Inorganic compound-starch co-treatment pre-gelatinization adjuvant, preparation method and application thereof

Abstract

The application discloses an inorganic compound-starch co-processing pre-gelatinization auxiliary material and a preparation method and application thereof. The preparation method comprises the following steps: mixing a medicinal inorganic salt and / or a medicinal inorganic oxide with water, and then mixing the medicinal inorganic salt and / or the medicinal inorganic oxide with starch; placing the mixed system in a microwave reactor for microwave treatment; and drying the microwave treatment product. The mixed system of the starch, the medicinal inorganic salt and / or the medicinal inorganic oxide is pre-gelatinized for the first time, the inorganic compound-starch co-processing pre-gelatinization auxiliary material is obtained, the functions of the pre-gelatinized starch and the inorganic compound as medicinal auxiliary materials are retained, and the flowability, the compressibility of the powder and the disintegration performance of the solid preparation prepared by using the inorganic compound-starch co-processing pre-gelatinization auxiliary material are improved. The preparation method is simple in process and low in equipment requirement, the co-processing auxiliary material prepared can be used as a whole for dry / wet granulation and powder direct compression raw material, which is of great significance for simplifying production steps, improving production efficiency and reducing production cost of enterprises.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical excipients technology, and specifically relates to an inorganic compound-starch co-treated pregelatinized excipient, its preparation method, and its application. Background Technology

[0002] Pregelatinized starch is a pharmaceutical excipient prepared by modifying starch through chemical or physical methods. Compared to starch, pregelatinized starch has better flowability and compressibility, and can be used as an excipient for direct compression of powder into tablets. Inorganic salts, as an important pharmaceutical excipient, are often used in combination with pregelatinized starch in tablet formulations.

[0003] Currently, the combined approach mainly involves first preparing pregelatinized starch using methods such as wet heat treatment, mechanical activation, ethanol-alkali method, and microwave method. Then, the pregelatinized starch is physically mixed with inorganic salts and other components, followed by dry or wet granulation and tableting, or direct tableting of the powder. This preparation method for pregelatinized starch is time-consuming, energy-intensive, complex, requires sophisticated equipment, and results in high production costs for enterprises.

[0004] Considering the application scenarios of pregelatinized starch and inorganic salts, exploring a method for preparing a mixed excipient that combines the functions of both raw materials and is convenient to use has become an urgent problem to be solved in this field. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the present invention provides an inorganic compound-starch co-treated pregelatinized excipient, its preparation method and application. The co-treated pregelatinized excipient retains the functions of the pregelatinized starch and the inorganic compound, while improving the powder properties of the prepared powder and enhancing the applicability of the formulation. Moreover, the preparation method is simple and helps to reduce production costs.

[0006] A first aspect of this invention provides a method for preparing an inorganic compound-starch co-treated pregelatinized excipient, comprising: mixing pharmaceutical inorganic salts and / or pharmaceutical inorganic oxides with water, and then mixing the mixture with starch; placing the mixture in a microwave reactor for microwave treatment; and drying the microwave-treated product. The mixing order of the pharmaceutical inorganic salts and / or pharmaceutical inorganic oxides with water and starch is crucial. If starch and water are mixed first, the overall viscosity of the liquid will increase. If the pharmaceutical inorganic salts and / or pharmaceutical inorganic oxides are then added, the increased resistance of the liquid may prevent them from mixing evenly with the starch.

[0007] According to a specific embodiment of the present invention, the mass ratio of pharmaceutical inorganic salt and / or pharmaceutical inorganic oxide, water and starch is 1:4 to 16:0.25 to 5.

[0008] According to a specific embodiment of the present invention, the pharmaceutical inorganic salt is selected from sodium carbonate, calcium carbonate, calcium hydrogen phosphate dihydrate, tricalcium phosphate, or calcium sulfate dihydrate.

[0009] According to a specific embodiment of the present invention, the pharmaceutical inorganic oxide is silicon dioxide.

[0010] According to a specific embodiment of the present invention, the starch is selected from corn starch, potato starch or wheat starch.

[0011] According to a specific embodiment of the present invention, in the microwave processing, the time and frequency of the microwave processing are adjusted so that the microwave energy obtained per gram of starch is 1310J to 21840J.

[0012] In a second aspect, the present invention provides an inorganic compound-starch co-treated pregelatinized excipient prepared according to the aforementioned method.

[0013] In a third aspect, the present invention provides a pharmaceutical formulation comprising the aforementioned inorganic compound-starch co-treated pregelatinized excipient.

[0014] A fourth aspect of the present invention provides the application of the aforementioned inorganic compound-starch co-treated pregelatinized excipient in dry or wet granulation.

[0015] In a fifth aspect, the present invention provides the application of the aforementioned inorganic compound-starch co-treated pregelatinized excipient in direct powder compression.

[0016] The beneficial effects of this invention are as follows:

[0017] The preparation method provided by this invention is the first to pregelatinize a mixture of starch and pharmaceutical inorganic salts and / or pharmaceutical inorganic oxides, resulting in a pregelatinized excipient co-treated with inorganic compounds and starch. This method retains the functions of both the pregelatinized starch and the inorganic compounds as pharmaceutical excipients while improving the powder's flowability, compressibility, and disintegration properties of solid dosage forms prepared using it. The preparation method is simple, requires minimal equipment, and the resulting co-treated excipient can be used as a whole as a raw material for dry / wet granulation and direct powder compression. This is of great significance for enterprises to simplify production steps, improve production efficiency, and reduce production costs. Attached Figure Description

[0018] Figure 1 The images are scanning electron microscope images of the samples: A: Sample from Example 1; B: Sample from Example 2. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, 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. Unless otherwise specified, the methods used in the embodiments of the present invention are conventional methods, and the reagents used are all commercially available.

[0020] This invention provides a method for preparing a pregelatinized excipient co-treated with pharmaceutical inorganic salts / or pharmaceutical inorganic oxides and starch. The method involves mixing pharmaceutical inorganic salts / or pharmaceutical inorganic oxides with starch excipients in a specific ratio, and then treating the mixture under different microwave conditions (controlling the microwave energy obtained per gram of starch to be 1310 J–21840 J) to obtain co-treated pregelatinized excipients with different degrees of pregelatinization. The formula for calculating microwave energy is: Microwave energy obtained per gram of starch = Microwave power output rate (%) × Output power (%) × Energy conversion efficiency (%) × Microwave treatment time (s) / Starch mass (g).

[0021] Example 1

[0022] A sodium carbonate-corn starch co-treated pregelatinizing additive MT 1310 The preparation method of -SC1MS1-UW4 includes the following steps:

[0023] (1) Preparation of sodium carbonate solution SC1-UM4: Sodium carbonate and ultrapure water were weighed and mixed evenly at room temperature according to the mass ratio of sodium carbonate to ultrapure water of 1:4 to obtain sodium carbonate solution SC1-UM4.

[0024] (2) Preparation of corn starch suspension containing sodium carbonate SC1MS1-UM4: The corn starch weighed is added to the sodium carbonate solution in step (1) according to the mass ratio of sodium carbonate to corn starch of 1:1. The mixture is stirred and mixed evenly at room temperature. The mixture is sealed with plastic wrap to prevent moisture loss, and the corn starch suspension containing sodium carbonate SC1MS1-UM4 is obtained.

[0025] (3) Sodium carbonate-corn starch co-treated pregelatinized auxiliary material MT 1310 Preparation of -SC1MS1-UW4: The corn starch suspension containing sodium carbonate prepared in step (2) was placed in a microwave reactor for treatment. The microwave energy value obtained per gram of corn starch was controlled to be 1310J. In order to make the microwave pregelatinization of corn starch uniform, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment was completed. Then, the prepared pregelatinized corn starch system containing sodium carbonate was freeze-dried to obtain a sodium carbonate-corn starch co-treated pregelatinization auxiliary material MT.1310 -SC1MS1-UW4.

[0026] Example 2

[0027] A sodium carbonate-corn starch co-treated pregelatinizing additive MT 21840 The preparation method of -SC1MS1-UW4 includes the following steps:

[0028] (1) Preparation of sodium carbonate solution SC1-UM4: Sodium carbonate and ultrapure water were mixed evenly at room temperature according to the mass ratio of sodium carbonate to ultrapure water of 1:4 to obtain sodium carbonate solution SC1-UM4.

[0029] (2) Preparation of corn starch suspension containing sodium carbonate SC1MS1-UM4: The corn starch weighed is added to the sodium carbonate solution in step (1) according to the mass ratio of sodium carbonate to corn starch of 1:1. The mixture is stirred and mixed evenly at room temperature. The mixture is sealed with plastic wrap to prevent moisture loss, and the corn starch suspension containing sodium carbonate SC1MS1-UM4 is obtained.

[0030] (3) Sodium carbonate-corn starch co-treated pregelatinized auxiliary material MT 21840 Preparation of -SC1MS1-UW4: The corn starch suspension containing sodium carbonate prepared in step (2) was placed in a microwave reactor for reaction. The energy value obtained per gram of corn starch was controlled to be 21840J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment was completed. Then, the prepared pregelatinized corn starch system containing sodium carbonate was freeze-dried to obtain a sodium carbonate-corn starch co-treated pregelatinization auxiliary material MT. 21840 -SC1MS1-UW4.

[0031] Example 3

[0032] MT of a sodium carbonate-corn starch co-treated pregelatinized auxiliary material 1310 The preparation method of -SC1MS5-UW4 includes the following steps:

[0033] (1) Preparation of sodium carbonate solution SC1-UM4: Sodium carbonate and ultrapure water were mixed evenly at room temperature according to the mass ratio of sodium carbonate to ultrapure water of 1:4 to obtain sodium carbonate solution SC1-UM4.

[0034] (2) Preparation of corn starch suspension containing sodium carbonate SC1MS5-UW4: The corn starch weighed out was added to the sodium carbonate solution in step (1) according to the mass ratio of sodium carbonate to corn starch of 1:5. The mixture was stirred and mixed evenly at room temperature, and sealed with plastic wrap to prevent moisture loss.

[0035] (3) Sodium carbonate-corn starch co-treated pregelatinized auxiliary material MT 1310 Preparation of -SC1MS5-UW4: The corn starch suspension containing sodium carbonate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 1310J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing sodium carbonate was freeze-dried to obtain a sodium carbonate-corn starch co-treated pregelatinization auxiliary material MT. 1310 -SC1MS5-UW4.

[0036] Example 4

[0037] A sodium carbonate-corn starch co-treated pregelatinizing additive MT 21840 The preparation method of -SC1MS5-UW4 includes the following steps:

[0038] (1) Preparation of sodium carbonate solution SC1-UM4: Sodium carbonate and ultrapure water were mixed evenly at room temperature according to the mass ratio of sodium carbonate to ultrapure water of 1:4 to obtain sodium carbonate solution SC1-UM4.

[0039] (2) Preparation of corn starch suspension containing sodium carbonate SC1MS5-UW4: The corn starch weighed out was added to the sodium carbonate solution in step (1) according to the mass ratio of sodium carbonate to corn starch of 1:5. The mixture was stirred and mixed evenly at room temperature, and sealed with plastic wrap to prevent moisture loss.

[0040] (3) Sodium carbonate-corn starch co-treated pregelatinized auxiliary material MT 21840 Preparation of -SC1MS5-UW4: The corn starch suspension containing sodium carbonate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 21840J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing sodium carbonate was freeze-dried to obtain a sodium carbonate-corn starch co-treated pregelatinization auxiliary material MT. 21840 -SC1MS5-UW4.

[0041] Example 5

[0042] A sodium carbonate-corn starch co-treated pregelatinizing additive MT 1310 The preparation method of -SC1MS1-UW8 includes the following steps:

[0043] (1) Preparation of sodium carbonate solution SC1-UM8: Sodium carbonate and ultrapure water were mixed evenly at room temperature according to the mass ratio of sodium carbonate to ultrapure water of 1:8 to obtain sodium carbonate solution SC1-UM8.

[0044] (2) Preparation of corn starch suspension containing sodium carbonate SC1MS1-UW8: According to the mass ratio of sodium carbonate to corn starch of 1:1, the weighed corn starch is added to the sodium carbonate solution in step (1), and stirred and mixed evenly at room temperature. The container is then sealed with plastic wrap to prevent moisture loss.

[0045] (3) Sodium carbonate-corn starch co-treated pregelatinized auxiliary material MT 1310 Preparation of -SC1MS1-UW8: The corn starch suspension containing sodium carbonate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 1310J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing sodium carbonate was freeze-dried to obtain a sodium carbonate-corn starch co-treated pregelatinization auxiliary material MT. 1310 -SC1MS1-UW8.

[0046] Example 6

[0047] A sodium carbonate-corn starch co-treated pregelatinizing additive MT 21840 The preparation method of -SC1MS1-UW8 includes the following steps:

[0048] (1) Preparation of sodium carbonate solution SC1-UM8: Sodium carbonate and ultrapure water were mixed evenly at room temperature according to the mass ratio of sodium carbonate to ultrapure water of 1:8 to obtain sodium carbonate solution SC1-UM8.

[0049] (2) Preparation of corn starch suspension containing sodium carbonate SC1MS1-UW8: According to the mass ratio of sodium carbonate to corn starch of 1:1, the weighed corn starch is added to the sodium carbonate solution in step (1), and stirred and mixed evenly at room temperature. The container is then sealed with plastic wrap to prevent moisture loss.

[0050] (3) Sodium carbonate-corn starch co-treated pregelatinized auxiliary material MT 21840Preparation of -SC1MS1-UW8: The corn starch suspension containing sodium carbonate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 21840J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing sodium carbonate was freeze-dried to obtain a sodium carbonate-corn starch co-treated pregelatinization auxiliary material MT. 21840 -SC1MS1-UW8.

[0051] Example 7

[0052] A sodium carbonate-corn starch co-treated pregelatinizing additive MT 1310 The preparation method of -SC1MS5-UW8 includes the following steps:

[0053] (1) Preparation of sodium carbonate solution SC1-UM8: Sodium carbonate and ultrapure water were mixed evenly at room temperature according to the mass ratio of sodium carbonate to ultrapure water of 1:8 to obtain sodium carbonate solution SC1-UM8.

[0054] (2) Preparation of corn starch suspension containing sodium carbonate SC1MS5-UW8: The corn starch weighed is added to the sodium carbonate solution in step (1) according to the mass ratio of sodium carbonate to corn starch of 1:5. The mixture is stirred and mixed evenly at room temperature, and sealed with plastic wrap to prevent moisture loss.

[0055] (3) Sodium carbonate-corn starch co-treated pregelatinized auxiliary material MT 1310 Preparation of -SC1MS5-UW8: The corn starch suspension containing sodium carbonate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 1310J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, i.e., stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing sodium carbonate was freeze-dried to obtain a sodium carbonate-corn starch co-treated pregelatinization auxiliary material MT. 1310 -SC1MS5-UW8.

[0056] Example 8

[0057] A sodium carbonate-corn starch co-treated pregelatinizing additive MT 21840 The preparation method of -SC1MS5-UW8 includes the following steps:

[0058] (1) Preparation of sodium carbonate solution SC1-UM8: Sodium carbonate and ultrapure water were mixed evenly at room temperature according to the mass ratio of sodium carbonate to ultrapure water of 1:8 to obtain sodium carbonate solution SC1-UM8.

[0059] (2) Preparation of corn starch suspension containing sodium carbonate SC1MS5-UW8: The corn starch weighed is added to the sodium carbonate solution in step (1) according to the mass ratio of sodium carbonate to corn starch of 1:5. The mixture is stirred and mixed evenly at room temperature, and sealed with plastic wrap to prevent moisture loss.

[0060] (3) Sodium carbonate-corn starch co-treated pregelatinized auxiliary material MT 21840 Preparation of -SC1MS5-UW8: The corn starch suspension containing sodium carbonate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 21840J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, i.e., stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing sodium carbonate was freeze-dried to obtain a sodium carbonate-corn starch co-treated pregelatinization auxiliary material MT. 21840 -SC1MS5-UW8.

[0061] Example 9

[0062] A pregelatinizing adjuvant MT co-treated with dicalcium phosphate dihydrate and corn starch 1310 The preparation method of -DCPD1MS1-UW4 includes the following steps:

[0063] (1) Preparation of calcium phosphate dihydrate suspension DCPD1-UW4: The calcium phosphate dihydrate and ultrapure water were mixed evenly at room temperature according to the mass ratio of calcium phosphate dihydrate to ultrapure water of 1:4 to obtain calcium phosphate dihydrate suspension DCPD1-UW4.

[0064] (2) Preparation of corn starch suspension containing calcium diphosphate dihydrate DCPD1MS1-UW4: The corn starch was weighed and added to the calcium diphosphate dihydrate suspension in step (1) according to the mass ratio of calcium diphosphate dihydrate to corn starch of 1:1. The mixture was stirred and mixed evenly at room temperature, and sealed with plastic wrap to prevent moisture loss, thus obtaining the corn starch suspension containing calcium diphosphate dihydrate DCPD1MS1-UW4.

[0065] (3) MT pregelatinized admixture co-treated with calcium phosphate dihydrate and corn starch 1310Preparation of -DCPD1MS1-UW4: The corn starch suspension containing calcium diphosphate dihydrate prepared in step (2) was placed in a microwave reactor for treatment. The microwave energy value obtained per gram of corn starch was controlled to be 1310J. In order to make the corn starch microwave pregelatinization uniform, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment was completed. Then, the prepared pregelatinized corn starch system containing calcium diphosphate dihydrate was dried to obtain a calcium diphosphate dihydrate-corn starch co-treated pregelatinization auxiliary material MT. 1310 -DCPD1MS1-UW4.

[0066] Example 10

[0067] A pregelatinizing adjuvant MT co-treated with dicalcium phosphate dihydrate and corn starch 21840 The preparation method of -DCPD1MS1-UW4 includes the following steps:

[0068] (1) Preparation of calcium phosphate dihydrate suspension DCPD1-UW4: The calcium phosphate dihydrate and ultrapure water were mixed evenly at room temperature according to the mass ratio of calcium phosphate dihydrate to ultrapure water of 1:4 to obtain calcium phosphate dihydrate suspension DCPD1-UW4.

[0069] (2) Preparation of corn starch suspension containing calcium diphosphate dihydrate DCPD1MS1-UW4: The corn starch was weighed and added to the calcium diphosphate dihydrate suspension in step (1) according to the mass ratio of calcium diphosphate dihydrate to corn starch of 1:1. The mixture was stirred and mixed evenly at room temperature, and sealed with plastic wrap to prevent moisture loss, thus obtaining the corn starch suspension containing calcium diphosphate dihydrate DCPD1MS1-UW4.

[0070] (3) MT pregelatinized admixture co-treated with calcium phosphate dihydrate and corn starch 21840 Preparation of -DCPD1MS1-UW4: The corn starch suspension containing calcium diphosphate dihydrate prepared in step (2) was placed in a microwave reactor for reaction. The energy value obtained per gram of corn starch was controlled to be 21840J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment was completed. Then, the prepared pregelatinized corn starch system containing calcium diphosphate dihydrate was freeze-dried to obtain a calcium diphosphate dihydrate-corn starch co-treated pregelatinization auxiliary material MT. 21840 -DCPD1MS1-UW4.

[0071] Example 11

[0072] MT of a pregelatinized auxiliary material co-treated with dicalcium phosphate dihydrate and corn starch 1310 -DCPD1MS 0.25-UW4 preparation method includes the following steps:

[0073] (1) Preparation of calcium phosphate dihydrate suspension DCPD1-UW4: The calcium phosphate dihydrate and ultrapure water were mixed evenly at room temperature according to the mass ratio of calcium phosphate dihydrate to ultrapure water of 1:4 to obtain calcium phosphate dihydrate suspension DCPD1-UW4.

[0074] (2) Corn starch suspension containing calcium phosphate dihydrate DCPD1MS 0.25 - Preparation of UW4: According to the mass ratio of dicalcium phosphate dihydrate to corn starch of 1:0.25, add the weighed corn starch to the dicalcium phosphate dihydrate suspension in step (1), stir and mix evenly at room temperature, and seal with plastic wrap to prevent moisture loss.

[0075] (3) MT pregelatinized admixture co-treated with calcium phosphate dihydrate and corn starch 1310 -DCPD1MS 0.25 Preparation of -UW4: The corn starch suspension containing calcium phosphate dihydrate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 1310J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing calcium phosphate dihydrate was freeze-dried to obtain a calcium phosphate dihydrate-corn starch co-treated pregelatinization auxiliary material MT. 1310 -DCPD1MS 0.25 -UW4.

[0076] Example 12

[0077] A pregelatinizing adjuvant MT co-treated with dicalcium phosphate dihydrate and corn starch 21840 -DCPD1MS 0.25 The preparation method of -UW4 includes the following steps:

[0078] (1) Preparation of calcium phosphate dihydrate suspension DCPD1-UW4: The calcium phosphate dihydrate and ultrapure water were mixed evenly at room temperature according to the mass ratio of calcium phosphate dihydrate to ultrapure water of 1:4 to obtain calcium phosphate dihydrate suspension DCPD1-UW4.

[0079] (2) Corn starch suspension containing calcium phosphate dihydrate DCPD1MS 0.25 - Preparation of UW4: According to the mass ratio of dicalcium phosphate dihydrate to corn starch of 1:0.25, add the weighed corn starch to the dicalcium phosphate dihydrate suspension in step (1), stir and mix evenly at room temperature, and seal with plastic wrap to prevent moisture loss.

[0080] (3) MT pregelatinized admixture co-treated with calcium phosphate dihydrate and corn starch 21840 -DCPD1MS 0.25 Preparation of -UW4: The corn starch suspension containing calcium diphosphate dihydrate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 21840J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing calcium diphosphate dihydrate was freeze-dried to obtain a calcium diphosphate dihydrate-corn starch co-treated pregelatinization auxiliary material MT. 21840 -DCPD1MS 0.25 -UW4.

[0081] Example 13

[0082] A pregelatinizing adjuvant MT co-treated with dicalcium phosphate dihydrate and corn starch 1310 The preparation method of -DCPD1MS1-UW8 includes the following steps:

[0083] (1) Preparation of calcium phosphate dihydrate suspension DCPD1-UW8: The calcium phosphate dihydrate and ultrapure water were mixed evenly at room temperature according to the mass ratio of calcium phosphate dihydrate to ultrapure water of 1:8 to obtain calcium phosphate dihydrate suspension DCPD1-UW8.

[0084] (2) Preparation of corn starch suspension containing calcium diphosphate dihydrate DCPD1MS1-UW8: According to the mass ratio of calcium diphosphate dihydrate to corn starch of 1:1, the weighed corn starch is added to the calcium diphosphate dihydrate suspension in step (1), and stirred and mixed evenly at room temperature. The container is then sealed with plastic wrap to prevent moisture loss.

[0085] (3) MT pregelatinized admixture co-treated with calcium phosphate dihydrate and corn starch 1310 Preparation of -DCPD1MS1-UW8: The corn starch suspension containing calcium diphosphate dihydrate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 1310J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing calcium diphosphate dihydrate was freeze-dried to obtain a calcium diphosphate dihydrate-corn starch co-treated pregelatinization auxiliary material MT. 1310 -DCPD1MS1-UW8.

[0086] Example 14

[0087] A pregelatinizing adjuvant MT co-treated with dicalcium phosphate dihydrate and corn starch 21840The preparation method of -DCPD1MS1-UW8 includes the following steps:

[0088] (1) Preparation of calcium phosphate dihydrate suspension DCPD1-UW8: The calcium phosphate dihydrate and ultrapure water were mixed evenly at room temperature according to the mass ratio of calcium phosphate dihydrate to ultrapure water of 1:8 to obtain calcium phosphate dihydrate suspension DCPD1-UW8.

[0089] (2) Preparation of corn starch suspension containing calcium diphosphate dihydrate DCPD1MS1-UW8: According to the mass ratio of calcium diphosphate dihydrate to corn starch of 1:1, the weighed corn starch is added to the calcium diphosphate dihydrate suspension in step (1), and stirred and mixed evenly at room temperature. The container is then sealed with plastic wrap to prevent moisture loss.

[0090] (3) MT pregelatinized admixture co-treated with calcium phosphate dihydrate and corn starch 21840 Preparation of -DCPD1MS1-UW8: The corn starch suspension containing calcium diphosphate dihydrate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 21840J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing calcium diphosphate dihydrate was freeze-dried to obtain a calcium diphosphate dihydrate-corn starch co-treated pregelatinization auxiliary material MT. 21840 -DCPD1MS1-UW8.

[0091] Example 15

[0092] A pregelatinizing adjuvant MT co-treated with dicalcium phosphate dihydrate and corn starch 1310 -DCPD1MS 0.25 The preparation method of -UW8 includes the following steps:

[0093] (1) Preparation of calcium phosphate dihydrate suspension DCPD1-UW8: The calcium phosphate dihydrate and ultrapure water were mixed evenly at room temperature according to the mass ratio of calcium phosphate dihydrate to ultrapure water of 1:8 to obtain calcium phosphate dihydrate suspension DCPD1-UW8.

[0094] (2) Corn starch suspension containing calcium phosphate dihydrate DCPD1MS 0.25 - Preparation of UW8: According to the mass ratio of dicalcium phosphate dihydrate to corn starch of 1:0.25, the weighed corn starch is added to the dicalcium phosphate dihydrate suspension in step (1), and stirred and mixed evenly at room temperature. The container is then sealed with plastic wrap to prevent moisture loss.

[0095] (3) MT pregelatinized admixture co-treated with calcium phosphate dihydrate and corn starch1310 -DCPD1MS 0.25 Preparation of -UW8: The corn starch suspension containing calcium phosphate dihydrate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 1310J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, that is, stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing calcium phosphate dihydrate was freeze-dried to obtain a calcium phosphate dihydrate-corn starch co-treated pregelatinization auxiliary material MT. 1310 -DCPD1MS 0.25 -UW8.

[0096] Example 16

[0097] A pregelatinizing adjuvant MT co-treated with dicalcium phosphate dihydrate and corn starch 21840 -DCPD1MS 0.25 The preparation method of -UW8 includes the following steps:

[0098] (1) Preparation of calcium phosphate dihydrate suspension DCPD1-UW8: The calcium phosphate dihydrate and ultrapure water were mixed evenly at room temperature according to the mass ratio of calcium phosphate dihydrate to ultrapure water of 1:8 to obtain calcium phosphate dihydrate suspension DCPD1-UW8.

[0099] (2) Corn starch suspension containing calcium phosphate dihydrate DCPD1MS 0.25 - Preparation of UW8: According to the mass ratio of dicalcium phosphate dihydrate to corn starch of 1:0.25, the weighed corn starch is added to the dicalcium phosphate dihydrate suspension in step (1), and stirred and mixed evenly at room temperature. The container is then sealed with plastic wrap to prevent moisture loss.

[0100] (3) MT pregelatinized admixture co-treated with calcium phosphate dihydrate and corn starch 21840 -DCPD1MS 0.25 Preparation of -UW8: The corn starch suspension containing calcium phosphate dihydrate prepared in step (2) was placed in a microwave reactor for treatment. The energy value obtained per gram of corn starch was controlled to be 21840J. To ensure uniform microwave pregelatinization of corn starch, an intermittent microwave method was adopted, i.e., stirring for 10s after each 1min of microwave treatment until the microwave treatment ended. Then, the prepared pregelatinized corn starch system containing calcium phosphate dihydrate was freeze-dried to obtain a calcium phosphate dihydrate-corn starch co-treated pregelatinization auxiliary material MT. 21840 -DCPD1MS 0.25 -UW8.

[0101] Following the preparation method of sodium carbonate-corn starch co-treated pregelatinizing adjuvant, sodium carbonate-wheat starch / potato starch co-treated pregelatinizing adjuvant was prepared. Following the preparation method of calcium phosphate dihydrate-corn starch co-treated pregelatinizing adjuvant, calcium phosphate dihydrate-wheat starch / potato starch co-treated pregelatinizing adjuvant, tricalcium phosphate-corn starch / wheat starch / potato starch co-treated pregelatinizing adjuvant, calcium carbonate-corn starch / wheat starch / potato starch co-treated pregelatinizing adjuvant, calcium sulfate dihydrate-corn starch / wheat starch / potato starch co-treated pregelatinizing adjuvant, and silica-corn starch / wheat starch / potato starch co-treated pregelatinizing adjuvant were also prepared. The preparation parameters of each co-treated pregelatinizing adjuvant are summarized in Table 1.

[0102] Table 1 Summary of preparation parameters for each co-processed pregelatinized auxiliary material

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] For the samples MT of Examples 1 and 2 above 1310 -SC1MS1-UW4、MT 21840 Electron microscopy (SEM) was performed on the SC1MS1-UW4 to analyze the particle size distribution and powder properties of samples from Examples 1-144. The results are shown in [Figure number missing]. Figure 1 The method is as follows:

[0110] 1. Instruments: Hitachi SU-8100 scanning electron microscope (Japan); Dandong Baite BT-2006 laser particle size analyzer; Baishan Jiujiu GJ03-09 powder comprehensive characteristic tester.

[0111] 2. SEM detection conditions: 2kV accelerating voltage, 500x amplification.

[0112] 3. Powder properties testing items:

[0113] (1) Loose density (ρ) 松Fixed volume method: Place the sample above a vibrating sieve, turn on the sieve, and under the action of vibration, the sample passes through the built-in sieve and fills a graduated cylinder with a fixed volume of 25 ml. Scrape off the excess powder, weigh the total weight of the powder and the container, and subtract the weight of the container to obtain the weight of the loosely packed powder (M). 松 (In triplicate)

[0114] ρ 松 =M 松 / 25

[0115] (2) Tap density (ρ) 振 ): Fixed mass method. Weigh approximately 10.0g (M 振 The sample was placed in a graduated cylinder with a capacity of 25 ml, and the rotation speed was set to 300 r / min for 10 min. After vibration, the volume of the sample in the graduated cylinder was read and recorded as the tapped volume (V). 振 ).

[0116] ρ 振 =M 振 / V 振

[0117] (3) Carr index and Hausnerby

[0118] The compressibility of powders reacted with the Karl elliptic index and the flowability of powders reacted with the Hausner-Nabi index can be calculated using the following formulas.

[0119] Cartesian exponent = (ρ 振 -ρ 松 ) / ρ 振

[0120] Hausnerbi = ρ 振 / ρ 松

[0121] It is not difficult to find that, such as Figure 1 In the SEM test results, MT 1310 The corn starch granules of -SC1MS1-UW4 exhibited water absorption and swelling, with a significant increase in volume. While the surface became uneven, it maintained its spherical shape, and a small amount of flocculent sodium carbonate crystals were adsorbed onto the surface. MT 21840 As the energy value imparted to corn starch by microwaves increases, some starch granules begin to lose their spherical shape and break into irregular fragments. A large amount of sodium carbonate crystal flocculents are adsorbed on the surface of the fragments.

[0122] Table 2 Particle Size Distribution

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129] As shown in Table 2, the Dv10, Dv50, and Dv90 values ​​represent the particle size when the cumulative particle percentage is 10%, 50%, and 90%, respectively. In Examples 1-144, the Dv10, Dv50, and Dv90 values ​​all show a gradually increasing trend with the increase of microwave energy applied to the starch, indicating a gradual increase in the degree of starch particle swelling, breakage, and reagglomeration. Simultaneously, the mass ratio of pharmaceutical inorganic salts and / or pharmaceutical inorganic oxides, and water to starch also has a certain influence on the particle size of the co-treated excipients, but the effect of microwave energy on particle size is more significant.

[0130] Table 3 Powder Properties Data

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137] As shown in Table 3, the powder properties of the samples prepared in Examples 1-144 showed a decreasing trend in angle of repose, Hausner ratio, and Karl Fischer index as the microwave energy imparted to starch increased, indicating an increasing trend in powder flowability and compressibility. Meanwhile, the mass ratio of pharmaceutical inorganic salts and / or pharmaceutical inorganic oxides, and water to starch also had some influence on the powder properties of the co-treated excipients, but the microwave energy had a more significant impact, which is consistent with the above conclusions regarding particle size.

[0138] Compression of blank effervescent tablets based on sodium carbonate-starch co-treated pregelatinized excipients prepared in Examples 1-8 and 17-32.

[0139] The sodium carbonate-starch co-treated pregelatinized excipients from Examples 1-8 and 17-32 were tableted according to the formulation in Table 4. The relevant inspection indicators are shown in the table.

[0140] Compression of blank sheets based on inorganic compound-starch co-treated pregelatinized excipients from Examples 9-16 and 33-144.

[0141] The inorganic compounds-starch co-treated pregelatinized excipients from Examples 9-16 and 33-144 were tableted according to the formulation in Table 5, and the relevant inspection indicators are shown in the table.

[0142] Table 4. Blank Effervescent Tablet Prescription Design

[0143]

[0144]

[0145] Table 5 Blank tablet prescription design

[0146] Excipient Name Proportion(%) Co-processing pregelatinized auxiliary materials 100

[0147] The following methods were used to prepare blank effervescent tablets: The co-treated pregelatinized excipients from Examples 1-8 and 17-32 were weighed according to the formulations in Table 4 as the basic excipients. The tablets were directly compressed to a weight of 350 mg, a diameter of 12.0 mm, a thickness of 3.5 mm, and a hardness controlled at 8-10 kg. Similarly, the co-treated pregelatinized excipients from Examples 9-16 and 33-144 were weighed according to the formulations in Table 5 as the basic excipients. The tablets were directly compressed to a weight of 350 mg, a diameter of 12.0 mm, a thickness of 3.5 mm, and a hardness controlled at 8-10 kg.

[0148] Determination of disintegration time: One tablet of each of the tablets prepared according to the above prescription was tested for disintegration time according to the method for determining the disintegration time of ordinary tablets in Part IV of the Chinese Pharmacopoeia.

[0149] Table 6. Disintegration Time of Tablets

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156] It can be seen that as the energy value imparted to starch by microwaves increases, the disintegration time of the compressed tablets is prolonged. Therefore, manufacturers can control the degree of starch pregelatinization by changing the microwave energy parameters to meet the disintegration time requirements of different tablets. This may have certain application value in oral solid sustained-release formulations and orally disintegrating tablets.

[0157] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. A method for preparing an inorganic compound-starch co-treated pregelatinized excipient, characterized in that, The preparation method includes: After mixing the pharmaceutical inorganic salts and / or pharmaceutical inorganic oxides with water, they are then mixed with starch. The mixture was placed in a microwave reactor for microwave treatment; Dry the microwave-treated product; The mass ratio of the pharmaceutical inorganic salt and / or pharmaceutical inorganic oxide, water and starch is 1:4~16:0.25~5; The pharmaceutical inorganic salts mentioned are selected from sodium carbonate, calcium carbonate, calcium hydrogen phosphate dihydrate, tricalcium phosphate, or calcium sulfate dihydrate; The pharmaceutical inorganic oxide mentioned is silicon dioxide; The starch mentioned is selected from corn starch, potato starch, or wheat starch; In the microwave processing, the time and frequency of the microwave processing are adjusted so that the microwave energy obtained per gram of starch is 1310 J to 21840 J.

2. The inorganic compound-starch co-treated pregelatinized excipient prepared according to the method described in claim 1.

3. A pharmaceutical preparation, characterized in that, It contains the inorganic compound-starch co-treated pregelatinized excipient as described in claim 2.

4. The application of the inorganic compound-starch co-treated pregelatinized excipient as described in claim 2 in dry or wet granulation.

5. The application of the inorganic compound-starch co-treated pregelatinized excipient as described in claim 2 in direct powder tableting.

Images