A ternary composite carrier material and a preparation method thereof

Abstract

The application discloses a ternary composite carrier material, characterized by being composed of any three components selected from the following cellulose components and silica components: the cellulose components include hydroxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, siliconized microcrystalline cellulose, hydroxyethyl cellulose, ethyl cellulose and hydroxypropyl cellulose; and the silica components include colloidal silica, fumed silica, hydrophobically modified silica and micronized silica; the fumed silica includes fumed hydrophilic silica. The product prepared by the application has a strong synergistic effect. The product has good flowability, strong formability, low hygroscopicity, high uniformity, excellent stability and wide versatility, and can be widely applied to the fields of medicine, food, veterinary drugs, feed, cosmetics and functional powder processing, can completely replace imported high-end products, fills the domestic blank of similar technologies, and has significant application value and market prospect.

Description

Technical Field

[0001] This invention belongs to the technical field of pharmaceutical excipients, food excipients, veterinary drug excipients, feed additives, and general functional processing aids. Specifically, it relates to a ternary composite carrier material. This carrier material, as a composite excipient, possesses high flowability, high formability, low hygroscopicity, high stability, and broad-spectrum versatility. It can be widely used as a processing aid for human drugs, veterinary drugs, feed, food, solid beverages, instant drinks, and other products. It is especially suitable as a filler, binder, flow aid, anti-caking agent, and stabilizer for tablets, capsules, granules, microcapsules, coatings, and other preparations. Background Technology

[0002] Currently, related carrier materials as composite excipients on the market are mainly divided into three categories: single excipients, binary compound carriers, and a small number of experimental composite excipients. Among them, single excipients and binary compound carriers are the most widely used. Single excipients are mostly used as basic processing aids, directly applied to molding, filling, and flow aid processes of various products. Binary compound carriers, on the other hand, attempt to compensate for the functional shortcomings of single excipients and adapt to certain specific production needs through simple blending or preliminary compounding of two excipients. The use of these existing excipient products has simplified production processes to a certain extent, shortened product development and production cycles, and reduced some production difficulties. Therefore, they have a certain application foundation in various fields and possess a certain market demand.

[0003] However, the mainstream single-component and binary compound carriers currently on the market still generally have significant shortcomings, making it difficult to meet the actual needs of high-end, stable, universally applicable, and low-cost industrial production. Specifically, single-component materials have limited functions and significant shortcomings in key properties such as flowability, formability, hygroscopicity, and stability, easily leading to problems such as particle agglomeration, sticking to the bottom, and uneven suspension, affecting product processing quality and batch stability. Although binary compound carriers involve simple combinations, they do not form a systematic functional complementarity system, and still suffer from poor versatility, limited functionality, and insufficient high-end adaptability, failing to meet the diverse production needs of various fields.

[0004] More importantly, there is currently no exhaustive ternary composite carrier system in China that uses cellulose and silica as core components. The combination schemes of related ternary composite carrier materials and their composite excipients have not been disclosed in existing technologies. Existing products are difficult to completely replace imported high-end excipients and have pain points such as incomplete functional coverage and insufficient stability, which cannot meet the core needs of high-end production in various fields.

[0005] In summary, existing carrier materials have many shortcomings as composite excipients. There is an urgent need to develop a new ternary composite carrier material as a composite excipient technology to address the shortcomings of existing technologies, fill gaps in related domestic fields, achieve import substitution, and meet the high-end, stable, and all-scenario industrial production needs of various fields. Summary of the Invention

[0006] The technical problem to be solved by this invention is to provide a ternary composite carrier material and its preparation method. This invention uses cellulose and silica as core components to construct an exhaustive ternary composite system. Compared with existing single excipients and binary composite carriers, the silica is preferably fumed silica or colloidal silica (synthetic amorphous silica). Through the synergistic effect of the ternary components, it overcomes the defects of existing excipients such as poor flowability, insufficient formability, strong hygroscopicity, poor stability, and limited versatility, improving the uniformity, compatibility, and functional comprehensiveness of the composite excipient. This achieves complete substitution for imported high-end excipients, meeting the needs of high-end, stable, all-scenario, and low-cost industrial production in various fields such as pharmaceuticals, food, veterinary drugs, and feed.

[0007] In a first aspect, the technical solution adopted by the present invention to solve the above-mentioned technical problem is as follows: a ternary composite carrier material, comprising any three components selected from the following cellulose-based and silica-based components:

[0008] The cellulose components include: hydroxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, silanized microcrystalline cellulose, hydroxyethyl cellulose, ethyl cellulose, and hydroxypropyl cellulose;

[0009] The silica-based components include: colloidal silica, fumed silica, hydrophobically modified silica, and micronized silica; the fumed silica includes fumed hydrophilic silica.

[0010] The combination of the three components can take one of the following two forms:

[0011] 1) Any combination of any two components from the cellulose group and any one component from the silica group;

[0012] 2) Any combination of any one of the cellulose components and any two of the silica components.

[0013] Furthermore, the micronized silica includes micronized silica gel MS200.

[0014] Furthermore, the ternary composite carrier material is selected from one of the following three combinations: 1) Combination 1: including hydroxypropyl methylcellulose, silicified microcrystalline cellulose, and fumed silica; 2) Combination 2: including hydroxypropyl methylcellulose, microcrystalline cellulose, and fumed silica; 3) Combination 3: including hydroxymethylcellulose, microcrystalline cellulose, and colloidal silica.

[0015] Furthermore, the components are calculated by weight as follows: cellulose-based single components: 10 to 30 parts; silica-based single components: 0.5 to 6 parts.

[0016] Furthermore, the materials are in a basic formulation, an optimal formulation, or a high-grade formulation; the basic formulation includes 15 parts hydroxypropyl methylcellulose, 2 parts fumed silica, and 25 parts silicified microcrystalline cellulose; the optimal formulation includes 20 parts hydroxypropyl methylcellulose, 3 parts fumed silica, and 30 parts silicified microcrystalline cellulose; and the high-grade formulation includes 25 parts hydroxypropyl methylcellulose, 4 parts fumed silica, and 35 parts silicified microcrystalline cellulose.

[0017] Furthermore, the ternary composite carrier material product of the present invention is a white or off-white powder with a particle size of 80-100 mesh, a moisture content of 3.0%-5.0%, a molding rate of ≥95%, an angle of repose of ≤25°, a 24-hour moisture absorption rate of <2%, and a mixing uniformity RSD of ≤3.0%.

[0018] In a second aspect, the present invention also provides a method for preparing a ternary composite carrier material, comprising the steps of raw material crushing, weighing, multi-stage mixing, and stabilization treatment.

[0019] Furthermore, the preparation method of the ternary composite carrier material includes the following steps in sequence: 1) the raw materials are crushed separately and passed through an 80-100 mesh sieve, and the treatment environment temperature is 15-30℃ and the humidity is 40%-65%; 2) the raw materials are automatically weighed according to the ratio with an accuracy of ≤±1%; 3) multi-stage stepwise mixing: premixing for 8-15 min, main mixing for 10-20 min, and final mixing for 5-10 min; 4) closed stabilization treatment: closed standing for 20-60 min, and the moisture content is controlled at 3.0%-5.0%.

[0020] In a third aspect, the present invention provides the application of the ternary composite carrier material in the preparation of human pharmaceuticals, veterinary drugs, feed, food, solid beverages, health foods, cosmetics, chemical functional powders and processing aids.

[0021] Compared with the prior art, the beneficial effects of the present invention are:

[0022] (1) The ternary composite carrier material product prepared by the present invention is a white or off-white powder with a particle size of 80-100 mesh, a moisture content of 3.0%-5.0%, a molding rate of ≥95%, an angle of repose of ≤25°, a moisture absorption rate of <2% in 24 hours, and a mixing uniformity of RSD of ≤3.0%.

[0023] (2) The three preferred combinations of the present invention are: 1) Combination 1: including hydroxypropyl methylcellulose, silicified microcrystalline cellulose, and fumed silica; 2) Combination 2: including hydroxypropyl methylcellulose, microcrystalline cellulose, and fumed silica; 3) Combination 3: including hydroxymethylcellulose, microcrystalline cellulose, and colloidal silica. The products prepared by these three optimal combinations have extremely strong synergistic effects. The overall carrier has good flowability, strong formability, low hygroscopicity, high uniformity, excellent stability, and wide versatility. It can be widely used in the fields of pharmaceuticals, food, veterinary drugs, feed, cosmetics, and functional powder processing. It can completely replace imported high-end products, fill the gap in similar technologies in China, and has significant application value and market prospects. Detailed Implementation

[0024] To better understand the content of this invention, further description is provided below with reference to specific embodiments. It should be understood that these embodiments are only for further illustration of the invention and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the description of this invention, those skilled in the art may make some non-essential modifications or adjustments to the invention, which still fall within the protection scope of this invention.

[0025] Example 1: Basic Proportioning

[0026] By weight: 15 parts hydroxypropyl methylcellulose, 2 parts fumed silica, and 25 parts silicified microcrystalline cellulose.

[0027] The composite material preparation method is as follows: 1) Raw materials are pulverized separately and passed through an 80-mesh sieve. The treatment environment temperature is 15-30℃ and the humidity is 40%-65%; 2) Automatic weighing is performed according to the formula, with an accuracy of ≤±1%; 3) Multi-stage stepwise mixing: premixing for 8-15 min, main mixing for 10-20 min, and final mixing for 5-10 min; 4) Sealed stabilization treatment: sealed and allowed to stand for 20-60 min, controlling the moisture content to 3.0%-5.0%. The resulting product has a molding rate of 95.2%, an angle of repose of 26.0°, a 24-hour moisture absorption rate of 1.90%, and a mixing uniformity RSD of 2.45%.

[0028] Example 2 Optimal Proportion

[0029] By weight: 20 parts hydroxypropyl methylcellulose, 3 parts fumed silica, and 30 parts silicified microcrystalline cellulose.

[0030] The composite material preparation method is as follows: 1) Raw materials are pulverized separately and passed through an 80-mesh sieve. The treatment environment temperature is 15-30℃ and the humidity is 40%-65%; 2) Automatic weighing is performed according to the formula, with an accuracy of ≤±1%; 3) Multi-stage stepwise mixing: premixing for 8-15 min, main mixing for 10-20 min, and final mixing for 5-10 min; 4) Sealed stabilization treatment: sealed and allowed to stand for 20-60 min, controlling the moisture content to 3.0%-5.0%. The resulting product has a molding rate of 97.5%, an angle of repose of 23.1°, a 24-hour moisture absorption rate of 1.59%, and a mixing uniformity RSD of 2.19%.

[0031] Example 3: High-grade formulation

[0032] By weight: 25 parts hydroxypropyl methylcellulose, 4 parts fumed silica, and 35 parts silicified microcrystalline cellulose.

[0033] The composite material preparation method is as follows: 1) Raw materials are pulverized separately and passed through an 80-mesh sieve. The treatment environment temperature is 15-30℃ and the humidity is 40%-65%; 2) Automatic weighing is performed according to the formula, with an accuracy of ≤±1%; 3) Multi-stage stepwise mixing: premixing for 8-15 min, main mixing for 10-20 min, and final mixing for 5-10 min; 4) Sealed stabilization treatment: sealed and allowed to stand for 20-60 min, controlling the moisture content to 3.0%-5.0%. The resulting product has a molding rate of 96.5%, an angle of repose of 24.0°, a 24-hour moisture absorption rate of 1.50%, and a mixing uniformity RSD of 2.25%.

[0034] The following section compares the composite material of this application with mainstream carriers in the market.

[0035] 1. Currently, the mainstream carriers on the market are divided into three categories: single excipients, binary compound carriers, and ternary composite carriers. Among them, single excipients and binary compound carriers generally have serious defects; the ternary composite carrier is a domestic first, and no existing technology has been disclosed. Table 1 compares the core defects of the three types of carriers.

[0036] Table 1. Comparison of core defects of three types of carriers (forming / flow / adsorption / batch / versatility / functionality / high-end carriers)

[0037] Comparison Dimensions Single excipient Binary composite carrier The ternary composite carrier of the present invention Molding properties Low forming rate, prone to sticking to the wall, clogging the screen, and powder shedding. Molding is generally poor, but it is still prone to delamination and sticking. Forming rate ≥95%, non-sticking to the wall, non-clogging of the mesh, and stable forming. Liquidity Poor fluidity, large angle of repose, uneven material feeding Liquidity is generally poor; bridging and material blockage are still common. Excellent fluidity, angle of repose ≤25°, stable continuous feeding Adsorption / Moisture Absorption Highly hygroscopic, prone to clumping, and has a short shelf life. It has high hygroscopicity, is still easily affected by moisture, and has poor stability. Moisture absorption rate <2%, extremely low moisture absorption, long-term stability without clumping Batch stability Large batch variation, poor uniformity, and high RSD. Batch stability is generally poor, and uniformity fluctuates greatly. Batch stability, uniformity RSD ≤ 3.0%, strong consistency Universality Only applicable to a single domain, limited to other domains It has limited versatility and is difficult to apply to all fields. Applicable to all fields: pharmaceuticals / food / feed / veterinary drugs / cosmetics Single function Single function, only filling or only assisting flow Limited functionality and difficulty in achieving multi-functional synergy Synergistic effects: filling + bonding + flow aid + anti-caking + stabilizing High-end carrier dependence Unable to meet high-end demand and reliant on imports Insufficient performance, still reliant on imports for high-end products Completely replaces imports, is self-sufficient and controllable, and significantly reduces costs.

[0038] 2. Comparative Analysis of Existing Technical Parameters

[0039] Table 2 Comparison of full parameters for three types of vectors

[0040] Test parameters Single excipient Binary composite carrier The ternary composite carrier of the present invention Molding rate 65%～75% 75%～85% ≥95% Angle of repose (fluidity) 35°～45° 30°～35° ≤25° 24-hour moisture absorption rate (adsorption) 8%～15% 4%～8% ＜2% Mixing uniformity RSD (batch) 5%～10% 3%～5% ≤3.0% granularity 40~80 mesh 60~100 mesh 80~100 mesh Moisture 6%～12% 4%～7% 3.0%～5.0% Bulk density 0.4~0.6 g / cm³ 0.5~0.7 g / cm³ 0.6~0.8 g / cm³ Anti-caking properties Poor quality, prone to clumping Generally, it is prone to clumping when exposed to moisture. Excellent, does not clump over a long period of time. Disintegration / Dispersion Unstable generally Rapid dispersion, quick dissolution and stability Tablet hardness Low hardness, prone to cracking Hardness is average Uniform hardness, not easy to crack Application areas Single field 2-3 fields Universal cost medium to low middle Medium to low cost (reducing costs by 60% to 75% by replacing imports) Supply stability generally generally Domestically produced, stable, and independently controllable

[0041] 3. Technical Field of Three Types of Formulation and Processing Aids

[0042] Table 3. Comparison of the technical applications of three types of formulation and processing aids.

[0043] Processing aids technology Specific application scenarios Recommended ratio Core processing aids function Adapt to industrial production requirements Powder processing aids Powder mixing, conveying, metering, anti-caking, and anti-segregation Basic proportions 1. Improve powder flowability and solve bridging and clogging problems; 2. Reduce hygroscopicity to prevent clumping during storage and production; 3. Improve mixing uniformity and ensure batch consistency. Continuous production, automated metering, anti-clogging and anti-caking, low cost Compression molding processing aids Tableting, granulation, extrusion molding, compression molding Optimal ratio 1. Improves molding yield to ≥97%, reducing chipping, powdering, and sticking; 2. Provides excellent adhesion and moldability, eliminating the need for additional adhesives; 3. Compatible with high-speed pressing equipment, improving production efficiency. High-speed molding, high yield rate, low loss, and stable process. Coating / film forming processing aids Film coating, microparticle coating, coating molding, film-forming carrier High-end formula 1. Excellent film-forming and adhesion properties, resulting in a uniform and firm coating layer; 2. Regulates surface properties, improving gloss and stability; 3. Synergistic effect, combining film-forming, flow-aiding, and anti-caking functions. High-end coating process, uniform film formation, strong adhesion, and excellent appearance. Feed / Veterinary Drug Processing Aids Premix carriers, pelleted feed processing, and veterinary drug powder dilution Basic proportions 1. Inert carrier, does not react with active ingredients; 2. Anti-caking, flow aid, and dilution, improving feed / veterinary drug uniformity; 3. Low cost, suitable for large-scale industrial production. Safety and non-toxicity, cost-sensitive, large-scale production, and high stability requirements Food / Solid Beverage Processing Aids Solid beverages, meal replacement powders, compressed candies, functional foods Optimal ratio 1. Instant dispersibility and good dispersibility enhance the reconstitution experience; 2. Anti-caking and moisture-proof, extending shelf life; 3. Delicate taste, no grittiness, improving product quality. Food-grade safe, excellent taste, instant dissolves, and has a long shelf life. Chemical / Industrial Processing Aids Industrial fillers, modifiers, dispersants, and stabilizers Basic / Optimal Ratio 1. Improves material dispersibility and processing performance; 2. Reduces costs and replaces expensive imported additives; 3. High versatility and adaptable to various industrial powder processing applications. Industrial-grade stability, cost reduction and efficiency improvement, wide applicability, and easy processing Processing aids technology Specific application scenarios Recommended ratio Core processing aids function Adapt to industrial production requirements

[0044] Table 4 Comparison of the present invention with imported high-end powder material carriers

[0045] project Imported high-end products This invention unit price 80-150 yuan / kg 25-38 yuan / kg Cost reduction — 60%～75% Molding performance good Superior to imports Liquidity better Superior to imports hygroscopic ≤3% ≤1.9% Supply stability Influenced by the international community Stable domestic mass production Patent barriers Foreign patent protection Independent intellectual property rights Substitute capability — Complete replacement

[0046] 5. Safety and Toxicological Data

[0047] Table 5 Raw Material Compliance

[0048] Testing items result in conclusion Acute oral toxicity Practically non-toxic Safety Skin / mucous membrane irritation Non-irritating Safety Allergenicity Non-allergenic Safety Cytotoxicity Non-toxic Safety Mutagenicity / Genetic Toxicity Negative Safety Heavy metal (Pb) ≤10 mg / kg Compliant with pharmacopoeia Arsenic salts ≤2 mg / kg Compliant with pharmacopoeia Microbial limits qualified No harmful bacteria

[0049] Table 5 Safety Summary: All raw materials used in this invention are pharmaceutical / food grade excipients permitted by the state. The product is non-toxic, non-irritating, non-sensitizing, non-mutagenic, and non-carcinogenic. It is physically inert and does not participate in metabolism in the body. It is safe for the elderly, adults, children, and pregnant women to use.

[0050] The foregoing description is not intended to limit the invention, nor is the invention limited to the examples given. Any changes, modifications, additions, or substitutions made by those skilled in the art within the scope of the invention should also be considered within the protection scope of the invention.

Claims

1. A ternary composite carrier material, characterized in that, It consists of any three components selected from the following cellulose and silica components: The cellulose components include: hydroxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, silanized microcrystalline cellulose, hydroxyethyl cellulose, ethyl cellulose, and hydroxypropyl cellulose; The silica-based components include: colloidal silica, fumed silica, hydrophobically modified silica, and micronized silica; the fumed silica includes fumed hydrophilic silica. The combination of the three components can take one of the following two forms: 1) Any combination of any two components from the cellulose group and any one component from the silica group; 2) Any combination of any one of the cellulose components and any two of the silica components.

2. The ternary composite carrier material according to claim 1, characterized in that, The ternary composite carrier material is selected from one of the following three combinations: 1) Combination 1: including hydroxypropyl methylcellulose, silicified microcrystalline cellulose, and fumed silica; 2) Combination 2: including hydroxypropyl methylcellulose, microcrystalline cellulose, and fumed silica; 3) Combination 3: including hydroxymethylcellulose, microcrystalline cellulose, and colloidal silica.

3. The ternary composite carrier material according to claim 2, characterized in that, The components are calculated by weight as follows: cellulose single component: 10 to 30 parts; silica single component: 0.5 to 6 parts.

4. The ternary composite carrier material according to claim 2, characterized in that, The materials are in a basic formulation, an optimal formulation, or a high-grade formulation. The basic formulation includes 15 parts hydroxypropyl methylcellulose, 2 parts fumed silica, and 25 parts silicified microcrystalline cellulose. The optimal formulation includes 20 parts hydroxypropyl methylcellulose, 3 parts fumed silica, and 30 parts silicified microcrystalline cellulose. The high-grade formulation includes 25 parts hydroxypropyl methylcellulose, 4 parts fumed silica, and 35 parts silicified microcrystalline cellulose.

5. A ternary composite carrier material according to any one of claims 1 to 4, characterized in that, The product is a white or off-white powder with a particle size of 80-100 mesh, a moisture content of 3.0%-5.0%, a molding rate of ≥95%, an angle of repose of ≤25°, a 24-hour moisture absorption rate of <2%, and a mixing uniformity RSD of ≤3.0%.

6. A method for preparing a ternary composite carrier material according to any one of claims 1 to 5, characterized in that, It includes steps such as raw material crushing, weighing, multi-stage mixing, and stabilization.

7. A method for preparing a ternary composite carrier material as described in claim 6, characterized in that, The steps are as follows: 1) Raw materials are crushed separately and passed through an 80-100 mesh sieve. The processing environment temperature is 15-30℃ and the humidity is 40%-65%; 2) Automatic weighing according to the formula, with an accuracy of ≤±1%; 3) Multi-stage step-by-step mixing: premixing for 8-15 min, main mixing for 10-20 min, and final mixing for 5-10 min; 4) Sealed stabilization treatment: sealed and allowed to stand for 20-60 min, with the moisture content controlled at 3.0%-5.0%.

8. The application of a ternary composite carrier material according to any one of claims 1 to 5, characterized in that, The ternary composite carrier material is used in the preparation of human drugs, veterinary drugs, feed, food, solid beverages, health foods, cosmetics, chemical functional powders and processing aids.