Oral liquid gel stability enhancement and anti-layering preparation process

Abstract

The application belongs to the technical field of Chinese medicine preparation, and provides a preparation process for improving the colloidal stability and preventing delamination of an oral liquid, which comprises the following steps: raw material pretreatment and extraction, gradient enzymolysis-fractionated membrane separation, dynamic crosslinking stable system construction, gradient density matching and homogenization, in-situ microencapsulation and hydrogen bond locking, and post-treatment and filling. In the application, a triple progressive stable system is constructed: the first step adopts gradient enzymolysis-fractionated membrane separation technology to realize accurate control of the molecular weight of colloids and optimization of the interface charge; the second step introduces a programmed temperature dynamic crosslinking composite stabilizer and gradient density matching technology to form a three-dimensional network enhanced structure; and the third step realizes long-term stability through in-situ microencapsulation and intermolecular hydrogen bond locking technology.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine preparation technology, and particularly relates to a preparation process for improving the colloidal stability of oral liquids and preventing stratification. Background Technology

[0002] Traditional Chinese medicine oral liquids are a modern formulation developed from traditional decoctions. They offer advantages such as convenient administration, rapid absorption, and definite efficacy, making them one of the important dosage forms in the Chinese patent medicine market. However, due to their complex composition, containing large amounts of colloidal substances such as polysaccharides, proteins, tannins, and flavonoids, traditional Chinese medicine oral liquids are prone to colloidal stratification, precipitation, and turbidity during storage. This severely affects the product's appearance and clinical efficacy, becoming a key technological bottleneck restricting the development of the traditional Chinese medicine oral liquid industry.

[0003] Currently, there are numerous studies both domestically and internationally on anti-stratification technologies for oral liquids, among which the following two are representative:

[0004] For example, Chinese Patent (Publication No.: CN121714973A) discloses a process for preparing oral liquids that clarifies, stabilizes, and prevents stratification. This process utilizes a three-stage cascade gradient filtration membrane module to achieve precise stratification and retention of impurities of different particle sizes. Combined with dynamic pressure control, the addition of a composite stabilizer, and online monitoring closed-loop control technology, it improves the clarity and short-term stability of the oral liquid. However, this technology has the following shortcomings: First, it lacks an enzymatic pretreatment step, which cannot effectively degrade large molecular weight cellulose, pectin, and other proteins in the extract, leading to easy clogging of the membrane module and a wide distribution of colloidal particle sizes. Second, the stabilization system is merely a simple mixture of suspending agents, thickeners, and surfactants, failing to form a dynamic cross-linked three-dimensional network structure, which is prone to relaxation during long-term storage. Third, it does not address molecular-level stabilization mechanisms, failing to fundamentally solve the problems of colloidal particle aggregation and migration.

[0005] For example, Chinese Patent (Publication No.: CN101411724A) discloses a composition and processing method for preventing flocculation and stratification of royal jelly oral liquid. By adding polyvinyl alcohol as a stabilizer, the stability of the royal jelly oral liquid is improved. However, this technology has the following shortcomings: First, it is only applicable to the specific system of royal jelly, resulting in poor general applicability and making it unsuitable for complex traditional Chinese medicine oral liquids; second, using only polyvinyl alcohol as a stabilizer has limited stabilizing effect, and excessive addition can affect the taste and clarity of the oral liquid; third, it does not involve advanced technologies such as colloidal particle size control, membrane separation, and microencapsulation, making it difficult to meet the long-term stability requirements of traditional Chinese medicine oral liquids.

[0006] In addition to the representative technologies mentioned above, existing technologies as a whole also have the following common defects:

[0007] Inaccurate control of colloidal particle size and molecular weight leads to poor basic stability: Existing technologies mostly use single filtration or centrifugation techniques to remove impurities, which cannot achieve precise control of colloidal molecular weight and particle size. The extract contains both large molecular impurities and effective colloidal components. Large molecular impurities easily aggregate to form precipitates, while small molecular effective components are easily lost. For example, conventional 0.22μm terminal filtration can only remove bacteria and larger particles, with almost no retention effect on substances within the colloidal particle size range; while using ultrafiltration membranes with even smaller pore sizes will retain a large amount of effective components such as polysaccharides and peptides, leading to a decrease in product efficacy. In addition, the lack of an enzymatic pretreatment step prevents the degradation of large molecular impurities, further exacerbating the instability of the colloidal system.

[0008] The existing stabilizer system is too simple and lacks long-term stability: Most technologies use single or simple mixtures of stabilizers to slow particle sedimentation by increasing the system viscosity. However, single stabilizers have inherent drawbacks: First, their suspension capacity is limited under low ionic strength conditions, and slow sedimentation may still occur; second, their solutions exhibit strong pseudoplasticity, resulting in high viscosity at rest, making pouring difficult, and the viscosity decreases rapidly after stirring, making the newly established network structure insufficient to completely prevent the flocculation and sedimentation of fine particles; third, their wettability and steric hindrance on the surface of colloidal particles of traditional Chinese medicine are not ideal, failing to fundamentally solve the problem of colloidal aggregation. Most products show obvious stratification after 3 months of accelerated testing, and the sedimentation rate exceeds 0.5% after 12 months of long-term stability testing.

[0009] Lacking a multi-level synergistic stabilization mechanism, the product has weak resistance to external interference: Most existing technologies only focus on increasing viscosity or slowing down particle sedimentation at the macro level, ignoring the microstructure and intermolecular interactions of the colloidal system. There are complex electrostatic interactions, hydrogen bonding interactions, and hydrophobic interactions between colloidal particles in traditional Chinese medicine oral liquids. The imbalance of these interactions is the root cause of colloidal stratification. Existing technologies have failed to effectively regulate these micro-interactions and have not constructed a multi-level synergistic stabilization mechanism from the molecular level to the macro system. Therefore, the product has a weak ability to resist interference from external factors such as temperature, pH value, and ionic strength, and is prone to quality fluctuations during transportation and storage.

[0010] Insufficient compatibility between process parameters and product characteristics, resulting in significant batch-to-batch variations: In existing oral liquid preparation processes, parameter control for key steps such as enzymatic hydrolysis, filtration, and homogenization is relatively crude, and a precise correspondence between parameters and product colloidal characteristics has not been established. For example, fluctuations in enzymatic hydrolysis time and temperature can lead to uneven distribution of colloidal molecular weight, changes in filtration pressure can affect the composition of the retentate, and differences in homogenization pressure and number of homogenization cycles can lead to differences in particle dispersion. These batch-to-batch variations not only affect the quality stability of the product but also bring difficulties to quality control in the production process.

[0011] Therefore, an improved colloidal stability and anti-stratification preparation process for oral liquids is needed to solve the above problems. Summary of the Invention

[0012] The purpose of this invention is to provide a preparation process for improving the colloidal stability of oral liquids and preventing stratification, thereby solving the problems mentioned in the background art.

[0013] To achieve the above objectives, the present invention provides the following technical solution:

[0014] A preparation process for improving the colloidal stability and preventing stratification of oral liquids includes the following steps:

[0015] S1. Raw material pretreatment and extraction: Weigh the Chinese medicinal materials according to the prescription amount, wash, soak and slice them, add 8-12 times the amount of purified water, heat and reflux to extract 2-3 times, 1-2 hours each time, combine the extracts and filter to obtain the initial filtrate.

[0016] S2, Gradient enzymatic hydrolysis-fractional membrane separation: Add a compound enzyme preparation to the initial filtrate and enzymatically hydrolyze for 1-2 hours at 40-50℃ and pH 4.5-6.0. After enzyme inactivation, pass the solution sequentially through a microfiltration membrane, a first ultrafiltration membrane, and a second ultrafiltration membrane for fractional separation. Collect the retentate with a molecular weight between 30-100kDa as the colloidal mother liquor.

[0017] S3. Construction of dynamic cross-linking stable system: Add composite stabilizer to colloidal mother liquor, stir to dissolve, and then keep warm at 60-70℃ for 30-60 minutes using a programmed temperature rise method to form a dynamic cross-linking three-dimensional network structure.

[0018] S4. Gradient density matching and homogenization: Add a density regulator to the above solution to adjust the system density to 1.02-1.08 g / cm³, and then homogenize it 2-3 times under a pressure of 20-40 MPa using a high-pressure homogenizer.

[0019] S5. In-situ microencapsulation and hydrogen bond locking: Add composite microencapsulation wall material and multi-hydroxy hydrogen bond promoter, and react at 50-60℃ for 20-40 minutes to complete in-situ microencapsulation and intermolecular hydrogen bond locking.

[0020] S6. Post-processing and filling: Adjust the pH value to 5.0-7.0, add flavoring agent and preservative, make up to volume, filter at the terminal, fill and sterilize to obtain the finished product.

[0021] Further, in step S2, the compound enzyme preparation contains at least cellulase, pectinase, and protease in a mass ratio of (2-4):(1-3):1, and is added at 0.1%-0.3% of the mass of the initial filtrate. This compound enzyme preparation can specifically degrade macromolecular cellulose, pectin, and miscellaneous proteins in the initial filtrate, breaking them down into smaller molecules, while retaining bioactive medium-molecular-weight colloidal components, thus achieving precise control of colloidal molecular weight.

[0022] Further, in step S2, during the graded membrane separation process, the microfiltration membrane has a pore size of 0.45 μm and an operating pressure of 0.1-0.2 MPa; the first ultrafiltration membrane has a molecular weight cutoff of 100 kDa and an operating pressure of 0.3-0.5 MPa; and the second ultrafiltration membrane has a molecular weight cutoff of 30 kDa and an operating pressure of 0.6-0.8 MPa. Through this three-stage gradient membrane separation technology, precise stratified retention of impurities and colloidal components of different particle sizes is achieved: the 0.45 μm microfiltration membrane removes large particles of drug residue and suspended solids, the 100 kDa ultrafiltration membrane retains large molecular impurities and aggregates, and the 30 kDa ultrafiltration membrane removes small molecular inorganic salts and monosaccharides. The final collected 30-100 kDa retentate is a homogeneous and stable colloidal mother liquor.

[0023] Further, in step S3, the composite stabilizer comprises at least xanthan gum, gellan gum, and sodium carboxymethyl cellulose, with a mass ratio of (1-3):1:(2-4), and the addition amount is 0.15%-0.4% of the mass of the colloidal mother liquor. This composite stabilizer forms a dynamic cross-linked three-dimensional network structure through synergistic action: xanthan gum provides high pseudoplasticity and shear resistance, gellan gum forms a thermally reversible gel network, and sodium carboxymethyl cellulose enhances the viscosity and stability of the system. The synergistic effect of these three components effectively encapsulates colloidal particles, preventing their aggregation and sedimentation.

[0024] Furthermore, in step S3, the programmed temperature rise method is as follows: first, the temperature is increased to 60°C at a rate of 1-3°C / min and held for 15-25 minutes, then the temperature is increased to 70°C at a rate of 0.5-1.5°C / min and held for 30-50 minutes. Programmed temperature rise allows the composite stabilizer molecules to gradually expand and cross-link with each other, forming a three-dimensional network structure with uniform structure and moderate strength, avoiding the problem of excessive or uneven local cross-linking caused by rapid heating.

[0025] Further, in step S4, the density regulator is a mixture of glycerol and sorbitol in a mass ratio of (0.8-1.2):1, and the amount added is 2%-5% of the solution mass. By adjusting the system density, the density of the colloidal particles is made as close as possible to the density of the continuous phase. According to Stokes' law, this significantly reduces the sedimentation rate of the particles, further improving the stability of the system. Simultaneously, glycerol and sorbitol also have moisturizing and flavor-correcting effects, which can improve the taste of the oral liquid.

[0026] Further, in step S5, the composite microencapsulated wall material comprises at least β-cyclodextrin and gum arabic in a mass ratio of (2-4):(1-3), and the amount added is 0.5%-1.5% of the solution mass. β-cyclodextrin has a unique cavity structure that can encapsulate hydrophobic colloidal particles within its cavity to form microcapsules; gum arabic enhances the stability and water solubility of the microcapsules. In-situ microencapsulation technology can significantly improve the surface properties and dispersibility of colloidal particles without altering their chemical properties.

[0027] Further, in step S5, the multi-hydroxyl hydrogen bond promoter is selected from at least one of trehalose, mannitol, and sorbitol, and the amount added is 0.3%-0.8% of the solution mass. The multi-hydroxyl compound molecule contains multiple hydroxyl groups, which can form a large number of intermolecular hydrogen bonds with hydroxyl, amino, and other groups on the surface of colloidal particles, as well as with composite stabilizer molecules, locking the colloidal particles in a three-dimensional network structure, preventing their migration and aggregation during storage, and achieving long-term stability.

[0028] Furthermore, in step S6, the terminal filtration uses a 0.22μm microporous membrane, and sterilization is performed by autoclaving at 115℃ for 25-35 minutes or autoclaving at 121℃ for 10-20 minutes. These sterilization conditions can effectively kill microorganisms in the oral liquid while avoiding the damage of high temperature to the colloidal structure and active ingredients.

[0029] Furthermore, the colloidal particle size distribution of the finished oral liquid is between 50-200 nm, the polydispersity index (PDI) is ≤0.15, and the absolute value of the zeta potential is ≥35 mV. These key quality indicators demonstrate that the oral liquid colloidal system prepared by this invention has good dispersibility and stability.

[0030] Compared with the prior art, the beneficial effects of the present invention are:

[0031] This invention utilizes a gradient enzymatic hydrolysis-fractional membrane separation technique to achieve precise control of colloidal particle size and optimization of interfacial charge, thus constructing a basic stable system. The invention employs a composite enzyme preparation composed of cellulase, pectinase, and protease to perform gradient enzymatic hydrolysis on traditional Chinese medicine extracts. This process specifically degrades macromolecular impurities while retaining bioactive medium-molecular-weight colloidal components. Subsequently, a three-stage tandem gradient membrane separation technique is used to achieve precise stratification and retention of substances with different particle sizes. The final product is a uniform colloidal mother liquor with a colloidal particle size distribution between 50-200 nm and a polydispersity index (PDI) ≤ 0.15. Simultaneously, this process effectively regulates the surface charge of colloidal particles, increasing the absolute value of the Zeta potential to above 30 mV. Electrostatic repulsion prevents colloidal particle aggregation. Compared to CN121714973A, this technology adds an enzymatic hydrolysis pretreatment step, reducing the probability of membrane blockage and increasing the retention rate of effective components, thus laying a solid foundation for the subsequent construction of a stable system.

[0032] A three-dimensional network-enhanced stabilization system is formed by using a dynamic cross-linking composite stabilizer and gradient density matching technology. This invention employs a composite stabilizer composed of xanthan gum, gellan gum, and sodium carboxymethyl cellulose. Dynamic cross-linking is achieved through programmed temperature rise, forming a three-dimensional network structure with uniform structure and moderate strength. This network structure can encapsulate colloidal particles and prevent their aggregation and sedimentation through steric hindrance. At the same time, this invention introduces gradient density matching technology, adjusting the system density by adding a mixture of glycerol and sorbitol, so that the density of colloidal particles is as close as possible to the density of the continuous phase. According to Stokes' law, the particle sedimentation rate can be reduced. Compared with the simple mixed sedimentation stabilization system of CN121714973A, the amount of material used in this composite stabilization system is reduced, while the stability is significantly improved.

[0033] Long-term stability is achieved through in-situ microencapsulation and intermolecular hydrogen bond locking technology: This invention combines in-situ microencapsulation technology with intermolecular hydrogen bond locking technology to construct a third long-term stabilizing system. The complex of β-cyclodextrin and gum arabic can form a dense microcapsule membrane on the surface of colloidal particles, improving their surface properties and dispersibility. The polyhydroxy hydrogen bond promoter can form a large number of intermolecular hydrogen bonds with the surface of colloidal particles and composite stabilizer molecules, firmly locking the colloidal particles in a three-dimensional network structure. This molecular-level stabilization mechanism can effectively resist the influence of external factors such as temperature, pH value, and ionic strength, so that the oral liquid remains uniform and stable after long-term stability tests, without obvious stratification and precipitation, and has a high retention rate of effective ingredients. Compared with the single stabilizer system of CN101411724A, the stabilizing effect is more lasting and the versatility is stronger.

[0034] The process parameters are precisely matched with product characteristics, resulting in small batch-to-batch differences and suitability for industrial production: This invention systematically optimizes key process parameters such as enzymatic hydrolysis temperature and time, membrane separation pressure, crosslinking temperature and time, and homogenization pressure and number of times, establishing a precise correspondence between parameters and product colloidal characteristics. Compared with existing extensive processes, this process reduces batch-to-batch differences and significantly improves quality stability. At the same time, the equipment used in this process is all conventional equipment in the pharmaceutical industry, requiring no additional special investment, and is easy to operate with low production costs, making it suitable for large-scale industrial production.

[0035] To more clearly illustrate the structural features and effects of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0036] Figure 1 This is a schematic diagram of the overall process of the present invention. Detailed Implementation

[0037] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0038] The specific implementation of the present invention will be described in detail below with reference to specific embodiments.

[0039] Example 1

[0040] This embodiment provides a preparation process for improving the colloidal stability and preventing stratification of oral liquids, used to prepare Aivixin oral liquid, including the following steps:

[0041] S1. Raw material pretreatment and extraction: Weigh the Chinese medicinal materials for Aivixin oral liquid according to the prescription amount, including silkworm cocoons, ox tongue grass, yellow willow, cloves, and fragrant blue orchids. After washing, soaking, and slicing, add 10 times the amount of purified water, heat and reflux twice, 1.5 hours each time, combine the extracts, and filter with double-layer gauze to obtain the initial filtrate.

[0042] S2. Gradient enzymatic hydrolysis-fractional membrane separation: A compound enzyme preparation composed of cellulase, pectinase and protease in a mass ratio of 3:2:1 is added to the primary filtrate at 0.2% of the primary filtrate mass. Enzymatic hydrolysis is carried out at 45℃ and pH 5.0 for 1.5 hours. Then, the enzyme is inactivated by heating to 100℃ for 10 minutes. After cooling to room temperature, the solution is sequentially passed through a 0.45μm microfiltration membrane, a 100kDa ultrafiltration membrane, and a 30kDa ultrafiltration membrane for fractional separation. The operating pressure of the microfiltration membrane is 0.15MPa, the operating pressure of the ultrafiltration membrane is 0.4MPa, and the operating pressure of the nanofiltration membrane is 0.7MPa. The 30-100kDa retentate is collected as the colloidal mother liquor.

[0043] S3. Construction of dynamic cross-linking stable system: A composite stabilizer was added to the colloidal mother liquor. The composite stabilizer was composed of xanthan gum, gellan gum and sodium carboxymethyl cellulose in a mass ratio of 2:1:3. The amount added was 0.25% of the mass of the colloidal mother liquor. After stirring and dissolving, dynamic cross-linking was carried out by a programmed temperature rise method: first, the temperature was raised to 60℃ at a rate of 2℃ / min and held for 20 minutes, and then the temperature was raised to 70℃ at a rate of 1℃ / min and held for 40 minutes to form a dynamic cross-linked three-dimensional network structure.

[0044] S4. Gradient density matching and homogenization: Add a density regulator to the above solution. The density regulator is a mixture of glycerol and sorbitol in a mass ratio of 1:1. The amount added is 3.5% of the solution mass. Adjust the density of the system to 1.05 g / cm³. Then homogenize twice under 30 MPa pressure using a high-pressure homogenizer.

[0045] S5. In-situ microencapsulation and hydrogen bond locking: A composite microencapsulation wall material and a polyhydroxy hydrogen bond promoter are added. The composite microencapsulation wall material is a complex of β-cyclodextrin and gum arabic in a mass ratio of 3:2, and the amount added is 1.0% of the solution mass. The polyhydroxy hydrogen bond promoter is trehalose, and the amount added is 0.5% of the solution mass. The reaction is carried out at 55℃ for 30 minutes to complete in-situ microencapsulation and intermolecular hydrogen bond locking.

[0046] S6. Post-processing and filling: Adjust the pH value to 6.0 with citric acid and sodium hydroxide, add an appropriate amount of steviol glycosides as a flavoring agent, add 0.05% potassium sorbate as a preservative, add purified water to make up to the specified volume, stir evenly, filter through a 0.22μm terminal filter, fill into 10ml oral liquid bottles, and autoclave at 115℃ for 30 minutes to obtain the finished product.

[0047] In this embodiment, the prepared Aivixin oral solution is a brownish-red liquid with an aromatic odor and a sweet, slightly bitter taste. Analysis showed that the colloidal particle size distribution was between 80-150 nm, the polydispersity index (PDI) was 0.12, and the zeta potential was -38 mV. After an accelerated stability test of 6 months (temperature 40℃±2℃, relative humidity 75%±5%), no obvious stratification or precipitation was observed, and the effective ingredient retention rate was 96.2%. After a long-term stability test of 24 months (temperature 25℃±2℃, relative humidity 60%±10%), it remained uniform and stable, with no obvious stratification or precipitation, and the effective ingredient retention rate was 94.7%.

[0048] Example 2

[0049] The difference between this embodiment and Example 1 is that the compound enzyme preparation in step S2 is composed of cellulase, pectinase and protease in a mass ratio of 2:3:1, the amount added is 0.1% of the mass of the initial filtrate, the enzymatic hydrolysis temperature is 40℃, and the enzymatic hydrolysis time is 2 hours.

[0050] In this embodiment, the prepared Aivixin oral solution has a colloidal particle size distribution between 90-180 nm, a polydispersity index (PDI) of 0.14, and a zeta potential of -36 mV. After 6 months of accelerated testing, there was no obvious stratification or precipitation, and the effective ingredient retention rate was 95.8%. After 24 months of long-term stability testing, it remained uniform and stable, with no obvious stratification or precipitation, and the effective ingredient retention rate was 94.2%.

[0051] Example 3

[0052] The difference between this embodiment and Embodiment 1 is that the compound enzyme preparation in step S2 is composed of cellulase, pectinase and protease in a mass ratio of 4:1:1, the amount added is 0.3% of the mass of the initial filtrate, the enzymatic hydrolysis temperature is 50℃, and the enzymatic hydrolysis time is 1 hour.

[0053] In this embodiment, the prepared Aivixin oral solution has a colloidal particle size distribution between 60-130 nm, a polydispersity index (PDI) of 0.11, and a zeta potential of -40 mV. After 6 months of accelerated testing, there was no obvious stratification or precipitation, and the effective ingredient retention rate was 95.5%. After 24 months of long-term stability testing, it remained uniform and stable, with no obvious stratification or precipitation, and the effective ingredient retention rate was 93.9%.

[0054] Example 4

[0055] The difference between this embodiment and Embodiment 1 is that the composite stabilizer in step S3 is composed of xanthan gum, gellan gum and sodium carboxymethyl cellulose in a mass ratio of 1:1:4, and the amount added is 0.15% of the mass of the colloidal mother liquor. The dynamic crosslinking process is to first heat the temperature to 60°C at a rate of 1°C / min and hold it for 25 minutes, and then heat the temperature to 70°C at a rate of 0.5°C / min and hold it for 50 minutes.

[0056] In this embodiment, the prepared Aivixin oral solution has a colloidal particle size distribution between 85-160 nm, a polydispersity index (PDI) of 0.13, and a zeta potential of -37 mV. After 6 months of accelerated testing, there was no obvious stratification or precipitation, and the effective ingredient retention rate was 96.0%. After 24 months of long-term stability testing, it remained uniform and stable, with no obvious stratification or precipitation, and the effective ingredient retention rate was 94.5%.

[0057] Example 5

[0058] The difference between this embodiment and Embodiment 1 is that the composite stabilizer in step S3 is composed of xanthan gum, gellan gum and sodium carboxymethyl cellulose in a mass ratio of 3:1:2, and the amount added is 0.4% of the mass of the colloidal mother liquor. The dynamic crosslinking process is to first heat the temperature to 60°C at a rate of 3°C / min and hold it for 15 minutes, and then heat the temperature to 70°C at a rate of 1.5°C / min and hold it for 30 minutes.

[0059] In this embodiment, the prepared Aivixin oral solution has a colloidal particle size distribution between 75-145 nm, a polydispersity index (PDI) of 0.12, and a zeta potential of -39 mV. After 6 months of accelerated testing, there was no obvious stratification or precipitation, and the effective ingredient retention rate was 95.7%. After 24 months of long-term stability testing, it remained uniform and stable, with no obvious stratification or precipitation, and the effective ingredient retention rate was 94.1%.

[0060] Example 6

[0061] The difference between this embodiment and Example 1 is that: in step S4, the density adjuster is a mixture of glycerol and sorbitol with a mass ratio of 0.8:1, and the amount added is 2% of the solution mass. The system density is adjusted to 1.02 g / cm³, the high-pressure homogenization pressure is 20 MPa, and the homogenization is performed 3 times.

[0062] In this embodiment, the prepared Aivixin oral solution has a colloidal particle size distribution between 95-170 nm, a polydispersity index (PDI) of 0.14, and a zeta potential of -35 mV. After 6 months of accelerated testing, there was no obvious stratification or precipitation, and the effective ingredient retention rate was 95.6%. After 24 months of long-term stability testing, it remained uniform and stable, with no obvious stratification or precipitation, and the effective ingredient retention rate was 93.8%.

[0063] Example 7

[0064] The difference between this embodiment and Example 1 is that: in step S4, the density adjuster is a mixture of glycerol and sorbitol with a mass ratio of 1.2:1, and the amount added is 5% of the solution mass. The system density is adjusted to 1.08 g / cm³, and the high-pressure homogenization pressure is 40 MPa, and the homogenization is performed twice; in step S5, the polyhydroxy hydrogen bond promoter is mannitol, and the amount added is 0.8% of the solution mass.

[0065] In this embodiment, the prepared Aivixin oral solution has a colloidal particle size distribution between 70-120 nm, a polydispersity index (PDI) of 0.10, and a zeta potential of -41 mV. After 6 months of accelerated testing, there was no obvious stratification or precipitation, and the effective ingredient retention rate was 95.3%. After 24 months of long-term stability testing, it remained uniform and stable, with no obvious stratification or precipitation, and the effective ingredient retention rate was 93.6%.

[0066] Example 8

[0067] The difference between this embodiment and Embodiment 1 is as follows: In preparing the compound honeysuckle syrup, in step S1, honeysuckle, forsythia, andrographis paniculata, isatis root and other Chinese medicinal materials are weighed according to the prescription amount, 12 times the amount of purified water is added, and the mixture is heated and refluxed three times, each time for 1 hour; in step S5, the composite microencapsulated wall material is a complex of β-cyclodextrin and gum arabic with a mass ratio of 4:1, and the amount added is 1.5% of the solution mass; in step S6, the pH value is adjusted to 5.5, and the mixture is autoclaved at 121℃ for 15 minutes.

[0068] In this embodiment, the prepared compound honeysuckle syrup is a brownish-red liquid with a sweet and slightly bitter taste. Analysis showed that the colloidal particle size distribution was between 70-160 nm, the polydispersity index (PDI) was 0.13, and the zeta potential was -37 mV. After 6 months of accelerated testing, no obvious stratification or precipitation was observed, and the retention rate of the active ingredient chlorogenic acid was 95.8%. After 24 months of long-term stability testing, it remained homogeneous and stable, with no obvious stratification or precipitation, and the retention rate of the active ingredient chlorogenic acid was 94.3%.

[0069] Working principle of the invention:

[0070] This invention is based on a triple progressive stabilization mechanism of "precise control of colloidal particle size - three-dimensional network enhancement - intermolecular hydrogen bond locking", which comprehensively improves the colloidal stability of traditional Chinese medicine oral liquids from the microscopic to the macroscopic level.

[0071] The first stabilization mechanism: precise control of colloidal particle size and optimization of interfacial charge. Traditional Chinese medicine extracts contain a large number of substances with different molecular weights. Large molecular impurities (such as cellulose, pectin, and miscellaneous proteins) are the main cause of colloidal aggregation and precipitation, while medium molecular weight colloidal components (such as polysaccharides, polypeptides, and flavonoids) are the main substances that exert the medicinal effects. This invention uses gradient enzymatic hydrolysis technology to degrade large molecular impurities into small molecules while retaining bioactive medium molecular weight colloidal components. Subsequently, a fractional membrane separation technology is used to achieve precise separation of substances with different particle sizes, obtaining a homogeneous and stable colloidal mother liquor. Simultaneously, this process effectively regulates the surface charge of colloidal particles, increasing the absolute value of the Zeta potential to above 30mV, preventing colloidal particle aggregation through electrostatic repulsion, and constructing a fundamentally stable system.

[0072] The second stabilization mechanism: Dynamic cross-linked three-dimensional network and gradient density matching: Under programmed temperature conditions, the composite stabilizer molecules gradually expand and cross-link with each other, forming a uniform and moderately strong three-dimensional network structure. This network structure can encapsulate colloidal particles, preventing their aggregation and sedimentation through steric hindrance. Simultaneously, by adding a density modifier, the system density is adjusted to make the density of the colloidal particles as close as possible to the density of the continuous phase, according to Stokes' law:

[0073] ;

[0074] in: For particle settling velocity, Where is the particle radius, Particle density, For continuous phase density, It is the acceleration due to gravity. The viscosity of the continuous phase can significantly reduce the settling velocity of particles. These two mechanisms work synergistically to form a more stable system.

[0075] The third stabilization mechanism: in-situ microencapsulation and intermolecular hydrogen bond locking: β-cyclodextrin has a unique hydrophobic cavity structure, which can encapsulate hydrophobic colloidal particles within its cavity, forming core-shell microcapsules; gum arabic can form a hydrophilic film on the surface of the microcapsules, enhancing their water solubility and stability. In-situ microencapsulation technology can significantly improve the surface properties and dispersibility of colloidal particles without altering their chemical properties. Simultaneously, the polyhydroxy compound molecules contain multiple hydroxyl groups, which can form numerous intermolecular hydrogen bonds with hydroxyl and amino groups on the surface of colloidal particles, as well as with composite stabilizer molecules, firmly locking the colloidal particles in a three-dimensional network structure, preventing migration and aggregation during storage, and achieving long-term stability.

[0076] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A preparation process for improving the colloidal stability and preventing stratification of oral liquids, characterized in that, Includes the following steps: S1. Raw material pretreatment and extraction: Weigh the Chinese medicinal materials according to the prescription amount, wash, soak and slice them, add 8-12 times the amount of purified water, heat and reflux to extract 2-3 times, 1-2 hours each time, combine the extracts and filter to obtain the initial filtrate. S2, Gradient enzymatic hydrolysis-fractional membrane separation: Add a compound enzyme preparation to the initial filtrate and enzymatically hydrolyze for 1-2 hours at 40-50℃ and pH 4.5-6.

0. After enzyme inactivation, pass the solution sequentially through a microfiltration membrane, a first ultrafiltration membrane, and a second ultrafiltration membrane for fractional separation. Collect the retentate with a molecular weight between 30-100kDa as the colloidal mother liquor. S3. Construction of dynamic cross-linking stable system: Add composite stabilizer to colloidal mother liquor, stir to dissolve, and then keep warm at 60-70℃ for 30-60 minutes using a programmed temperature rise method to form a dynamic cross-linking three-dimensional network structure. S4. Gradient density matching and homogenization: Add a density regulator to the above solution to adjust the system density to 1.02-1.08 g / cm³, and then homogenize it 2-3 times under a pressure of 20-40 MPa using a high-pressure homogenizer. S5. In-situ microencapsulation and hydrogen bond locking: Add composite microencapsulation wall material and multi-hydroxy hydrogen bond promoter, and react at 50-60℃ for 20-40 minutes to complete in-situ microencapsulation and intermolecular hydrogen bond locking. S6. Post-processing and filling: Adjust the pH value to 5.0-7.0, add flavoring agent and preservative, make up to volume, filter at the terminal, fill and sterilize to obtain the finished product.

2. The oral liquid colloidal stability enhancement and anti-stratification preparation process according to claim 1, characterized in that, In step S2, the compound enzyme preparation contains at least cellulase, pectinase and protease, with a mass ratio of (2-4):(1-3):1, and the amount added is 0.1%-0.3% of the mass of the initial filtrate.

3. The oral liquid colloidal stability enhancement and anti-stratification preparation process according to claim 1, characterized in that, In step S2, during the fractionation membrane separation process, the microfiltration membrane has a pore size of 0.45 μm and an operating pressure of 0.1-0.2 MPa; the first ultrafiltration membrane has a molecular weight cutoff of 100 kDa and an operating pressure of 0.3-0.5 MPa; and the second ultrafiltration membrane has a molecular weight cutoff of 30 kDa and an operating pressure of 0.6-0.8 MPa.

4. The oral liquid colloidal stability enhancement and anti-stratification preparation process according to claim 1, characterized in that, In step S3, the composite stabilizer contains at least xanthan gum, gellan gum and sodium carboxymethyl cellulose in a mass ratio of (1-3):1:(2-4), and the amount added is 0.15%-0.4% of the mass of the colloidal mother liquor.

5. The oral liquid colloidal stability enhancement and anti-stratification preparation process according to claim 1, characterized in that, In step S3, the programmed heating method is as follows: first, heat to 60°C at a rate of 1-3°C / min, hold for 15-25 minutes, then heat to 70°C at a rate of 0.5-1.5°C / min, and hold for 30-50 minutes.

6. The oral liquid colloidal stability enhancement and anti-stratification preparation process according to claim 1, characterized in that, In step S4, the density regulator is a mixture of glycerol and sorbitol in a mass ratio of (0.8-1.2):1, and the amount added is 2%-5% of the solution mass.

7. The oral liquid colloidal stability enhancement and anti-stratification preparation process according to claim 1, characterized in that, In step S5, the composite microencapsulated wall material contains at least β-cyclodextrin and gum arabic in a mass ratio of (2-4):(1-3), and the amount added is 0.5%-1.5% of the solution mass.

8. The oral liquid colloidal stability enhancement and anti-stratification preparation process according to claim 1, characterized in that, In step S5, the polyhydroxy hydrogen bond promoter is selected from at least one of trehalose, mannitol, and sorbitol, and the amount added is 0.3%-0.8% of the solution mass.

9. The oral liquid colloidal stability enhancement and anti-stratification preparation process according to claim 1, characterized in that, In step S6, the terminal filter uses a 0.22μm microporous filter membrane, and the sterilization is performed by autoclaving at 115℃ for 25-35 minutes or autoclaving at 121℃ for 10-20 minutes.

10. The oral liquid colloidal stability enhancement and anti-stratification preparation process according to any one of claims 1-9, characterized in that, The finished oral liquid has a colloidal particle size distribution between 50-200 nm, a polydispersity index (PDI) ≤ 0.15, and an absolute value of zeta potential ≥ 35 mV.

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