Production process of compound gastrodia elata oral liquid

Abstract

The invention discloses a compound gastrodia elata oral liquid production technology, and relates to the technical field of oral liquid production, and the specific steps are as follows: adding ethanol into a compound gastrodia elata raw material, carrying out reflux extraction twice, 1-3 hours each time, filtering the extract, recovering ethanol from the filtrate until no alcohol smell exists, concentrating until the relative density is 1.15, carrying out centrifugal filtration, adding cane sugar and potassium sorbate into the filtrate, and uniformly stirring to obtain a mixed solution; and adding adsorption microspheres into the mixed solution, filtering, adjusting the total amount, uniformly stirring, filling and sterilizing to obtain the product. The adsorption microspheres have two layers; on one hand, the temperature change of the microspheres can be reduced, on the other hand, the temperature influence degree of the structure is reduced, the structure loosening degree is reduced, the water absorption capacity is reduced, stability reduction and adsorption capacity reduction caused by expansion of the microspheres are prevented, and the high temperature resistance and stability are improved while the adsorption capacity is improved.

Description

Technical Field

[0001] The invention relates to the technical field of oral liquid production, and in particular to a production process of compound gastrodia elata oral liquid. Background Art

[0002] Chinese medicine oral liquid is a new dosage form developed on the basis of decoction, injection and syrup. It absorbs the characteristics of Chinese medicine injection process, adds some additives according to the production process of syrup, and then makes sterile or semi-sterile oral liquid preparations according to the injection filling process. It has the advantages of small dosage, convenience, rapid absorption, good efficacy, safety and hygiene. However, in actual production, due to long-term storage, the oral liquid often has a darker color, precipitation or increased precipitation, which makes patients doubt and do not want to take it; although the oral liquid is sterilized and sealed in production, it will also change if it is stored for too long, especially some unstable components in water are more likely to change.

[0003] For example, the Chinese patent, application number CN202310428405.4, a Wuzi Yanzong oral liquid and its preparation method, relates to the field of oral liquid preparation technology, including the following raw materials in parts by weight: 200-400 parts of wolfberry; 200-400 parts of dodder seed (fried); 100-200 parts of raspberry; 30-40 parts of schisandra (steamed with vinegar); 50-90 parts of plantain (fried with salt); the above five flavors are extracted with ethanol for two times, each time for 1-3 hours, the extracts are combined, filtered, and ethanol is recovered from the filtrate until there is no alcohol taste, concentrated, centrifuged and filtered, sucrose and potassium sorbate are added to the filtrate, stirred to obtain a mixed solution, and then adsorption microspheres are added to the mixed solution, filtered, the total amount is adjusted, stirred, filled, and sterilized to obtain; after the extraction of each Chinese medicine raw material, there may be many tannins in the extract, which are characterized by many phenolic hydroxyl groups, which are easy to polymerize with each other, resulting in the increase of molecules, and slowly agglomerating and precipitating. Therefore, the present invention adds adsorption microspheres of gelatin and xanthan gum to perform flocculation adsorption on them, thereby reducing the influence of the substances on the clarity of the oral liquid.

[0004] Due to the intensified molecular thermal motion in high temperature environment, the interaction between the molecular chains of low-temperature cross-linked microspheres will be affected, resulting in a looser structure, which is easier to absorb water and expand, causing the microspheres to be destroyed and lose their function. Summary of the invention

[0005] The present application solves the problem of reduced function caused by reduced stability of microspheres at high temperatures in the prior art, and achieves better high temperature resistance and stability.

[0006] The embodiment of the present application provides a production process for compound Gastrodia elata oral liquid, and the specific steps are: adding ethanol to the compound Gastrodia elata raw material and refluxing and extracting it twice, each time for 1-3 hours, filtering the extract, recovering ethanol from the filtrate until there is no alcohol taste, concentrating it to a relative density of 1.15, centrifuging and filtering, adding sucrose and potassium sorbate to the filtrate, stirring to obtain a mixed solution, adding adsorption microspheres to the mixed solution, filtering, adjusting the total amount, stirring, filling, and sterilizing to obtain; the adsorption microspheres have a double layer.

[0007] Furthermore, the raw materials of the compound Gastrodia elata include, by weight: 10 parts of Gastrodia elata, 5 parts of Schisandra chinensis, and 10 parts of Radix Ophiopogonis; the amount of adsorption microspheres added accounts for 1-3wt% of the mixed solution.

[0008] Furthermore, the preparation method of the adsorption microspheres is as follows: Adding an aqueous solution containing gelatin and xanthan gum to paraffin oil and edible oil, mixing them evenly, adjusting the temperature, washing and filtering, and obtaining primary microspheres, the particle size of which is 30-100 μm; Then the primary microspheres are cross-linked at low temperature, specifically, the primary microspheres are placed in a PBS solution containing EDC and NHS, frozen cross-linked at -20°C for 100 hours, thawed, rinsed with dehydrating agent ethanol, precipitated, and frozen to obtain single-layer microspheres; The single-layer microspheres were immersed in a solution containing gelatin and xanthan gum for 1 hour, and then the immersed single-layer microspheres were placed in paraffin oil and edible oil to form primary double-layer microspheres; then low-temperature cross-linking was performed again to obtain double-layer adsorption microspheres.

[0009] Furthermore, the mass ratio of gelatin to xanthan gum is 1:1.

[0010] Furthermore, the primary microspheres are pre-frozen before low-temperature cross-linking, and the pre-freezing is performed without using a cross-linking agent.

[0011] Further, pre-freezing is specifically: The primary microspheres were pre-frozen at -20°C for 1 hour to promote the formation and growth of ice crystals in the primary microspheres, and then thawed and placed at room temperature for 3 hours before low-temperature cross-linking.

[0012] Furthermore, the primary double-layer microspheres are also pre-frozen before low-temperature cross-linking, specifically: The primary double-layer microspheres were pre-frozen at -1°C for 4 h to promote the formation of ice crystals in the primary microspheres, and then thawed and placed at room temperature for 3 h before low-temperature cross-linking.

[0013] Furthermore, the pre-freezing step in the preparation process of the inner layer of the adsorption microspheres also includes a gradient temperature change.

[0014] Furthermore, the gradient temperature change is specifically: The primary microspheres were pre-frozen at -1°C for 1 hour to promote the formation and growth of ice crystals in the primary microspheres. The temperature was then uniformly cooled to -20°C within 1 hour and maintained for 0.5 hours. The microspheres were then taken out for thawing and placed at room temperature for 3 hours before low-temperature cross-linking.

[0015] Furthermore, sucrose accounts for 10% of the total weight and potassium sorbate accounts for 0.1% of the total weight.

[0016] One or more technical solutions provided in the embodiments of the present application have at least the following technical effects or advantages: First, the mixture of xanthan gum and gelatin will polymerize at about 40-50°C, and because of its water solubility and insolubility in paraffin oil and edible oil, it forms preliminarily polymerized microspheres, and then solidifies and loads again to prepare double-layer adsorption microspheres. The double-layer adsorption microspheres have a larger specific surface area and a more complex structure, and show a stronger adsorption capacity, which can increase the adsorption capacity of substances with poor stability in Chinese medicine oral liquids and increase the adsorption amount; the double-layer adsorption microspheres reduce the temperature change of the microspheres on the one hand, and on the other hand reduce the degree to which the structure is affected by temperature, reduce the looseness of the structure, and reduce the water absorption, so as to prevent the stability and adsorption capacity from decreasing due to its expansion; Second, pre-freezing is performed without the use of a cross-linking agent. The primary microspheres are placed in liquid nitrogen and rapidly frozen at -20°C. Rapid freezing produces ice crystals that grow rapidly. The formation of ice crystals will occupy the space inside the microspheres and leave pores during the thawing process. Since the pre-freezing is performed without a cross-linking agent, the formation of ice crystals and the leaving of pores are physical processes and will not be interfered by the cross-linking reaction. Since the pre-freezing is performed without a cross-linking agent, the size and distribution of these pores are relatively uniform. In the subsequent cross-linking process, these pores are fixed to form a double-layer microsphere with a large-pore inner layer. Third, during the pre-freezing process, water molecules form tiny ice crystals on the outer layer of the microspheres. These ice crystals melt during the subsequent thawing process, leaving tiny pores. This gives the outer layer of the microspheres more channels and active sites, making the surface of the microspheres rougher and more uneven, thereby improving their adsorption capacity. At the same time, the increase in porosity also helps to disperse the internal stress of the microspheres and reduce structural deformation caused by material aggregation or temperature changes. Fourthly, the porous inner structure allows the adsorbed substances to be evenly dispersed inside the microspheres, preventing the substances from aggregating and precipitating, thereby improving the performance stability of the microspheres during long-term use. Through the pre-freezing step with gradient temperature changes, the inner layer of the microspheres forms a more uniform and dense pore structure, which can better maintain the shape and dimensional stability of the microspheres in a high temperature environment, and reduce thermal expansion and deformation. DETAILED DESCRIPTION

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by technicians in the technical field to which the present invention belongs; the terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention; the term "and / or" used herein includes any and all combinations of one or more related listed items.

[0018] Embodiment 1: A production process of compound Tianma oral liquid, comprising the following specific steps: adding ethanol to the compound Tianma raw material for reflux extraction twice, each time for 1-3 hours, filtering the extract, recovering ethanol from the filtrate until there is no alcohol taste, concentrating to a relative density of 1.15, centrifuging, adding sucrose and potassium sorbate to the filtrate, stirring well to obtain a mixed solution, adding adsorption microspheres to the mixed solution, filtering, adjusting the total amount, stirring well, filling, sterilizing, and obtaining the product; The adsorption microspheres have a double layer, and the preparation method is as follows: adding an aqueous solution containing gelatin and xanthan gum to paraffin oil and edible oil, mixing evenly, adjusting the temperature, washing and filtering, and obtaining primary microspheres, the particle size of the primary microspheres is 30-100 μm; Then the primary microspheres are cross-linked at low temperature, specifically, the primary microspheres are placed in a PBS solution containing EDC and NHS, frozen cross-linked at -20°C for 100 hours, thawed, rinsed with dehydrating agent ethanol, precipitated, and frozen to obtain single-layer microspheres; The single-layer microspheres were immersed in a solution containing gelatin and xanthan gum for 1 hour, and then the immersed single-layer microspheres were placed in paraffin oil and edible oil to form primary double-layer microspheres; and then low-temperature cross-linking was performed again to obtain double-layer adsorption microspheres; Among them, the mass ratio of gelatin and xanthan gum is 1:1; the raw materials of the compound Gastrodia elata include, by weight: 10 parts of Gastrodia elata, 5 parts of Schisandra chinensis, and 10 parts of Ophiopogon japonicus; the added amount of adsorption microspheres accounts for 1-3wt% of the mixed solution; sucrose accounts for 10% of the total weight, and potassium sorbate accounts for 0.1% of the total weight.

[0019] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: The mixture of xanthan gum and gelatin will polymerize at about 40-50°C, and due to its water solubility and insolubility in paraffin oil and edible oil, a preliminary polymerized microsphere is formed, and then double-layer adsorption microspheres are prepared by loading again after solidification. The double-layer adsorption microspheres have a larger specific surface area and a more complex structure, and show a stronger adsorption capacity, which can increase the adsorption capacity of substances with poor stability in Chinese medicine oral liquids and increase the adsorption amount; the double-layer adsorption microspheres reduce the temperature change of the microspheres on the one hand, and on the other hand reduce the degree to which the structure is affected by temperature, reduce the looseness of the structure, and reduce the water absorption, so as to prevent the stability and adsorption capacity from decreasing due to its expansion; The double-layer adsorption microspheres can more effectively disperse and stabilize the ingredients in traditional Chinese medicine preparations through their unique double-layer structure; by adsorbing substances that are easily precipitated or precipitated in traditional Chinese medicine preparations, the double-layer adsorption microspheres improve the clarity and stability of the preparations, thereby improving the appearance and taste of the preparations and enhancing patients' medication compliance.

[0020] Embodiment 2: The above embodiment not only increases the adsorption capacity but also increases its high temperature resistance through the design of multi-layer microspheres. Therefore, on this basis, it is possible to increase the pore size of the microspheres without causing the microspheres to break and improve their adsorption rate, which is further improved on the basis of embodiment 1.

[0021] The primary microspheres are also pre-frozen before low-temperature cross-linking. The pre-freezing is performed without using a cross-linking agent. Specifically: The primary microspheres were pre-frozen at -20°C for 1 hour to promote the formation and growth of ice crystals in the primary microspheres, and then thawed and placed at room temperature for 3 hours before low-temperature cross-linking.

[0022] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: Pre-freezing is to place the primary microspheres in liquid nitrogen without using a cross-linking agent, and then quickly freeze them at -20°C. Rapid freezing produces ice crystals and grows rapidly. The formation of ice crystals will occupy the space inside the microspheres and leave pores during the thawing process. Since pre-freezing is carried out without a cross-linking agent, the formation of ice crystals and the leaving of pores are physical processes and will not be interfered by the cross-linking reaction. Since pre-freezing is carried out without a cross-linking agent, the size and distribution of these pores are relatively uniform. In the subsequent cross-linking process, these pores are fixed to form a double-layer microsphere with a large-pore inner layer. The presence of the large-pore inner layer increases the specific surface area of ​​the microspheres, providing more active sites for adsorption; easily precipitated or precipitated substances in traditional Chinese medicine preparations can more easily enter the large pores inside the microspheres, thereby improving the adsorption efficiency; the large-pore inner layer also helps to adsorb larger molecular substances, broadening the application range of the microspheres; and reduces the accumulation of some substances on the surface of the microspheres to produce reactions, resulting in polymerization reactions on the surface of the microspheres, and increasing the molecular weight causes the microspheres to be deposited together; The large-pore inner layer helps to disperse and stabilize the substances inside the microspheres, reducing the precipitation or flocculation caused by the aggregation of substances; the double-layer structure itself also improves the physical and chemical stability of the microspheres, enabling them to maintain stable adsorption performance when facing the complex components and environmental conditions in traditional Chinese medicine preparations; By enhancing adsorption capacity and stability, the double-layer adsorption microspheres improve the clarity and stability of Chinese medicine preparations, thereby improving the appearance and taste of the preparations; stable preparations reduce quality changes caused by component precipitation or precipitation, and extend the shelf life of Chinese medicine preparations.

[0023] Embodiment 3: Embodiment 2 is further improved on the basis of Embodiment 2 by pre-freezing to increase the pore size of the inner layer of microspheres and further optimize the adsorption capacity of the microspheres, in order to increase the ability of substances to enter the inner layer of the microspheres and increase the porosity of the outer layer of microspheres.

[0024] The primary double-layer microspheres are also pre-frozen before low-temperature cross-linking. The pre-freezing is performed without using a cross-linking agent. Specifically: The primary double-layer microspheres were pre-frozen at -1°C for 4 h to promote the formation of ice crystals in the primary microspheres, and then thawed and placed at room temperature for 3 h before low-temperature cross-linking.

[0025] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: Pre-freezing treatment on the outer layer of microspheres can promote the formation of ice crystals and the subsequent increase in porosity even at a high freezing temperature (-1°C), but the speed of ice crystal formation slows down. However, the increase in pre-freezing time increases the number of ice crystals on the outer layer, and ultimately the outer layer obtains more and smaller ice crystals, which produce a large number of tiny gaps after rewarming. These tiny gaps provide more channels for substances to enter the inner layer of the microspheres, thereby improving the adsorption capacity of the microspheres. Although the pores in the outer layer are small in size, they can still effectively adsorb small molecules and allow some molecules to diffuse through the pores to the inner layer for further adsorption, reducing problems such as aggregation caused by the increase in the number of local molecules, and reducing structural deformation caused by material aggregation or temperature changes; the uniform distribution of tiny pores makes the microsphere structure more compact and uniform, thereby improving its physical stability. After cross-linking, the surface of the microsphere is more stable, preventing the microsphere from being destroyed or reduced in stability due to chemical reactions during storage or use; The increase in the porosity of the outer layer can quickly diffuse the heat inside the microsphere, reducing the thermal stress and deformation caused by local excessive temperature; the uniform distribution of tiny pores makes the microsphere structure more uniform, thereby improving its high temperature resistance; During the pre-freezing process, water molecules form tiny ice crystals on the outer layer of the microspheres. These ice crystals melt during the subsequent thawing process, leaving tiny pores. This gives the outer layer of the microspheres more channels and active sites, making the surface of the microspheres rougher and more uneven, thereby improving their adsorption capacity. At the same time, the increase in porosity also helps to disperse the internal stress of the microspheres and reduce structural deformation caused by material aggregation or temperature changes. It can also more effectively adsorb easily precipitated or precipitated substances in traditional Chinese medicine preparations, thereby improving adsorption efficiency and capacity. The increase in porosity makes the microsphere structure more compact and uniform, thereby improving its physical and chemical stability. At the same time, the increase in porosity also helps to improve the high temperature resistance of the microsphere, making it stable in a wider range of application environments; Embodiment 4: Embodiment 3 is further improved on the basis of Embodiment 3 by preparing an outer layer with many pores and small pore size to increase the abnormal environmental stability of the microspheres, increase the initial adsorption capacity, and have a wider range of applications.

[0026] The pre-freezing step in the preparation process of the inner layer of the adsorption microspheres also includes a gradient temperature change, specifically: The primary microspheres were pre-frozen at -1°C for 1 hour to promote the formation and growth of ice crystals in the primary microspheres. The temperature was then uniformly cooled to -20°C within 1 hour and maintained for 0.5 hours. The microspheres were then taken out for thawing and placed at room temperature for 3 hours before low-temperature cross-linking.

[0027] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: By pre-freezing at -1°C for 1 hour, the water in the primary microspheres begins to form ice crystals, and then the temperature is uniformly cooled to -20°C within 1 hour. This process will promote the further growth of ice crystals, and the ice crystals will leave pores after thawing, thereby increasing the porosity and pore size of the inner layer of the microspheres; The inner layer structure with large pore size and many pores provides more channels and adsorption sites for adsorbed substances, which helps to improve the adsorption capacity of the microspheres; It is conducive to the diffusion of adsorbate molecules inside the microspheres, shortens the time for adsorption to reach equilibrium, and improves the adsorption efficiency of the microspheres, especially when dealing with large molecules or high-concentration solutions. Although the increase in inner voids may weaken the structural support of the microspheres to a certain extent, a more uniform and dense pore structure is formed through the pre-freezing step with gradient temperature changes. This structure can better disperse the stress inside the microspheres, improve the mechanical strength and compressive resistance of the microspheres, and reduce the impact of reduced structural stability due to increased pore size. The porous double-layer structure allows the adsorbed substances to be evenly dispersed inside the microspheres, preventing the substances from aggregating and settling, and improving the performance stability of the microspheres during long-term use. Through the pre-freezing step with gradient temperature changes, the inner layer of the microspheres forms a more uniform and dense pore structure, which can better maintain the shape and dimensional stability of the microspheres in a high temperature environment, and reduce thermal expansion and deformation. The porous inner structure facilitates the rapid conduction and dispersion of heat, preventing damage to the microspheres caused by local overheating. At the same time, the air or other gases in the pores can act as a thermal insulation layer at high temperatures, improving the thermal stability of the microspheres.

[0028] By increasing the porosity and pore size, the microspheres can adsorb more substances and improve adsorption efficiency and capacity. By forming a more uniform and dense pore structure, the structural support, thermal stability and high temperature resistance of the microspheres are significantly improved. The pre-freezing step with gradient temperature change is a simple and effective method for optimizing the preparation process of the inner layer of the microspheres. By adjusting the pre-freezing temperature and time parameters, the porosity and pore size distribution of the inner layer of the microspheres can be flexibly controlled to meet the needs of different application scenarios.

[0029] The oral liquids obtained in Examples 1 to 4 were tested for experiments, and a control test was set up (the only difference from Example 1 is that the control test uses a single-layer microsphere), and the transmittance and soluble solids were tested at 20° C. The results are shown in Table 1:

[0030] Experiments were conducted on Examples 1 to 4, and a control test was set up (the only difference from Example 1 is that the control test uses a single-layer microsphere), and a stability test was conducted at 50° C. After 2 months, the transmittance and soluble solids were tested. The results are shown in Table 2:

[0031] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A production process of compound Tianma oral liquid, characterized in that: The specific steps are: add ethanol to the compound Gastrodia elata raw material and reflux extract twice, each time for 1-3 hours, filter the extract, recover ethanol from the filtrate until there is no alcohol taste, concentrate to a relative density of 1.15, centrifuge and filter, add sucrose and potassium sorbate to the filtrate, stir well to obtain a mixed solution, add adsorption microspheres to the mixed solution, filter, adjust the total amount, stir well, fill, and sterilize to obtain; the adsorption microspheres have a double layer.

2. The production process of a compound Tianma oral liquid as claimed in claim 1, characterized in that: The raw materials of the compound Tianma include, by weight: 10 parts of Tianma, 5 parts of Schisandra chinensis, and 10 parts of Radix Ophiopogonis; the amount of the adsorption microspheres added accounts for 1-3wt% of the mixed solution.

3. The production process of a compound Tianma oral liquid as claimed in claim 1, characterized in that: The preparation method of the adsorption microspheres is as follows: Adding an aqueous solution containing gelatin and xanthan gum to paraffin oil and edible oil, mixing them evenly, adjusting the temperature, washing and filtering, and obtaining primary microspheres, the particle size of which is 30-100 μm; Then the primary microspheres are cross-linked at low temperature, specifically, the primary microspheres are placed in a PBS solution containing EDC and NHS, frozen cross-linked at -20°C for 100 hours, thawed, rinsed with dehydrating agent ethanol, precipitated, and frozen to obtain single-layer microspheres; The single-layer microspheres were immersed in a solution containing gelatin and xanthan gum for 1 hour, and then the immersed single-layer microspheres were placed in paraffin oil and edible oil to form primary double-layer microspheres; Then low-temperature cross-linking is performed again to obtain double-layer adsorption microspheres.

4. The production process of a compound Tianma oral liquid as claimed in claim 3, characterized in that: The mass ratio of gelatin to xanthan gum is 1:

1.

5. The production process of a compound Tianma oral liquid as claimed in claim 1, characterized in that: The primary microspheres are also pre-frozen before low-temperature cross-linking, and the pre-freezing is freezing without using a cross-linking agent.

6. The production process of a compound Tianma oral liquid as claimed in claim 5, characterized in that: Pre-freezing is as follows: The primary microspheres were pre-frozen at -20°C for 1 hour to promote the formation and growth of ice crystals in the primary microspheres, and then thawed and placed at room temperature for 3 hours before low-temperature cross-linking.

7. The production process of a compound Tianma oral liquid as claimed in claim 6, characterized in that: The primary double-layer microspheres were also pre-frozen before low-temperature cross-linking, specifically: The primary double-layer microspheres were pre-frozen at -1°C for 4 h to promote the formation of ice crystals in the primary microspheres, and then thawed and kept at room temperature for 3 h before low-temperature cross-linking.

8. The production process of a compound Tianma oral liquid as claimed in claim 7, characterized in that: The pre-freezing step in the preparation process of the inner layer of the adsorption microspheres also includes a gradient temperature change.

9. The production process of a compound Tianma oral liquid as claimed in claim 8, characterized in that: The gradient temperature change is as follows: The primary microspheres were pre-frozen at -1°C for 1 hour to promote the formation and growth of ice crystals in the primary microspheres. The temperature was then uniformly cooled to -20°C within 1 hour and maintained for 0.5 hours. The microspheres were then taken out for thawing and placed at room temperature for 3 hours before low-temperature cross-linking.

10. The production process of the compound Tianma oral liquid according to claim 1, characterized in that: Sucrose accounts for 10% of the total weight and potassium sorbate accounts for 0.1% of the total weight.

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