Production and preparation method of compound double-flower oral liquid for enhancing palatability

Abstract

The invention discloses a production and preparation method of palatability-enhanced compound double-flower oral liquid, and relates to the technical field of traditional Chinese medicine preparations. The production and preparation method of the oral liquid comprises the following steps: pretreatment of medicinal materials: taking herba andrographitis, honeysuckle, radix isatidis, fructus forsythiae, honey and dark plum, washing, denucleating and slicing the dark plum (the honey is in a liquid state and does not need to be pretreated), ultrasonic extraction, integrated purification, filtrate collection, dynamic taste modification, sterilization and filling; the method has the advantages that bitter components are accurately neutralized by an innovative gradient inclusion process, qualitative leap of a bitter masking effect is realized, sensory evaluation is verified according to international standards, children acceptance score reaches an excellent level (full score of 10 scores), the core problem that children refer to take medicines due to bitter taste is thoroughly solved, the treatment compliance of patients is remarkably improved, and the treatment cost is reduced. The continuity of medication is ensured, a breakthrough solution is provided for the field of medication for children, and meanwhile, a technical normal form is provided for improvement of medicines similar to bitter taste.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine preparations, and particularly to a production preparation method of compound Shuanghua oral liquid with enhanced palatability. Background Technique

[0002] Compound Shuanghua oral liquid is composed of medicinal materials such as honeysuckle, isatis root, forsythia, and andrographis paniculata, and has the effects of clearing heat and detoxifying, and relieving sore throat and swelling. However, components such as andrographolide in andrographis paniculata have a strong bitter taste (the bitter taste threshold is as low as 0.001%), resulting in the following problems: 1. Poor compliance in taking medicine: Children are sensitive to bitter taste and are prone to resisting taking medicine, which affects the treatment effect.

[0003] 2. Limited taste masking effect: The existing technology relies on chemical sweeteners (such as acesulfame potassium, sucralose) and single cyclodextrin inclusion (such as hydroxypropyl-β-cyclodextrin), but the bitter taste residue rate is still as high as 30% - 50%.

[0004] 3. Insufficient process stability: In the traditional water extraction and alcohol precipitation process, the transfer rate of effective components such as chlorogenic acid fluctuates greatly (±15%), and the batch quality varies significantly.

[0005] 4. Doubts about long-term safety: The long-term use of chemical flavoring agents may affect the balance of intestinal flora.

[0006] Summary of the defects of the existing technology: Comparative document 1 (application number 201310379305.3) uses supercritical CO2 extraction, but does not solve the bitter taste problem. Comparative document 2 (application number 202311418866.X) improves the component content by adjusting the decocting order, but the taste masking still relies on synthetic sweeteners. In the existing technology, the addition of honey does not cooperate deeply with the inclusion process, and the flavor correction is not thorough. Therefore, we propose a production preparation method of compound Shuanghua oral liquid with enhanced palatability. Summary of the Invention

[0007] The purpose of the present invention is to provide a production preparation method of compound Shuanghua oral liquid with enhanced palatability.

[0008] To achieve the above purpose, the present invention provides the following technical solution: A production preparation method of compound Shuanghua oral liquid with enhanced palatability, including the production preparation method of oral liquid, and the production preparation method of oral liquid includes the following steps: (1) Pretreatment of medicinal materials: Take andrographis paniculata, honeysuckle, isatis root, forsythia, honey and Chinese quince, wash them, and remove the core of Chinese quince and slice it (honey is liquid and does not require pretreatment); (2) Ultrasonic extraction: Ultrasonically treat the medicinal materials with water, and obtain the extract after rough filtration; (3) Integrated purification: Synchronously carry out supercritical CO2 extraction and ceramic membrane filtration on the extract, and collect the filtrate; (4)Gradient inclusion: ① Add hydroxypropyl- -cyclodextrin to the filtrate and stir for inclusion at 60°C; ② Cool down to 45°C, add -cyclodextrin and stir for inclusion; (5)Dynamic flavor correction: Calculate the dosage of sweetener based on the mathematical model of bitterness intensity and sweetener dosage, add honey (containing natural fructose) and smoked plum extract (containing organic acids) to synergistically correct the flavor and make up the volume; (6)Sterilization and filling: Sterilize and fill the medicinal liquid after filtration.

[0009] As a further scheme of the present invention: The dosages of the medicinal materials in step (1) are as follows: 250 g of Andrographis paniculata, 250 g of Lonicera japonica, 250 g of Isatis indigotica, 250 g of Forsythia suspense, 150 g of honey (liquid state) and 100 g of smoked plum.

[0010] As a further scheme of the present invention: The parameters of the ultrasonic treatment in step (2) are: frequency 40 kHz, temperature 60°C and time 60 min, and the water addition amount is 8 times the total mass of the medicinal materials.

[0011] As a further scheme of the present invention: The parameters of the supercritical CO2 extraction in step (3) are: pressure 25 MPa, temperature 35°C and time 2 h, and the molecular weight cut-off of the ceramic membrane is 1 kDa.

[0012] As a further scheme of the present invention: The addition amount of hydroxypropyl- -cyclodextrin in step (4) is 4% of the total mass of the filtrate, The addition amount of

[0013] -cyclodextrin is 2% of the total mass of the filtrate. ; In the formula, is the total amount of sweetener (unit: g), is the bitterness intensity coefficient ( = andrographolide content × 0.8), is the bitterness threshold (0.001%), is the relative sweetness of the sweetener (such as honey fructose = 0.7 (taking sucrose as 1), and smoked plum organic acid helps to balance the bitterness), is the inclusion efficiency (measured value 0.92).

[0014] As a further scheme of the present invention: In step (6), moist heat sterilization method is adopted for sterilization, and the parameters are 115°C and 30 min.

[0015] As a further solution of the present invention: in step (6), the liquid medicine is filtered through a 0.22 μm microporous filter membrane before filling.

[0016] The present invention also provides a compound Shuanghua oral liquid, whose bitterness acceptance score ≥ 9.0 (ISO3972 standard), and the relative standard deviation (RSD) of the chlorogenic acid transfer rate < 5%.

[0017] As a further solution of the present invention: prepared by the said method, and the content of andrographolide ≥ 98 mg / mL.

[0018] Adopting the above technical solutions, compared with the prior art, the beneficial effects of the present invention are as follows: 1. The present invention precisely neutralizes bitter components through an innovative gradient inclusion process, achieving a qualitative leap in the bitter masking effect. The sensory evaluation is verified according to international standards, and the children's acceptance score reaches an excellent level (full score 10 points), completely solving the core problem that children resist taking medicine due to bitterness. This technology significantly improves the treatment compliance of patients, ensures the continuity of medication, provides a breakthrough solution for the field of children's medication, and at the same time provides a technical paradigm for the improvement of similar bitter drugs. 2. The present invention adopts an integrated extraction and purification technology to replace the traditional multi-step separation process, achieving a breakthrough in shortening the production cycle and reducing energy consumption. This process significantly converges the fluctuations in the transfer rate of active ingredients and significantly reduces the quality differences between batches, meeting the strict standards of large-scale industrial production. The technological breakthrough ensures the stability and reliability of the product efficacy, sets a new benchmark for the standardized production of traditional Chinese medicine preparations, and promotes the upgrading of industrial technology. 3. The present invention completely replaces chemical synthetic additives with natural flavoring components, fundamentally avoiding the safety risks of long-term medication. The synergistic effect of honey (containing natural fructose) and dark plum (containing malic acid and citric acid) in the innovative formula has been scientifically verified. While significantly improving the taste (sweet and sour balance), it simultaneously enhances the core efficacy of clearing heat and detoxifying, achieving the technical balance of "flavoring without sacrificing efficacy". This design breaks through the limitations of traditional flavor masking technologies, provides a solution with both excellent palatability and clinical efficacy for patients, and promotes the safety upgrade of traditional Chinese medicine preparations. Description of the Drawings

[0019] Figure 1 It is the process flow chart of the gradient inclusion process of the present invention; Figure 2 It is the process flow chart of the production and preparation process of the present invention; Figure 3 It is the calculation diagram of the dynamic flavoring model of the present invention. Detailed Embodiments

[0020] The following further describes the specific embodiments of the present invention in conjunction with the accompanying drawings. It should be noted here that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation to the present invention.

[0021] In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0022] Please refer to the attached Figure 1 - attached Figure 3 , a production and preparation method of a compound honeysuckle oral liquid for enhancing palatability of the present invention, including an oral liquid production and preparation method, and the oral liquid production and preparation method includes the following steps: (1) Medicinal material pretreatment: Take andrographis paniculata, honeysuckle, isatis root, forsythia, honey and smoked plum, wash them, and remove the pits of the smoked plum and slice it (honey is in liquid state and does not require pretreatment); (2) Ultrasonic extraction: Add water to the medicinal materials for ultrasonic treatment, and obtain an extract after rough filtration; (3) Integrated purification: Synchronously perform supercritical CO2 extraction and ceramic membrane filtration on the extract, and collect the filtrate; (4) Gradient inclusion: ① Add hydroxypropyl- - cyclodextrin to the filtrate, and stir and include it at 60 °C; ② Cool down to 45 °C, add - cyclodextrin, and stir and include it; (5) Dynamic flavor correction: Calculate the dosage of the sweetener based on the mathematical model of the bitterness intensity and the dosage of the sweetener, add honey (containing natural fructose) and smoked plum extract (containing organic acids) to synergistically correct the flavor and make up the volume; (6) Sterilization and filling: Filter the medicinal liquid and then sterilize and fill it.

[0023] In an embodiment of the present invention: The dosage of the Chinese medicinal materials in step (1) is: 250 g of andrographis paniculata, 250 g of honeysuckle, 250 g of isatis root, 250 g of forsythia, 150 g (liquid) of honey, and 100 g of smoked plum.

[0024] In an embodiment of the present invention: The parameters of the ultrasonic treatment in step (2) are: frequency 40 kHz, temperature 60 °C, and time 60 min, and the water addition amount is 8 times the total mass of the medicinal materials.

[0025] In an embodiment of the present invention: The parameters of the supercritical CO2 extraction in step (3) are: pressure 25 MPa, temperature 35 °C, and time 2 h, and the molecular weight cut-off of the ceramic membrane is 1 kDa.

[0026] In an embodiment of the present invention: The addition amount of hydroxypropyl- - cyclodextrin in step (4) is 4% of the total mass of the filtrate, The addition amount of β-cyclodextrin is 2% of the total mass of the filtrate.

[0027] In one embodiment of the present invention: the formula of the mathematical model in step (5) is: ; In the formula, is the total amount of sweeteners (unit: g), is the bitterness intensity coefficient ( = andrographolide content × 0.8), is the bitterness threshold (0.001%), is the relative sweetness of the sweetener (such as honey fructose = 0.7 (taking sucrose as 1), and organic acids in smoked plum assist in balancing bitterness), is the inclusion efficiency (measured value 0.92).

[0028] In one embodiment of the present invention: in step (6), moist heat sterilization method is adopted for sterilization, and the parameters are 115 °C and 30 min.

[0029] In one embodiment of the present invention: before filling in step (6), the liquid medicine is filtered through a 0.22 μm microporous membrane filter.

[0030] The present invention also provides a compound Shuanghua oral liquid, whose bitterness acceptance score ≥ 9.0 (ISO3972 standard), and the relative standard deviation (RSD) of chlorogenic acid transfer rate < 5%.

[0031] In one embodiment of the present invention: prepared by the method, and the andrographolide content ≥ 98 mg / mL.

[0032] Example 1. Preparation of compound Shuanghua oral liquid (basic scheme) Prescription: Andrographis paniculata 250 g, Flos Lonicerae 250 g, Radix Isatidis 250 g, Forsythia suspensa 250 g, honey 150 g (liquid state) and smoked plum 100 g.

[0033] Preparation steps: 1. Pretreatment of medicinal materials: Remove the pits and slice the smoked plums, directly add the honey (liquid state), and wash and set aside together with other medicinal materials (Andrographis paniculata, Flos Lonicerae, Radix Isatidis, Forsythia suspensa).

[0034] 2. Ultrasonic extraction: Add the medicinal materials into water with 8 times the mass (total mass of medicinal materials × 8), and treat under the conditions of 40 kHz ultrasonic wave and 60 °C for 60 minutes. After rough filtration, an extraction solution is obtained.

[0035] 3. Integrated purification: The extract is simultaneously subjected to supercritical CO2 extraction (pressure 25 MPa, temperature 35 °C, time 2 hours) and ceramic membrane filtration (molecular weight cut-off 1 kDa), and the filtrate is collected. This step replaces the traditional alcohol precipitation - water precipitation process, shortening the process by 50%.

[0036] 4. Gradient inclusion: Step ①: Add hydroxypropyl - -cyclodextrin (addition amount is 4% of the total mass of the filtrate) to the filtrate, and stir at 60 °C for 1 hour to include andrographolide (the main bitter component).

[0037] Step ②: Cool down to 45 °C, add -cyclodextrin (addition amount is 2% of the total mass of the filtrate), and stir for 1 hour to include residual small-molecule bitter substances (such as alkaloids).

[0038] 5. Dynamic flavor correction: Calculate the dosage of sweetener based on a mathematical model: ; where (bitter intensity coefficient) = andrographolide content × 0.8 (measured 98.5 mg / mL → , (bitter threshold) = 0.001%, (relative sweetness of sweetener, dark plum) = 200, (inclusion efficiency) = 0.92 (measured value).

[0039] Calculation result: (dark plum), add dark plum, and make up the volume to 1000 mL.

[0040] 6. Sterilization and filling: The medicinal liquid is filtered through a 0.22 μm microporous membrane, sterilized by moist heat at 115 °C for 30 minutes, and then filled to obtain the product.

[0041] Test result:

[0042] Table 1 Example 2. Optimize the proportion of flavor-correcting medicinal materials (improve the adaptability to sweetness) Prescription: 250 g of andrographis paniculata, 250 g of honeysuckle, 250 g of isatis root, 250 g of forsythia, 150 g of honey (liquid) and 100 g of dark plum.

[0043] Preparation steps: 1. Pretreatment of medicinal materials: After washing, remove the pits and slice the dark plums (honey is liquid and does not require pretreatment), and wash the other medicinal materials (the same as in Example 1).

[0044] 2. Ultrasonic extraction: The parameters are the same as in Example 1 (40 kHz, 60 °C, 60 min, adding 8 times the amount of water).

[0045] 3. Integrated purification: Supercritical CO2 extraction (25 MPa, 35 °C, 2 h) is synchronized with ceramic membrane filtration (1 kDa).

[0046] 4. Gradient inclusion: Hydroxypropyl- -cyclodextrin (4%) and The inclusion steps of -cyclodextrin (2%) are the same as in Example 1.

[0047] 5. Dynamic flavor correction: Adjust the dosage of sweeteners according to the mathematical model: The measured content of andrographolide is 97.8 mg / mL → ; Other parameters remain unchanged ( ); Calculation result: (Smoked plum); Add 42.5 g of smoked plum and make up the volume to 1000 mL.

[0048] 6. Sterilization and filling: The same as in Example 1 (filtration with 0.22 μm, sterilization at 115 °C for 30 min).

[0049] Test result:

[0050] Table 2 Note: In this example, by increasing the proportion of smoked plum (150 g), further utilizing the high sweetness of smoked plum (200 times that of sucrose), while ensuring the medicinal effect (clearing heat and detoxifying), the sweet taste covering ability is significantly improved, and the acceptance of children is increased to 9.3 points.

[0051] Example 3. Industrialized scale-up production (verifying scale adaptability) Prescription: 2500 g of andrographis paniculata, 2500 g of honeysuckle, 2500 g of isatis root, 2500 g of forsythia, 1500 g of honey and 1000 g of smoked plum (prescription amount × 10).

[0052] Preparation steps: 1. Pretreatment of medicinal materials: After washing, remove the pits and slice the smoked plum (honey is liquid and does not need pretreatment), and wash the other medicinal materials (equipment: industrial medicine cutter).

[0053] 2. Ultrasonic extraction: Process in an industrial ultrasonic bath (frequency 40 kHz, temperature 60 °C), with the water addition being 8 times the total mass of the medicinal materials, and process in two batches (60 minutes for each batch).

[0054] 3. Integrated purification: Use a large-scale supercritical CO2 extraction device (pressure 25 MPa, temperature 35 °C, time extended to 3 hours) in combination with an industrial ceramic membrane system (molecular weight cut-off 1 kDa).

[0055] 4. Gradient inclusion: Step ①: Add hydroxypropyl- -cyclodextrin (4% of the total mass of the filtrate), and stir at 60 °C for 1.5 hours (extend the stirring time to ensure uniform inclusion).

[0056] Step ②: Cool down to 45 °C, add -cyclodextrin (2% of the total mass of the filtrate), and stir for 1.5 hours.

[0057] 5. Dynamic flavor correction: Calculate the dosage of sweetener according to the mathematical model: The measured content of andrographolide is 98.2 mg / mL → ; Other parameters remain unchanged ( ); Calculation result: (427 g of smoked plums in total); Add 427 g of smoked plums, and make up the volume to 10000 mL.

[0058] 6. Sterilization and filling: The medicinal liquid is filtered through an industrial 0.22 μm microporous membrane system, continuously sterilized at 115 °C for 30 minutes, and automatically filled.

[0059]

[0060] Table 3 Note: This example verifies the feasibility of industrial production: 1. By extending the supercritical extraction time (3 h) and stirring time (1.5 h), ensure the stability of the component transfer rate (RSD < 5%) on a large scale; 2. The dynamic flavor correction model supports batch scale-up calculation, and the dosage of sweetener is accurately matched; 3. The process stability meets market demands.

[0061] Although the present invention is disclosed above in a preferred embodiment, it is not intended to limit the present invention. Any person skilled in the art can make possible changes and modifications without departing from the spirit and scope of the present invention. Therefore, all modifications, equivalent changes and decorations made to the above embodiments based on the technical essence of the present invention without departing from the technical solution of the present invention fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for producing and preparing a compound honeysuckle oral liquid with enhanced palatability, including a method for producing and preparing an oral liquid, characterized in that: The production and preparation method of the oral liquid comprises the following steps: (1) Pretreatment of medicinal materials: Take andrographis paniculata, honeysuckle, isatis root, forsythia suspensa, honey and smoked plum, wash them, and cut the smoked plum after removing the stone; (2) Ultrasonic extraction: Add water to the medicinal materials for ultrasonic treatment, and obtain the extract after rough filtration; (3) Integrated purification: Synchronously carry out supercritical CO2 extraction and ceramic membrane filtration on the extract, and collect the filtrate; (4) Gradient inclusion; ① Add hydroxypropyl- -cyclodextrin to the filtrate and stir for inclusion at 60 °C; ②Cool down to 45°C and add -cyclodextrin, stir for inclusion complexation; (5) Dynamic flavor correction: Calculate the dosage of the sweetener based on the mathematical model of the bitterness intensity and the dosage of the sweetener, add honey and the smoked plum extract to synergistically correct the flavor and make up the volume; (6) Sterilization and filling: Sterilize and fill the medicinal liquid after filtration; 2. The production preparation method of a compound honeysuckle oral liquid for enhancing palatability according to claim 1, characterized in that: In step (1), the dosages of the medicinal materials are as follows: 250 g of andrographis paniculata, 250 g of honeysuckle, 250 g of isatis root, 250 g of forsythia suspensa, 150 g of honey and 100 g of smoked plum.

3. The production preparation method of a compound honeysuckle oral liquid for enhancing palatability according to claim 1, wherein: In step (2), the parameters of the ultrasonic treatment are as follows: frequency 40 kHz, temperature 60 °C and time 60 min, and the water addition amount is 8 times the total mass of the medicinal materials.

4. The production and preparation method of a compound honeysuckle oral liquid for enhancing palatability according to claim 1, characterized in that: In step (3), the parameters of the supercritical CO2 extraction are as follows: pressure 25 MPa, temperature 35 °C and time 2 h, and the molecular weight cut-off of the ceramic membrane is 1 kDa.

5. The production preparation method of a compound honeysuckle oral liquid for enhancing palatability according to claim 1, characterized in that: In step (4), the addition amount of hydroxypropyl- -cyclodextrin is 4% of the total mass of the filtrate, -cyclodextrin is 2% of the total mass of the filtrate.

6. The production preparation method of a compound honeysuckle oral liquid for enhancing palatability according to claim 1, characterized in that: In step (5), the formula of the mathematical model is: ； In the formula, is the total amount of sweeteners, is the bitterness intensity coefficient, is the bitterness threshold, is the relative sweetness of the sweetener, is the inclusion efficiency.

7. A production and preparation method of a compound honeysuckle oral liquid for enhancing palatability according to claim 1, characterized in that: In step (6), moist heat sterilization method is adopted for sterilization, and the parameters are 115 °C and 30 min.

8. The production preparation method of a compound honeysuckle oral liquid for enhancing palatability according to claim 1, characterized in that: Before filling in step (6), the medicinal liquid is filtered through a 0.22 μm microporous membrane.

9. The compound Shuanghua oral liquid prepared by the method according to any one of claims 1-8, characterized in that, Its bitterness acceptance score ≥ 9.0, and the relative standard deviation of the chlorogenic acid transfer rate < 5%.

10. A compound Shuanghua oral liquid, characterized in that, Prepared by the method according to any one of claims 1-8, and the andrographolide content ≥ 98 mg / mL.

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