighed and added to a dissolution vessel, and the dissolution rate of irbesartan in 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer was determined according to the above dissolution test method.

[0035] The dissolution rates of irbesartan solid dispersions using PVP / VA64 as a carrier in Examples 1 and 2 were statistically analyzed in different media, and the results are as follows: Figure 2 As shown. Based on Figure 2 The results shown are presented in Table 1 below, which illustrates the dissolution results of irbesartan solid dispersion with PVP / VA64 as the carrier in different media.

[0036] Table 1. Dissolution rate of irbesartan solid dispersion with PVP / VA64 as carrier in different media.

[0037] Example 3 In this embodiment, PVP / VA 55 was used as a carrier to prepare irbesartan solid dispersion. The weight percentages of each component were: 10% irbesartan, 75% PVP / VA 64, and 15% glycerol polyoxyethylene ether hydroxy stearate.

[0038] The specific preparation process is as follows: Irbesartan, PVP / VA 55, and glycerol polyoxyethylene ether hydroxy stearate, as specified in the above ratio, are passed through a 60-mesh sieve and mixed in a mixer at 10 rpm for 15 minutes. The extrusion parameters of a twin-screw hot-melt extruder are set as follows: the temperature gradient from the feed port to the die is set to 50℃-80℃-110℃-150℃-170℃-170℃-170℃-170℃-150℃, and the screw speed is 100 rpm. The material is extruded and cooled into a solid. A hammer mill with a 1.0mm sieve is used for granulation at 400 rpm to obtain an irbesartan solid dispersion.

[0039] Example 4 In this embodiment, the irbesartan solid dispersion of Example 2 was mixed with hydrochlorothiazide, microcrystalline cellulose, and croscarmellose sodium at 10 rpm for 10 minutes, and then magnesium stearate was added and mixed at 10 rpm for 5 minutes. The mixture was then compressed into tablets at 130 N. The weight percentages of the above raw materials were: 70% irbesartan solid dispersion, 5% hydrochlorothiazide, 20% microcrystalline cellulose, 4.5% croscarmellose sodium, and 0.5% magnesium stearate.

[0040] Based on the above, samples were taken at 10 different locations in the mixture to test the mixing uniformity. The dissolution rate of the prepared irbesartan hydrochlorothiazide tablets in 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer was determined.

[0041] Example 5 In this embodiment, the irbesartan solid dispersion of Example 3 was mixed with lactose, microcrystalline cellulose, and croscarmellose sodium at 10 rpm for 10 minutes, and then magnesium stearate was added and mixed at 10 rpm for 5 minutes. The mixture was then compressed into tablets at 130 N. The weight percentages of the above raw materials were: 80% irbesartan solid dispersion, 3% lactose, 14% microcrystalline cellulose, 2.5% low-substituted hydroxypropyl cellulose, and 0.5% magnesium stearate.

[0042] Based on the above, samples were taken at 10 different locations in the mixture to test the mixing uniformity. The dissolution rate of the prepared irbesartan hydrochlorothiazide tablets in 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer was determined.

[0043] The mixing uniformity obtained in Examples 4 and 5 is shown in Table 2.

[0044] Table 2 Results of Mixing Uniformity Test

[0045] The irbesartan dissolution rates measured in Examples 4 and 5 were summarized, and the results are as follows: Figure 3 As shown in Table 3, the dissolution rates of irbesartan components in single-agent and combination formulations prepared using irbesartan solid dispersions are presented below.

[0046] Table 3. Dissolution results of irbesartan components in single-agent and combination formulations prepared using irbesartan solid dispersions.

[0047] Based on the above, it can be seen that the formulation prepared using irbesartan solid dispersion particles exhibits excellent mixing uniformity. The dissolution rate reaches over 85% in 0.1 mol / L hydrochloric acid after 15 minutes, and over 85% in pH 4.5 acetate buffer and pH 6.8 phosphate buffer after 30 minutes.

[0048] Example 6 In this embodiment, an irbesartan solid dispersion was prepared using stearoyl polyoxyethylene glycerol as a plasticizer. The weight percentages of each component were: 10% irbesartan, 85% PVP / VA 55, and 5% stearoyl polyoxyethylene glycerol.

[0049] The specific preparation process is as follows: Irbesartan, PVP / VA 55, and stearoyl polyoxyethylene glycerol ester, as specified in the above ratio, are passed through a 60-mesh sieve and mixed in a mixer at 10 rpm for 15 minutes. The extrusion parameters of a twin-screw hot-melt extruder are set as follows: the temperature gradient from the feed inlet to the die is set to 50℃-80℃-110℃-160℃-180℃-180℃-180℃-180℃-160℃, and the screw speed is 500 rpm. The material is extruded and cooled into a solid. A hammer mill with a 1.0mm sieve is used for granulation at 400 rpm to prepare an irbesartan solid dispersion.

[0050] Example 7 This embodiment uses irbesartan solid dispersion prepared with stearoyl polyoxyethylene glycerol ester and glycerol polyoxyethylene ether hydroxystearate as plasticizers. The weight percentages of each component are: 15% irbesartan, 75% PVP / VA55, 5% glycerol polyoxyethylene ether hydroxystearate, and 5% stearoyl polyoxyethylene glycerol ester.

[0051] The specific preparation process is as follows: Irbesartan, PVP / VA 55, glyceryl polyoxyethylene ether hydroxystearate, and stearoyl polyoxyethylene glycerol ester, as specified in the above ratio, are passed through a 60-mesh sieve and mixed in a mixer at 10 rpm for 15 minutes. The extrusion parameters of a twin-screw hot-melt extruder are set as follows: the temperature gradient from the feed port to the die is set to 60℃-90℃-120℃-150℃-180℃-180℃-180℃-180℃-180℃-160℃, and the screw speed is 800 rpm. The material is extruded and cooled into a solid. A hammer mill with a 1.2mm sieve is used for granulation at 500 rpm to prepare an irbesartan solid dispersion.

[0052] Comparative Example 1 This comparative example mainly focuses on the determination of the original dissolution rate of irbesartan. Specifically, 150 mg of irbesartan was added to a dissolution vessel, and the original dissolution rate of irbesartan was determined using the above dissolution method. The results are shown in Table 4.

[0053] Table 4 Irbesartan Original Dissolution Rate

[0054] Table 4 shows that irbesartan is pH dependent, with the highest solubility in 0.1 mol / L hydrochloric acid solution (rapid dissolution), almost insoluble in pH 4.5 acetate buffer, and a solubility of 82.0% in pH 6.8 phosphate buffer after 60 minutes.

[0055] Comparative Example 2 This comparative example mainly tested the dissolution rate of irbesartan hydrochlorothiazide tablets AVALIDE (batch number: 8A506) developed by Sanofi Winthrop Industrie in 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer. The results are shown in Table 5.

[0056] Table 5 Dissolution rate of irbesartan in AVALIDE

[0057] As can be seen from Table 5, the dissolution rate of irbesartan in AVALIDE is similar to that of irbesartan in its original form. It dissolves rapidly in 0.1 mol / L hydrochloric acid solution, with a dissolution rate of less than 10% in pH 4.5 acetate buffer, and a dissolution rate of 85.2% in pH 6.8 phosphate buffer after 60 minutes.

[0058] Furthermore, comparing the dissolution results of irbesartan in Tables 1 to 5, the present invention obtained the following results: the irbesartan solid dispersion dissolves rapidly in 0.1 mol / L hydrochloric acid, and the dissolution rate reaches more than 90% in pH 4.5 and pH 6.8 media within 20 minutes; the irbesartan formulation dissolves rapidly in 0.1 mol / L hydrochloric acid, and the dissolution rate reaches more than 90% in pH 4.5 and pH 6.8 media within 30 minutes.

[0059] Therefore, by adopting the above-mentioned method for preparing irbesartan solid dispersion and its formulation, irbesartan is made into a solid dispersion and then into tablets. This not only improves the electrostatic aggregation of irbesartan to enhance the uniformity of formulation mixing, but also significantly improves the dissolution performance of irbesartan and enhances the bioavailability of the drug. This effectively solves the problems of insufficient uniformity of subsequent mixing due to electrostatic aggregation, poor dissolution performance due to low solubility, and low bioavailability of irbesartan in formulation preparation.

[0060] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0061] This document uses specific examples to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, those skilled in the art will recognize that, based on the ideas of the present invention, there will be changes in the specific implementation methods and application scope. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. An irbesartan solid dispersion, characterized in that, The irbesartan solid dispersion is composed of the following components by weight percentage: irbesartan 10-30%, copovidone 60-90%, and plasticizer 5-15%. The irbesartan solid dispersion is prepared by hot melt extrusion process and is used to improve the electrostatic aggregation of irbesartan to enhance the mixing uniformity in subsequent formulations, and to improve the dissolution performance of irbesartan to improve its bioavailability. It is also used as a raw material to prepare irbesartan single-component tablets or irbesartan compound tablets.

2. The irbesartan solid dispersion according to claim 1, characterized in that, The plasticizer is a nonionic surfactant selected from one or more of glycerol polyoxyethylene ether hydroxy stearate and stearoyl polyoxyethylene glycerate.

3. The irbesartan solid dispersion according to claim 1, characterized in that, The copovidone is selected from one or more of PVP / VA 64 and PVP / VA 55, and the K value of the copovidone is in the range of 22 to 36.

4. A method for preparing an irbesartan solid dispersion as described in any one of claims 1 to 3, characterized in that, Includes the following steps: S1. According to the preset ratio, mix irbesartan, copovidone and plasticizer evenly to obtain a mixture; S2. Set the temperature of different heating sections of the twin-screw extruder to 50~200℃ and the screw speed to 50~1000rpm. After the temperature reaches the set temperature, start the screw and extrude the mixture after melting and shearing. S3. Cool the extrudate into a solid and then mechanically crush it to a suitable particle size to obtain irbesartan solid dispersion.

5. The method for preparing an irbesartan solid dispersion according to claim 4, characterized in that, In S2, the temperature of the heating section of the twin-screw extruder is set in a gradient from the feed port to the die.

6. An irbesartan formulation, characterized in that, The formulation comprises irbesartan solid dispersion as described in any one of claims 1 to 3, and pharmaceutically conventional excipients; the formulation is a tablet, and the excipients include fillers, disintegrants, and lubricants; the formulation is a single-ingredient or combination formulation.

7. An irbesartan formulation according to claim 6, characterized in that, The filler is selected from one or more of microcrystalline cellulose, lactose, starch, and mannitol; the disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, and low-substituted hydroxypropyl cellulose; and the lubricant is magnesium stearate.

8. An irbesartan formulation according to claim 6, characterized in that, When the preparation is a compound preparation, it also contains hydrochlorothiazide.

9. An irbesartan formulation according to claim 6, characterized in that, The irbesartan solid dispersion has a dissolution rate of not less than 90% within 20 minutes in pH 4.5 and pH 6.8 media, and the tablets have a dissolution rate of not less than 90% within 30 minutes in pH 4.5 and pH 6.8 media.

10. A method for preparing an irbesartan formulation as described in claim 6, characterized in that, Includes the following steps: Irbesartan solid dispersion is mixed evenly with filler and disintegrant, then lubricant is added and mixed evenly, and finally compressed into tablets.

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