A pharmaceutical excipient and preparation method thereof

Abstract

The present invention relates to a pharmaceutical excipient and a preparation method thereof, wherein the pharmaceutical excipient comprises the following components by mass: 50-100 parts of microcrystalline cellulose, 1-8 parts of mannitol, 1-5 parts of sodium stearyl fumarate, 1-10 parts of sodium carboxymethyl starch, 1-5 parts of auxiliary agents, and 5-10 parts of modified silicon dioxide; wherein the modified silicon dioxide is xanthan gum modified silicon dioxide. The present invention adopts microcrystalline cellulose as the main body, and is compounded with components such as modified silicon dioxide, mannitol, sodium stearyl fumarate, etc. to prepare a pharmaceutical excipient, wherein the modified silicon dioxide is xanthan gum modified silicon dioxide, and xanthan gum molecules are grafted on the surface of silicon dioxide, thereby introducing a large number of active functional groups on the surface of inorganic particles, improving the dispersibility and compatibility of the components, and being able to produce a synergistic effect with other components, thereby improving the stability of the product and the drug loading and release performance.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical excipients, in particular to a pharmaceutical excipient and a preparation method thereof. Background Art

[0002] Pharmaceutical excipients are mixed excipients obtained by mixing multiple excipients in a certain proportion using a specific process, such as simple blending, co-drying, hot melt extrusion, freeze drying, etc. They can have multiple specific functions and a uniform appearance, and are one of the important raw materials in the field of pharmaceutical preparations.

[0003] At present, mixed excipient products are mainly divided into direct compression tablet premixed excipients and film coating premixed excipients. Direct compression tablet premixed excipients can be pressed into tablets by mixing with the main drug ingredients; while film coating premixed excipients can be used for coating of preparations by adding only an appropriate amount of solvent. Therefore, the use of mixed excipients is very convenient, which not only maintains the stability of production, but also reduces the research and development and production time of preparations, and has huge application potential.

[0004] However, current pharmaceutical excipient products still generally have certain defects. For example, raw material particles are prone to clumping, sticking to the bottom, uneven suspension, and insufficient stability, which may cause drug quality problems and fail to meet drug production requirements.

[0005] In summary, it is necessary to develop a new technical solution to solve the deficiencies in the prior art. Summary of the invention

[0006] Based on this, the present invention provides a pharmaceutical excipient and a preparation method and application thereof. The present invention adopts microcrystalline cellulose as the main body, and compounded with modified silicon dioxide, mannitol, sodium stearyl fumarate and other components to prepare a pharmaceutical excipient, wherein the modified silicon dioxide is xanthan gum modified silicon dioxide, and xanthan gum molecules are grafted on the surface of the silicon dioxide, thereby introducing a large number of active functional groups on the surface of the inorganic particles, improving the dispersibility and compatibility of the components, and being able to produce a synergistic effect with other components, thereby improving the stability of the product and the drug loading and release performance.

[0007] An object of the present invention is to provide a pharmaceutical excipient, wherein the pharmaceutical excipient comprises the following components in parts by weight:

[0008]

[0009] Wherein, the modified silica is xanthan gum modified silica.

[0010] Furthermore, the preparation method of the modified silicon dioxide comprises the following steps:

[0011] S1. Adding silica to a mixture of concentrated sulfuric acid and hydrogen peroxide, heating and stirring the reaction to obtain hydroxylated silica;

[0012] S2. xanthan gum, potassium carbonate and methyl bromoacetate are added to a solvent, stirred for reaction, the pH is adjusted to acidic, and then water and ethanol are added to heat the reaction, and carboxylated xanthan gum is obtained after purification;

[0013] S3. The hydroxylated silica and carboxylated xanthan gum are blended and subjected to ultrasonic heating reaction to obtain modified silica.

[0014] Furthermore, in step S1, the temperature of the heating and stirring reaction is 60-80°C and the time is 1-3h.

[0015] Furthermore, in step S1, the volume ratio of concentrated sulfuric acid to hydrogen peroxide is (6-9):(1-4).

[0016] Furthermore, in step S2, the stirring reaction time is 10-20 hours; the heating reaction temperature is 80-140° C., and the time is 10-20 hours.

[0017] Furthermore, in step S3, the mass ratio of the hydroxylated silica to the carboxylated xanthan gum is 1:(5-10).

[0018] Furthermore, in step S3, the temperature of the ultrasonic heating reaction is 60-90° C., and the time is 1-5 h.

[0019] Furthermore, the auxiliary agent is selected from one or more of a dispersant, a binder, a lubricant, a disintegrant, a flavoring agent, an essence, a salt, and a pigment.

[0020] Another object of the present invention is to provide a method for preparing the above-mentioned pharmaceutical excipient, the method for preparing the pharmaceutical excipient comprising the following steps:

[0021] The microcrystalline cellulose, mannitol, sodium stearyl fumarate, sodium carboxymethyl starch, adjuvants and modified silicon dioxide are mixed and stirred evenly, and ground through a 80-100 mesh sieve to obtain the pharmaceutical excipient.

[0022] Another object of the present invention is to provide the use of the above-mentioned pharmaceutical excipients in the preparation of pharmaceutical compositions.

[0023] The present invention has the following beneficial effects:

[0024] The pharmaceutical excipient provided by the present invention adopts microcrystalline cellulose as the main component, and is compounded with components such as mannitol, sodium stearyl fumarate, sodium carboxymethyl starch and modified silicon dioxide. In the modified silicon dioxide, silicon dioxide is first hydroxylated, and then xanthan gum is reacted with methyl bromoacetate (substituent) after being treated with potassium carbonate (hydrogen extraction agent) to introduce a methyl ester structure, and then heated and hydrolyzed to obtain carboxylated xanthan gum, and then the active hydroxyl groups on the surface of the hydroxylated silicon dioxide react with the carboxylated xanthan gum to achieve the grafting of xanthan gum molecules, thereby, the surface of the obtained modified silicon dioxide introduces an organic molecular structure, and has a large number of hydroxyl groups, carboxyl groups, benzene rings and other groups, effectively improving the compatibility and drug loading capacity of silicon dioxide, and reducing the possibility of component agglomeration and precipitation. In addition, the active functional groups of the various components can also play a synergistic role through intermolecular forces such as hydrogen bonds, further improving product stability, solubility and other multiple performances. DETAILED DESCRIPTION

[0025] In order to more clearly illustrate the technical solution of the present invention, the following examples are listed. Unless otherwise stated, the raw materials, reactions and post-treatment methods shown in the examples are common raw materials on the market and technical methods well known to those skilled in the art.

[0026] The words "preferred", "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain circumstances. However, other embodiments may also be preferred under the same circumstances or other circumstances. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not applicable, nor is it intended to exclude other embodiments from the scope of the present invention.

[0027] It should be understood that, except in any operating examples, or where otherwise indicated, all numbers indicating, for example, the amounts of ingredients used in the specification and claims should be understood to be modified in all cases by the term "about". Therefore, unless indicated to the contrary, the numerical parameters set forth in the following specification and the appended claims are approximate values ​​that vary depending on the desired properties to be obtained by the present invention.

[0028] The auxiliary agent in the embodiment of the present invention is povidone K30.

[0029] The silica particle size in the embodiment of the present invention is 10-20 nm.

[0030] The xanthan gum in the examples of the present invention was purchased from Maohesheng.

[0031] The preparation method of modified silicon dioxide in the embodiment of the present invention comprises the following steps:

[0032] S1. The silica was immersed in a sufficient volume ratio of 70:30 in a mixture of concentrated sulfuric acid and hydrogen peroxide (concentration 30%), heated at 70 ° C for 1 h, washed and dried to obtain hydroxylated silica;

[0033] S2. 20 g of xanthan gum was added to 500 mL of N, N-dimethylformamide, stirred for 30 min, then 36 g of potassium carbonate was added, and stirring was continued for 30 min, then 23 mL of methyl bromoacetate was added, and the reaction was stirred for 12 h, and then the pH was adjusted to 3, and after removing the solvent, the mixture was washed and dried, and then 800 mL of water and 200 mL of ethanol were added, and the mixture was reacted at 100 ° C for 20 h, and the solvent was removed and dried to obtain carboxylated xanthan gum;

[0034] S3. Using ethanol as solvent, the hydroxylated silica and carboxylated xanthan gum are mixed in a mass ratio of 1:6, subjected to ultrasonic reaction at 80° C. for 1.5 h, and the modified silica is obtained by washing, filtering and drying.

[0035] The "parts" in the embodiments of the present invention refer to parts by mass.

[0036] Example 1

[0037] A pharmaceutical excipient, comprising the following components in parts by weight:

[0038]

[0039] The preparation method of the pharmaceutical excipient comprises the following steps:

[0040] According to the above mass fractions, microcrystalline cellulose, mannitol, sodium stearyl fumarate, sodium carboxymethyl starch, adjuvants and modified silicon dioxide are mixed and stirred uniformly, and ground through a 100-mesh sieve to obtain the pharmaceutical excipient.

[0041] Example 2

[0042] A pharmaceutical excipient, comprising the following components in parts by weight:

[0043]

[0044] The preparation method of the pharmaceutical excipient comprises the following steps:

[0045] According to the above mass fractions, microcrystalline cellulose, mannitol, sodium stearyl fumarate, sodium carboxymethyl starch, adjuvants and modified silicon dioxide are mixed and stirred uniformly, and ground through a 100-mesh sieve to obtain the pharmaceutical excipient.

[0046] Example 3

[0047] A pharmaceutical excipient, comprising the following components in parts by weight:

[0048]

[0049] The preparation method of the pharmaceutical excipient comprises the following steps:

[0050] According to the above mass fractions, microcrystalline cellulose, mannitol, sodium stearyl fumarate, sodium carboxymethyl starch, adjuvants and modified silicon dioxide are mixed and stirred uniformly, and ground through a 100-mesh sieve to obtain the pharmaceutical excipient.

[0051] Comparative Example

[0052] A pharmaceutical excipient. The difference between this comparative example and Example 1 is that the modified silicon dioxide is replaced by a mixture obtained by mixing and stirring silicon dioxide and xanthan gum in a mass ratio of 1:5. The other ingredients and preparation method are the same as those in Example 1.

[0053] Test Case

[0054] The performance tests were performed on the pharmaceutical excipients prepared in Examples 1-3 and the comparative example.

[0055] The test method is as follows:

[0056] The pharmaceutical excipients prepared in Examples 1-3 and the comparative example were respectively mixed with vitamin C at a mass ratio of 4:1 and then compressed to obtain tablets.

[0057] Performance testing is carried out in accordance with the provisions of the Chinese Pharmacopoeia (2020 edition).

[0058] The test results are shown in Table 1.

[0059] Table 1 Performance test results

[0060] project Example 1 Example 2 Example 3 Comparative Example Appearance Smooth and even Smooth and even Smooth and even Smooth and even friability qualified qualified qualified Failure Dissolution / % 99.4 98.9 99.0 98.5

[0061] According to Table 1, it can be concluded that the pharmaceutical excipients prepared in Examples 1-3 of the present invention have good comprehensive performance. The comparative example replaces the modified silicon dioxide, resulting in a decrease in the friability and solubility of the prepared tablets, and the performance is lower than that of the examples. In summary, the pharmaceutical excipients of the present invention have excellent performance, solve the defects existing in the prior art, and have good application prospects.

[0062] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0063] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A pharmaceutical excipient, characterized in that: The pharmaceutical excipients include the following components in parts by weight: Wherein, the modified silicon dioxide is xanthan gum modified silicon dioxide; The preparation method of the modified silicon dioxide comprises the following steps: S1. Adding silica to a mixture of concentrated sulfuric acid and hydrogen peroxide, heating and stirring the reaction to obtain hydroxylated silica; S2. xanthan gum, potassium carbonate and methyl bromoacetate are added to a solvent, stirred for reaction, the pH is adjusted to acidic, and then water and ethanol are added to heat the reaction, and carboxylated xanthan gum is obtained after purification; S3. The hydroxylated silica and carboxylated xanthan gum are blended and subjected to ultrasonic heating reaction to obtain modified silica; The auxiliary agent is selected from one or more of a dispersant, a binder, a lubricant, a disintegrant, a flavoring agent, an essence, a salt, and a pigment.

2. The pharmaceutical excipient according to claim 1, characterized in that: In step S1, the temperature of the heating and stirring reaction is 60-80°C and the time is 1-3h.

3. The pharmaceutical excipient according to claim 1, characterized in that: In step S1, the volume ratio of concentrated sulfuric acid to hydrogen peroxide is (6-9):(1-4).

4. The pharmaceutical excipient according to claim 1, characterized in that: In step S2, the stirring reaction time is 10-20 hours; the heating reaction temperature is 80-140° C., and the time is 10-20 hours.

5. The pharmaceutical excipient according to claim 1, characterized in that: In step S3, the mass ratio of the hydroxylated silicon dioxide to the carboxylated xanthan gum is 1:(5-10).

6. The pharmaceutical excipient according to claim 1, characterized in that: In step S3, the temperature of the ultrasonic heating reaction is 60-90° C. and the time is 1-5 h.

7. The method for preparing the pharmaceutical excipient according to any one of claims 1 to 6, characterized in that: The preparation method of the pharmaceutical excipient comprises the following steps: The microcrystalline cellulose, mannitol, sodium stearyl fumarate, sodium carboxymethyl starch, adjuvants and modified silicon dioxide are mixed and stirred evenly, and ground through a 80-100 mesh sieve to obtain the pharmaceutical excipient.

8. Use of the pharmaceutical excipient according to any one of claims 1 to 6 in the preparation of a pharmaceutical composition.

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