Sarcandra glabra compound preparation and preparation method thereof

Abstract

The invention provides a sarcandra glabra and honeysuckle compound preparation and a preparation method thereof, and during preparation, part of sarcandra glabra and honeysuckle are subjected to supercritical carbon dioxide extraction, volatile oil and medicine residues are collected, and the medicine residues and the rest of sarcandra glabra and honeysuckle are subjected to water extraction. A proper amount of beta-cyclodextrin is added into a water extract for inclusion, then concentration and supercritical extraction are performed to obtain volatile oil, and beta-cyclodextrin is used for inclusion, so that on the basis of increasing the efficacy of the volatile oil, the contents of chlorogenic acid and isofraxidin are increased, the curative effect of the medicine is enhanced, the synergistic effect of all components of the medicine is exerted, and the treatment effect of the medicine is improved. Menthol is clathrated with beta-cyclodextrin and then added into the paste powder to be mixed, granulated and tableted. On the premise of not influencing the dissolution of menthol and the direct stimulation effect on the throat, the effects of dispelling wind, clearing heat, relieving sore throat and relieving pain of the medicine are further enhanced, and meanwhile the problems that the quality of the product is not stable enough due to environmental change during storage, menthol is volatilized and is easy to crystallize, separate out and deteriorate are effectively solved.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to a Herba Spinosae Biflorae compound preparation and a preparation method thereof. Background Art

[0002] In the field of research and development of drugs for treating throat diseases, numerous patents have explored throat-clearing and analgesic preparations. Patent No. ZL200410012694.7 discloses a throat-clearing and analgesic preparation, providing a prescription, dosage, and a general preparation process for lozenges, sprays, or aerosols. Subsequently, Patent No. 201010234641.5 further expanded the dosage forms to include tablets, capsules, and other types, and described the corresponding preparation methods. Patent No. 201410405764.9, also focusing on tablets and capsules, provides a preparation method for a traditional Chinese medicine preparation for clearing heat, relieving throat pain, and alleviating pain. To address the low content of active ingredient groups and storage issues, attempts were made to increase the active ingredient content and address the problem of menthol precipitation in tablets by adjusting the process, such as dissolving menthol in ethanol and adding it to the decoction for concentration, and using clarifiers. However, menthol is highly volatile, and a large amount evaporates with the water during the concentration process. This not only fails to effectively address the problem of menthol crystallization, but also reduces its content in the concentrate.

[0003] To address these issues, patent application number 201410637776.4 uses automated fluidized bed drying granulation technology to shorten processing and drying time and reduce loss of active ingredients; while patent application number 201510337006.2 develops rapidly disintegrating dispersible tablets by adding various excipients. However, overall, existing patents still face numerous technical challenges:

[0004] ① Low content of active ingredient groups: During the preparation production process, due to the limitations of the preparation technology, the active ingredients in the prescription cannot be fully retained and enriched, resulting in a low content of active ingredient groups in the preparation, affecting the efficacy of the drug.

[0005] Poor quality stability of the preparation: During storage, preparations are significantly affected by factors such as ambient temperature and humidity, often leading to problems such as darkening of color and shortened shelf life. Menthol's volatility makes improper handling prone to loss, crystallization, and even oxidation, seriously affecting the internal and external quality of the preparation.

[0006] ③ Ignoring the extraction and application of volatile oils: The volatile oils in Sarcandra scabra and Lonicera japonica have important functions such as dispelling wind and relieving fever, antiviral and anti-inflammatory. However, the existing patents do not extract them, ignoring the key value of volatile oils in drug treatment and failing to give full play to the therapeutic potential of drugs.

[0007] Sarcandra glabra, the dried whole herb of the plant Sarcandra glabra (Cerataceae), is mild in nature and has the effects of clearing heat and cooling blood, promoting blood circulation and removing freckles, and dispelling wind and unblocking meridians. It is rich in various components, including sesquiterpenes and flavonoids. Its active ingredients, such as isoflurane, volatile components, and rosmarinic acid, have been extensively studied and exhibit significant pharmacological activity in anti-tumor, antibacterial, and anti-inflammatory settings. Honeysuckle, the dried buds or newly opened flowers of the plant Lonicera japonica (Caprifoliaceae), is known for its heat-clearing, detoxifying, and wind-heat dispersing properties. Its characteristic components, volatile oils and chlorogenic acid, possess strong pharmacological activity, demonstrating significant antibacterial and antiviral effects. Menthol, obtained from the fresh stems and leaves of mint (Lamiaceae) through steam distillation and other processes, has pharmacological effects such as antipruritic and analgesic effects. In this prescription, Sarcandra glabra serves as the main herb, honeysuckle as the auxiliary herb, and menthol as the adjuvant. Pharmacological and clinical trials have confirmed that isoflurane and chlorogenic acid in the formula are important medicinal ingredients, and the volatile oils of Sarcandra scabra and honeysuckle are of great significance in enhancing the drug's effects of dispelling wind and fever, relieving sore throat and relieving pain, and have a good therapeutic effect on pharyngitis and other throat diseases.

[0008] Therefore, it is of great practical significance to develop a throat-relieving and analgesic preparation and preparation method that can increase the content of effective ingredient groups, enhance the quality stability of the preparation, and fully extract and utilize the volatile oils of Sarcandra scabra and honeysuckle. Summary of the Invention

[0009] In order to overcome the problems of the prior art, the present invention provides a compound preparation of Coral biflorus and a preparation method thereof.

[0010] It should be noted that the present invention is completed based on the following findings of the inventors:

[0011] The process development of compound Chinese herbal preparations must closely integrate the characteristics of the compound, comprehensively considering factors such as its chemical composition and pharmacological efficacy, to maximize the retention of active substances, maximize the combined efficacy of the active ingredients, and ensure clinical therapeutic results. For example, numerous studies have demonstrated that the volatile oils of Radix Sarcandrae and Flos Lonicerae have significant efficacy in dispelling wind and fever, combating viruses, and combating inflammation and bactericidal effects, particularly in the treatment of oral diseases. Chlorogenic acid, a key active ingredient in these two herbs, possesses antibacterial and anti-inflammatory properties, but it is heat-sensitive and easily degrades at high temperatures. Although strict control of heating temperature and duration is often employed in production to prevent chlorogenic acid degradation, this approach is not ideal and places high demands on production equipment and material flow. Furthermore, isoflurane, the main active ingredient in the formulation, belongs to the coumarin class and has low solubility in aqueous extracts. Comparative experiments and stability testing revealed that the tendency for crystallization and darkening of color during storage is primarily related to the oxidation and deterioration of menthol due to environmental influences. Therefore, in order to improve the intrinsic quality of preparations and solve practical problems, exploring reasonable preparation methods is crucial to enhancing drug efficacy and preparation storage.

[0012] The present invention aims to follow the theory of traditional Chinese medicine, respect traditional medication experience, fully consider the characteristics of the prescription drug ingredients, and take into account the safety and effectiveness of clinical medication. To this end, the advantages of supercritical low-temperature extraction technology and water extraction process technology are combined to achieve efficient extraction of the active ingredient groups of the prescription to meet the needs of clinical application. Specifically:

[0013] Optimizing the volatile oil extraction process: Using supercritical carbon dioxide extraction technology to extract volatile oils from Sargassum truncatum and honeysuckle not only preserves the natural aroma of the raw materials but also increases the volatile oil extraction rate. Adding an appropriate amount of beta-cyclodextrin to the extract for inclusion treatment further enhances the efficacy of the volatile oils.

[0014] Improving the content and stability of key active ingredients: By using an appropriate proportion of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin to encapsulate chlorogenic acid and isoflurane in the extract, on the one hand, the stability of heat-sensitive ingredients such as chlorogenic acid is improved to prevent their degradation due to heat during the concentration and drying process; on the other hand, the solubility of active ingredients such as isoflurane is increased, thereby improving the overall content of active ingredients.

[0015] Solving menthol-related issues: Menthol is encapsulated with beta-cyclodextrin and added to the paste powder for granulation and tableting. This method does not affect the dissolution of menthol or its direct irritation to the throat, fully unleashing its wind-clearing, antipyretic, and sore throat relieving effects. It also effectively addresses the issue of unstable product quality caused by environmental changes during storage, preventing menthol volatilization and crystallization.

[0016] In view of this, the purpose of the present invention is achieved like this:

[0017] A first aspect of the present invention provides a method for preparing a compound preparation of Herba Spinosae, the compound preparation comprising the following Chinese medicinal raw materials in parts by weight: 30-40 parts of Radix Sarcandrae, 10-20 parts of Flos Lonicerae, and 0.1-2 parts of menthol. The preparation method comprises the following steps:

[0018] (1) Pretreatment of medicinal materials:

[0019] Pre-treatment of medicinal materials for water extraction: clean and select the medicinal materials of Sarcandra scabra and Flos Lonicerae respectively, chop them into pieces, and obtain the medicinal pieces for water extraction;

[0020] Pre-treatment of medicinal materials for supercritical fluid: clean and select Radix Sarcandrae and Flos Lonicerae respectively, crush them, and pass them through a 10-30 mesh sieve to obtain coarse powder for supercritical fluid;

[0021] (2) taking coarse powder of Sarcandra scabra supercritical and coarse powder of Flos Lonicerae supercritical and mixing them, adding them into a supercritical carbon dioxide extraction tank, performing supercritical extraction, and collecting volatile oil and the extracted medicinal residues;

[0022] (3) taking the water-extracted slices of Radix Scutellariae and the water-extracted slices of Flos Lonicerae, as well as the residues after supercritical extraction obtained in step (2), adding water and boiling them twice, adding water 8 to 15 times the weight of the slices for the first time, boiling them for 1 to 2 hours, and adding water 5 to 10 times the weight of the slices for the second time, boiling them for 0.5 to 1.5 hours, combining the decoctions, filtering, and preparing an extract;

[0023] (4) Take the above extract, add a mixture of 1% to 5% of the amount of the decoction piece of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin while it is hot, mix and dissolve, and continue to stir and include for 20 to 40 minutes; pump the liquid into a self-circulating vacuum concentrator, continue the inclusion treatment while decompressing and concentrating, and wait until the liquid is concentrated to a clear paste with a relative density of 1.05 to 1.30, filter it while it is hot, and obtain a clear paste;

[0024] (5) Inclusion treatment:

[0025] The volatile oil and the Chinese medicinal raw material menthol prepared in step (2) are added with ethanol in an amount of 2 to 5 times the weight of the two, and stirred to fully dissolve them, thereby preparing an ethanol mixture of the volatile oil and menthol;

[0026] Take volatile oil and menthol 5 to 10 times the weight of beta-cyclodextrin, then add water 3 to 5 times the weight of beta-cyclodextrin, mix, stir at 40 to 50° C. to dissolve, to prepare a beta-cyclodextrin solution;

[0027] Transfer the beta-cyclodextrin solution to a stirrer with a constant temperature function, maintain constant temperature at 40-50°C with stirring, and slowly and uniformly add the ethanol mixture of the volatile oil and menthol dropwise. Continue constant temperature stirring for 1-3 hours to obtain the beta-cyclodextrin inclusion solution, place it at 2-8°C for 8-12 hours, and filter it to obtain the inclusion compound;

[0028] (6) Take sucrose powder, clear paste and inclusion compound, mix them evenly, granulate them, dry them, shape them into whole particles, and compress them into tablets to obtain the said double flower coral compound preparation.

[0029] Furthermore, in step (1), the weight ratio of the medicinal materials for water extraction to the medicinal materials for supercritical extraction is 3:7.

[0030] Furthermore, in step (2), the supercritical extraction conditions are: temperature 30-40° C., extraction pressure 15-25 MPa, carbon dioxide flow rate 20-30 L / h, and extraction time 1.0-2.0 h.

[0031] Furthermore, in step (4), in the mixture of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin, the weight ratio of beta-cyclodextrin to hydroxypropyl-beta-cyclodextrin is 1:1-2.

[0032] Furthermore, in step (4), the vacuum degree in the self-circulating vacuum concentrator is controlled at -0.05 to -0.09 MPa, and the vapor pressure is adjusted so that the concentration temperature is maintained at 60 to 70°C for vacuum concentration. During the concentration process, the drug solution is kept in a continuous circulation state to promote continued inclusion of the components.

[0033] Furthermore, in step (6), the drying treatment conditions include: the air outlet temperature is set to 60-70° C., and the drying time is 15-30 minutes.

[0034] Furthermore, in step (6), after granulation, appropriate amounts of magnesium stearate and talc are added, and tableting is completed after mixing.

[0035] The second aspect of the present invention provides a compound preparation of Coral Recutita prepared by the method described in the first aspect.

[0036] The advantages and beneficial effects of the present invention are:

[0037] 1. The present invention compares the volatile oil collection of different extraction methods and rationally selects the ratio of oil-extracted slices. Compared with the original process, the volatile oil extraction is added, which supplements the wind-dispelling and heat-dissipating effects of the volatile oil, and synergizes with other medicinal ingredients to significantly enhance the efficacy of the drug and improve the therapeutic effect of the drug;

[0038] 2. The present invention considers the advantages and disadvantages of different preparation methods based on the properties of the prescription drug's flavor and efficacy ingredients, selects multiple indicators to compare and evaluate different preparation methods, and rationally selects an appropriate extraction method. Volatile oils are extracted using supercritical carbon dioxide extraction technology, which is then included and then reintroduced into the drug, thereby retaining unstable components such as volatile oils and chlorogenic acid, thereby enhancing the drug's efficacy.

[0039] 3. The present invention utilizes the inclusion effect of beta-cyclodextrin and its derivatives. An appropriate amount of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin in a certain proportion are added to the extract to include heat-sensitive and poorly water-soluble coumarins such as chlorogenic acid in the extract, thereby improving the structural stability of the heat-sensitive components and increasing the solubility of components such as isoflurane, thereby increasing the content of the active ingredients.

[0040] 4. In the prior art, menthol is dissolved in ethanol and then sprayed onto the granules for tableting, which easily leads to the problem of darkening of the product color and crystallization during storage. The present invention, however, utilizes inclusion technology to include the menthol that is easily volatile and crystallizes, thereby minimizing the loss of menthol due to volatilization and effectively solving the problem of crystallization and deterioration during storage, thereby increasing the stability of the preparation quality and extending the shelf life.

[0041] 5. The present invention utilizes beta-cyclodextrin and its derivatives with good inclusion and compressibility to effectively mask the bitter taste of traditional Chinese medicine, enhance the drug's user experience and facilitate patient acceptance. At the same time, it acts as a partial sucrose excipient, which helps improve tableting formability and smoothness. Secondly, by encapsulating sensitive ingredients to prevent moisture absorption and deliquescence, the product's stability in air, high temperature and high humidity conditions is improved, and the product's shelf life is extended.

[0042] 6. There are many extraction technologies for volatile oils from traditional Chinese medicine. The steam distillation method and the co-distillation method commonly used in the prior art have been widely used because of their simple equipment and easy operation. However, the high temperature during distillation can easily destroy the heat-sensitive medicinal components in the raw materials. The present invention adopts supercritical carbon dioxide extraction, which has the characteristics of low extraction temperature, non-toxic solvent and high extract yield. It can retain the natural aroma of the raw materials, effectively prevent the volatile and other heat-sensitive components from being thermally decomposed and oxidized, and cause little damage to the raw material components. DETAILED DESCRIPTION

[0043] The examples are provided to better illustrate the present invention, but are not intended to limit the present invention to the examples. Therefore, non-essential improvements and adjustments to the embodiments made by those skilled in the art based on the above-mentioned invention still fall within the scope of protection of the present invention.

[0044] The endpoints of the ranges and any values disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0045] The present invention will be described in detail below through examples. It should be understood that the following examples are only used to further explain and illustrate the content of the present invention in detail, and are not intended to limit the present invention.

[0046] In the following examples, Sarcandra scabra, honeysuckle, and menthol were obtained from Guangxi Changhong Pharmaceutical Co., Ltd. Beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin were obtained from Qufu Tianli Pharmaceutical Excipients Co., Ltd. All of the above raw materials and excipients met the quality requirements of the 2020 edition of the Chinese Pharmacopoeia.

[0047] Beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin are cyclic compounds with a slightly sweet taste. Due to their excellent water solubility, safety, and inclusion properties, they are widely used in the food and pharmaceutical industries. Their inclusion properties are often used to encapsulate volatile and heat-sensitive active ingredients, contributing to the stability of the ingredient structure and maintaining product quality, thereby ensuring the efficacy of the drug. Furthermore, by encapsulating sensitive ingredients, they prevent moisture absorption and deliquescence, improving product stability in air, high temperature, and high humidity conditions, and extending the product's shelf life. Beta-cyclodextrin can effectively mask the bitterness of traditional Chinese medicines in lozenges and can also be used as a general excipient, such as a filler.

[0048] Example 1:

[0049] This embodiment provides a compound preparation of Herba Cynanchifoliae, which comprises the following Chinese medicinal materials in parts by weight: 37.5 parts of Sarcandrae scabra, 15.5 parts of Flos Lonicerae, and 1 part of menthol. The preparation method comprises the following steps:

[0050] (1) Pretreatment of medicinal materials:

[0051] Pre-treatment of medicinal materials for water extraction: clean and select the medicinal materials of Sarcandra scabra and Flos Lonicerae respectively, chop them into pieces, and obtain the medicinal pieces for water extraction;

[0052] Pretreatment of medicinal materials for supercritical use: respectively select the medicinal materials of Sarcandra scabra and Flos Lonicerae, crush them, and pass them through a 10-30 mesh sieve to obtain coarse powder for supercritical use.

[0053] (2) According to 10% of the total weight of the above raw materials, the supercritical coarse powder of Sarcandra glabra and the supercritical coarse powder of Lonicera japonica were mixed (i.e., 3.75 parts of supercritical coarse powder of Sarcandra glabra and 1.55 parts of supercritical coarse powder of Lonicera japonica), and the mixture was added to a supercritical carbon dioxide extraction tank. Supercritical extraction was performed for 1.5 hours at an extraction temperature of 35°C, an extraction pressure of 20 MPa, and a carbon dioxide flow rate of 25 L / h. The volatile oil and the extracted medicinal residues were collected.

[0054] (3) According to 90% of the total weight of the above raw materials, take the water-extracted decoction pieces of Radix Cynoglossi and the water-extracted decoction pieces of Flos Lonicerae (i.e., 33.75 parts of the water-extracted decoction pieces of Radix Cynoglossi and 13.95 parts of the water-extracted decoction pieces of Flos Lonicerae), and the medicinal residue after supercritical extraction obtained in step (2), add water and boil twice, add 10 times the weight of the decoction pieces for the first time, boil for 1.5 hours, add 8 times the weight of the decoction pieces for the second time, boil for 1.0 hour, combine the decoctions, filter, and prepare an extract.

[0055] (4) Take the above extract, add 3% of a mixture of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin in a ratio of 1:1 while hot, mix and dissolve, and continue stirring for 30 minutes; pump the liquid into a self-circulating vacuum concentrator, control the vacuum degree at -0.05 to -0.09 MPa, adjust the vapor pressure to keep the concentration temperature at 60°C to 70°C for vacuum concentration, and keep the liquid in a continuous circulation state during the concentration process to promote the continued inclusion of the components. When the liquid is concentrated to a clear paste with a relative density of 1.18, filter it while hot to obtain a clear paste.

[0056] (5) Inclusion treatment:

[0057] The volatile oil and the Chinese medicinal raw material menthol prepared in step (2) are added with ethanol in an amount twice the weight of the two, and stirred to fully dissolve them, thereby preparing an ethanol mixture of the volatile oil and menthol;

[0058] Take volatile oil and menthol 8 times the weight of beta-cyclodextrin, then add water 4 times the weight of beta-cyclodextrin, mix, stir at 40-50°C to dissolve, to prepare a beta-cyclodextrin solution;

[0059] Transfer the beta-cyclodextrin solution to a thermostatic container with a stirring function, maintain constant temperature of 40-50°C with stirring, and slowly and uniformly add the ethanol mixture of the volatile oil and menthol. Continue constant temperature stirring for 2 hours to obtain the beta-cyclodextrin inclusion liquid, place it at 2-8°C for 8h-12h, filter it, and obtain the inclusion compound.

[0060] (6) Mix the sucrose powder, the clear paste, and the inclusion compound, granulate them, and dry them at a temperature of 60°C to 70°C for 15 to 30 minutes. Add an appropriate amount of magnesium stearate and talc to the granules, mix them, and compress them into tablets to obtain the compound preparation of the Herba Dianthus Spinosaris.

[0061] Example 2:

[0062] This embodiment provides another compound preparation of Coral Recutita (B. biflora) prepared by referring to the preparation method of Example 1, with the only difference being that in steps (2) and (3), the ratios of the raw materials subjected to supercritical extraction and water extraction are different:

[0063] (2) 30% by weight of the total weight of the above raw materials, mixed with Sarcandra supercritical coarse powder and Flos Lonicerae supercritical coarse powder (i.e., 11.25 parts of Sarcandra supercritical coarse powder and 4.65 parts of Flos Lonicerae supercritical coarse powder), and subjected to supercritical extraction in the same manner as in Example 1, and the volatile oil and the extracted medicinal residue were collected;

[0064] (3) According to 70% of the total weight of the above raw materials, water-extracted slices of Radix Cynoglossi and water-extracted slices of Flos Lonicerae (i.e., 26.25 parts of water-extracted slices of Radix Cynoglossi and 10.85 parts of water-extracted slices of Flos Lonicerae) were taken, and water extraction was carried out in the same manner as in Example 1 to prepare an extract.

[0065] Example 3:

[0066] This embodiment provides another compound preparation of Coral Recutita (B. biflora) prepared by referring to the preparation method of Example 1, with the only difference being that in steps (2) and (3), the ratios of the raw materials subjected to supercritical extraction and water extraction are different:

[0067] (2) 50% by weight of the total weight of the above raw materials, mixed with Sarcandra supercritical coarse powder and Flos Lonicerae supercritical coarse powder (i.e., 18.75 parts of Sarcandra supercritical coarse powder and 7.75 parts of Flos Lonicerae supercritical coarse powder), and subjected to supercritical extraction in the same manner as in Example 1, and the volatile oil and the extracted medicinal residue were collected;

[0068] (3) According to 50% of the total weight of the above raw materials, water-extracted slices of Radix Cynoglossi and water-extracted slices of Flos Lonicerae (i.e., 18.75 parts of water-extracted slices of Radix Cynoglossi and 7.75 parts of water-extracted slices of Flos Lonicerae) were taken, and water extraction was carried out in the same manner as in Example 1 to prepare an extract.

[0069] Example 4:

[0070] This embodiment provides another compound preparation of Coral Recutita Spinosa, which is prepared according to the method of Example 1, except that all the Radix Sarcandrae and Flos Lonicerae medicinal materials are only subjected to supercritical fluid pretreatment, and supercritical extraction is performed in the same manner as in Example 1, and the volatile oil and the extracted residue are collected.

[0071] Example 5:

[0072] This embodiment provides another compound preparation of Coral Recutita, which is prepared according to the method of Example 2, except that in step (4), the 1:1 mixture of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin is completely replaced with beta-cyclodextrin, while keeping the total addition amount unchanged.

[0073] Example 6:

[0074] This embodiment provides another compound preparation of Coral Recutita, which is prepared according to the method of Example 2, except that in step (4), the 1:1 mixture of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin is completely replaced with hydroxypropyl-beta-cyclodextrin, while keeping the total addition amount unchanged.

[0075] Example 7:

[0076] This embodiment provides another compound preparation of Coral Recutita, which is prepared according to the method of Example 2, except that in step (4), a mixture of 1% beta-cyclodextrin and hydroxypropyl beta-cyclodextrin in a ratio of 1:1 is added to the extract while it is hot.

[0077] Example 8:

[0078] This embodiment provides another compound preparation of Coral Recutita, which is prepared according to the method of Example 2, except that in step (4), a mixture of 5% beta-cyclodextrin and hydroxypropyl beta-cyclodextrin in a ratio of 1:1 is added to the extract while it is hot.

[0079] Example 9:

[0080] This embodiment provides another compound preparation of Coral Recutita, which is prepared according to the method of Example 2, except that in step (4), the 1:1 mixture of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin is completely replaced with sucrose.

[0081] Example 10:

[0082] This embodiment provides another compound preparation of Coral Recutita Biflora, which is prepared by referring to the method of Example 2, except that in step (4), no auxiliary materials are added to the extract.

[0083] Example 11:

[0084] This embodiment provides another compound preparation of Coral Recutita (Scutellaria bispinosa) prepared by the method of Example 2, with the following differences: no menthol is added during the inclusion treatment in step (5); after the menthol is granulated in step (6), the menthol is dissolved in 3 times its weight of ethanol, sprayed into the granules and mixed, and the mixture is sealed overnight. An appropriate amount of magnesium stearate and an appropriate amount of talc are added, mixed, and tableted to obtain the product.

[0085] Comparative Example 1:

[0086] This comparative example provides another compound preparation of Coral Recutita, which comprises the following Chinese medicinal materials in parts by weight: 37.5 parts of Sarcandra scabra, 15.5 parts of Honeysuckle, and 1 part of menthol. The preparation method uses steam distillation to extract volatile oil from the raw materials, specifically comprising the following steps:

[0087] (1) Pretreatment of medicinal materials: Separately select the medicinal materials of Sarcandra scabra and Flos Lonicerae, chop them into pieces, and obtain Sarcandra scabra decoction pieces and Flos Lonicerae decoction pieces.

[0088] (2) According to the prescription ratio, take the pieces of Radix Sarcandrae and Flos Lonicerae, soak them for 1 hour, add 3 times the weight of the pieces of water, steam distill for 3 hours, collect the volatile oil, the extract after distillation and the residue.

[0089] (3) Take the medicinal residue and heat it and boil it twice. The first time, add 10 times the weight of the medicinal piece of water and boil it for 1.5 hours. The second time, add 8 times the weight of the medicinal piece of water and boil it for 1 hour. Filter it to obtain the extract.

[0090] (4) Take the above extract, control the vacuum degree at -0.05~-0.09MPa, adjust the vapor pressure so that the concentration temperature is maintained at 60℃~70℃, and concentrate under reduced pressure to a clear paste with a relative density of 1.18. Filter while hot to obtain a clear paste.

[0091] (5) Take volatile oil and menthol, and carry out inclusion treatment in the same manner as step (5) of Example 1 to obtain an inclusion compound.

[0092] (6) Take the clear paste, inclusion compound and an appropriate amount of sucrose powder, mix them evenly, granulate them, dry them, set the drying air outlet temperature to 60°C to 70°C, and dry them for 15 to 30 minutes. Then, shape the particles, add an appropriate amount of magnesium stearate and an appropriate amount of talc, mix them, and press them into tablets to obtain the double flower coral compound preparation.

[0093] Comparative Example 2:

[0094] This comparative example provides another compound preparation of Herba Cyperi. Biflori, which comprises the following Chinese medicinal raw materials in parts by weight: 37.5 parts of Radix Sarcandrae, 15.5 parts of Flos Lonicerae, and 1 part of menthol. The preparation method does not extract volatile oil from the raw materials, and specifically comprises the following steps:

[0095] (1) Pretreatment of medicinal materials: Separately select the medicinal materials of Sarcandra scabra and Flos Lonicerae, chop them into pieces, and obtain Sarcandra scabra decoction pieces and Flos Lonicerae decoction pieces.

[0096] (2) According to the prescription ratio, take the slices of Radix Sarcandrae and Flos Lonicerae, heat and boil them twice, add 10 times the weight of the slices of water for the first time, boil for 2 hours, add 10 times the weight of the slices of water for the second time, boil for 1 hour, filter and obtain the extract.

[0097] (3) Take the above extract, control the vacuum degree at -0.05~-0.09MPa, adjust the vapor pressure so that the concentration temperature is maintained at 60℃~70℃, and concentrate under reduced pressure to a clear paste with a relative density of 1.18. Filter while hot to obtain a clear paste.

[0098] (4) Take appropriate amounts of sucrose powder and clear paste, mix them evenly, granulate them, dry them, set the drying air outlet temperature to 60°C to 70°C, and dry them for 15 to 30 minutes. Whole the granules, dissolve menthol in 3 times the weight of ethanol, spray it into the granules and mix them evenly, seal them overnight, add appropriate amounts of magnesium stearate and talc, mix them, and press them into tablets to obtain the double flower coral compound preparation.

[0099] Test Example 1:

[0100] In order to explore the effect of different raw material ratios treated by supercritical extraction and water extraction on the content of effective ingredients in the double flower coral compound preparation, this test example used high performance liquid chromatography to determine Examples 1 to 11 and Comparative Examples 1 to 2, respectively, to obtain the contents of isoflurane, chlorogenic acid and rosmarinic acid in the double flower coral compound preparation.

[0101] The determination was performed according to the high-performance liquid chromatography method specified in General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia. An Agilent 1100 high-performance liquid chromatograph was used, with an AQ C18 column (250 mm × 4.6 mm, 5 μm); the column temperature was 25°C; the mobile phase was acetonitrile (A)-0.2% formic acid solution (B); the gradient was 11% (A) from 0 to 20 minutes, 11% to 16% (A) from 20 to 32 minutes, and 16% to 28% (A) from 32 to 55 minutes. The detection wavelength was 320 nm.

[0102] Preparation of reference solution: Take appropriate amount of isoflurane, chlorogenic acid and rosmarinic acid reference substances, weigh accurately, and add 65% methanol to make a mixed reference solution with a concentration of 20 μg / ml each.

[0103] Preparation of test solution: Take 1 g of the test sample, accurately weigh it, place it in a stoppered conical flask, accurately add 25 ml of 65% methanol, stopper it, weigh it, ultrasonically treat it (400 W, frequency 24 kHz) for 30 minutes, let it cool, weigh it again, make up the lost weight with 65% methanol, shake it well, filter it, and obtain it.

[0104] Determination method: Accurately aspirate 10 μL of reference solution and test solution respectively, inject into liquid chromatograph and determine.

[0105] The preparations obtained in Examples 1 to 11 and Comparative Examples 1 to 2 (the final preparation amounts were the same) were analyzed and the contents of isoflurane, chlorogenic acid, and rosmarinic acid were determined and calculated using the above analytical methods. The results are shown in Tables 1 and 2 below.

[0106] Test Example 2:

[0107] To investigate the effects of different menthol addition methods on the active ingredient content in the Coral Recutita (Double Flower Grass) compound preparation, this test case measured the menthol content according to the menthol content determination item in Part I of the Chinese Pharmacopoeia (2020 edition). Furthermore, according to the Chinese Pharmacopoeia (2020 edition) General Chapter 9001, Stability Testing Guidelines for Active Pharmaceutical Ingredients and Preparations, the preparations were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months, and at a relative humidity of 30°C ± 2°C and 65% ± 5% for 2 years. The results are shown in Table 3 below.

[0108] Table 1

[0109]

[0110] Table 2

[0111]

[0112]

[0113] Table 3

[0114]

[0115] Extraction with different supercritical fluid ratios: From the results of Examples 1 to 4, it can be seen that when the ratio of the fluid used for supercritical carbon dioxide extraction of volatile oil is 10% and 30%, there is no significant difference in the volatile oil extraction rate and the content of isofraquinone, chlorogenic acid and rosmarinic acid. When the ratio of the fluid used is 50%, the volatile oil yield and the content of isofraquinone, chlorogenic acid and rosmarinic acid decrease slightly; when the ratio of the fluid used is 100%, the volatile oil yield decreases by about 8% compared with Example 2, and the content of isofraquinone, chlorogenic acid and rosmarinic acid decreases by about 11%. This may be because the larger the amount of fluid used for oil extraction, the more saturated the volatile oil is during supercritical extraction, and the extraction efficiency decreases. The main reason for the decrease in the content of isofraquinone, chlorogenic acid and rosmarinic acid is that when the amount of fluid used is large, the amount of component loss after supercritical extraction increases, and the very small amount of components contained in the volatile oil is not enough to make up for the loss, resulting in a relative decrease in the content transferred to the water extract. Based on the results of the above embodiments, a 30% ratio of decoction pieces was temporarily adopted for supercritical extraction to carry out subsequent process optimization.

[0116] Comparison of Different Types and Amounts of Excipients in the Extract: Comparison of the results of Examples 5, 6, 9, and 10 shows that the addition of either beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin to the extract significantly increased the contents of isofraquinone, chlorogenic acid, and rosmarinic acid. There was no significant difference between Example 9 and Example 10, indicating that the addition of sucrose to the extract had no significant effect on the contents of the above three components. Furthermore, it was found that the content of isofraquinone in Example 5 was approximately 7.0% higher than that in Example 6, while the content of chlorogenic acid in Example 6 was approximately 6.9% higher than that in Example 5. There was no significant difference in the content of rosmarinic acid between Examples 5 and 6, which may be due to the different inclusion effects of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin on different components. Considering the properties of the active ingredients in the formulation, beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin were mixed in a certain ratio and then added to the extract. According to Examples 7-8, as the amount of cyclodextrin added increased, the content of isofraquinone, chlorogenic acid, and rosmarinic acid in the extract also increased. When the cyclodextrin dosage reached 5%, the increase in the content of isofraquinone, chlorogenic acid, and rosmarinic acid tended to be gradual. Therefore, further increasing the amount of beta-cyclodextrin in the extract had no significant effect on increasing the content of these three ingredients. These results demonstrate that controlling the beta-cyclodextrin dosage to 1% to 5% can meet the principle of minimizing the amount of formulation excipients. Furthermore, it can greatly prevent the degradation of heat-sensitive ingredients due to heat. At the same time, the inclusion effect of beta-cyclodextrin can effectively include active ingredients with poor water solubility, thereby increasing the content of the active ingredients overall.

[0117] Different preparation methods, the difference between menthol content and preparation properties in the preparation is compared: by comparing Examples 2 and 11, the difference in the content of menthol in the two is not much, indicating that the two preparation methods are suitable for the utilization rate of menthol. Example 2, by inclusion, has no significant difference in the content, properties and disintegration of menthol when placed under high temperature conditions and normal temperature conditions, while Example 11, without inclusion, has a significant decrease in the menthol content when placed under high temperature conditions and normal temperature conditions for the corresponding time, and the preparation appearance color deepens, and white matter separates out. Thus, inclusion can effectively avoid the decrease in menthol content, prevent menthol from being susceptible to environmental influences during storage and causing crystallization and deterioration, thereby ensuring the stability of the preparation during storage and extending the preparation validity period.

[0118] Comparison of the quality of preparations prepared by different methods: The results of Example 2 and Comparative Example 1 show that the yield of volatile oil obtained by supercritical carbon dioxide extraction is significantly higher than that obtained by steam distillation. As can be seen from Example 2, Comparative Example 1, and Comparative Example 2, the contents of isofraquinone, chlorogenic acid, and rosmarinic acid in Example 2 are significantly higher than those in Comparative Examples 1 and 2. The isofraquinone content in the preparation obtained by extraction in Example 2 is approximately 38.6% higher than that in Comparative Example 1, while the chlorogenic acid and rosmarinic acid contents are 3.5 times and 1.7 times those in Comparative Example 2, respectively. The isofraquinone content in Example 2 is 2.2 times that of Comparative Example 1, while the chlorogenic acid and rosmarinic acid contents are 2.8 times and 1.9 times those in Comparative Example 1, respectively. This indicates that supercritical carbon dioxide extraction can effectively prevent the degradation of heat-sensitive components due to the long-term high temperature of steam distillation, and that the addition of beta-cyclodextrin inclusion to the extract can effectively retain the above-mentioned components. The menthol content in Example 2, Comparative Example 1, and Comparative Example 2 was comparable. However, as the storage time increased, the menthol content in Comparative Example 2 decreased significantly due to the influence of ambient temperature and humidity, and the color of the preparation darkened, with the precipitation of white matter. Thus, the inclusion of menthol in the preparation stage by beta-cyclodextrin followed by granulation and molding can effectively avoid a decrease in menthol content compared to directly spraying menthol into the granules and then molding. The shelf life of Examples 2 and 11 and Comparative Examples 1 and 2 shows that the shelf life of the menthol preparation with beta-cyclodextrin can reach 3 years when stored at room temperature.

[0119] 150 patients with pharyngeal discomfort were selected and randomly divided into 4 groups for efficacy test. The symptoms of the 150 patients were: dry and itchy throat, swelling and pain, cough with sputum, hoarseness or aphonia, and foreign body sensation in the throat.

[0120] The efficacy test was conducted after preparation according to Example 2, Comparative Example 1 and Comparative Example 2, and the evaluation criteria were as follows:

[0121] Clinical recovery: Pharyngeal symptoms are relieved within 3 days of medication and signs disappear within 1 week.

[0122] Markedly effective: Pharyngeal symptoms were significantly alleviated within 1 week, and most signs disappeared.

[0123] Effective: Symptoms are alleviated and some signs disappear within 1 week.

[0124] Ineffective: There was no significant improvement in pharyngeal symptoms.

[0125] Treatment outcomes can be categorized as cure, marked effect, effectiveness, and ineffectiveness. A cure refers to an efficacy index greater than or equal to 95% after treatment, with no recurrence within one month of discontinuation; a marked effect refers to an efficacy index less than 95% but greater than or equal to 70% after treatment; an effectiveness refers to an efficacy index greater than or equal to 30% but less than 70% after treatment; and an ineffectiveness refers to an efficacy index less than 30% after treatment. The total number of effective cases = cured cases + marked effect cases + effective cases.

[0126] The comparison of the above efficacy test results is shown in Table 4 below.

[0127] Table 4

[0128] Experiment number Number of cases invalid efficient Significantly effective get well Total efficiency Example 2 50 2 10 25 13 96％ Comparative Example 1 50 5 15 21 9 90％ Comparative Example 2 50 7 19 18 6 86％

[0129] By analyzing the efficacy test results of Example 2, Comparative Example 1 and Comparative Example 2, it can be seen that the throat-relieving Chinese medicine preparations prepared in the above Examples and Comparative Examples all have the effects of dispelling wind and relieving heat, relieving throat pain and relieving pain. The total effective rate results are in the order of Example 2 > Comparative Example 1 > Comparative Example 2, indicating that the present invention can better synergize the effective ingredients to exert the drug efficacy after optimizing the prescription preparation process.

[0130] Finally, it should be noted that the above is only used to illustrate the technical solution of the present invention and is not limiting. Although the present invention is described in detail with reference to the preferred arrangement scheme, ordinary technicians in this field should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for preparing a compound preparation of Coral Recutita, comprising the following Chinese medicinal materials in parts by weight: 30-40 parts of Sarcandra scabra, 10-20 parts of Honeysuckle, and 0.1-2 parts of menthol, characterized in that: The preparation method comprises the following steps: (1) Pretreatment of medicinal materials: Pre-treatment of medicinal materials for water extraction: clean and select the medicinal materials of Sarcandra scabra and Flos Lonicerae respectively, chop them into pieces, and obtain the medicinal pieces for water extraction; Pre-treatment of medicinal materials for supercritical fluid: clean and select Radix Sarcandrae and Flos Lonicerae respectively, crush them, and pass them through a 10-30 mesh sieve to obtain coarse powder for supercritical fluid; (2) taking coarse powder of Sarcandra scabra supercritical and coarse powder of Flos Lonicerae supercritical and mixing them, adding them into a supercritical carbon dioxide extraction tank, performing supercritical extraction, and collecting volatile oil and the extracted medicinal residues; (3) taking the water-extracted slices of Radix Scutellariae and the water-extracted slices of Flos Lonicerae, as well as the residues after supercritical extraction obtained in step (2), adding water and boiling them twice, adding water 8 to 15 times the weight of the slices for the first time, boiling them for 1 to 2 hours, and adding water 5 to 10 times the weight of the slices for the second time, boiling them for 0.5 to 1.5 hours, combining the decoctions, filtering, and preparing an extract; (4) Take the above extract, add a mixture of 1% to 5% of the amount of the decoction piece of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin while it is hot, mix and dissolve, and continue to stir and include for 20 to 40 minutes; pump the liquid into a self-circulating vacuum concentrator, continue the inclusion treatment while decompressing and concentrating, and wait until the liquid is concentrated to a clear paste with a relative density of 1.05 to 1.30, filter it while it is hot, and obtain a clear paste; (5) Inclusion treatment: The volatile oil and the Chinese medicinal raw material menthol prepared in step (2) are added with ethanol in an amount of 2 to 5 times the weight of the two, and stirred to fully dissolve them, thereby preparing an ethanol mixture of the volatile oil and menthol; Take volatile oil and menthol 5 to 10 times the weight of beta-cyclodextrin, then add water 3 to 5 times the weight of beta-cyclodextrin, mix, stir at 40 to 50° C. to dissolve, to prepare a beta-cyclodextrin solution; Transfer the beta-cyclodextrin solution to a stirrer with a constant temperature function, maintain constant temperature at 40-50°C with stirring, and slowly and uniformly add the ethanol mixture of the volatile oil and menthol dropwise. Continue constant temperature stirring for 1-3 hours to obtain the beta-cyclodextrin inclusion solution, place it at 2-8°C for 8-12 hours, and filter it to obtain the inclusion compound; (6) Take sucrose powder, clear paste and inclusion compound, mix them evenly, granulate them, dry them, shape them into whole particles, and compress them into tablets to obtain the said double flower coral compound preparation.

2. The preparation method according to claim 1, characterized in that In step (1), the weight ratio of the medicinal materials for water extraction to the medicinal materials for supercritical fluid extraction is 3:

7.

3. The preparation method according to claim 1, characterized in that In step (2), the supercritical extraction conditions are: temperature 30-40° C., extraction pressure 15-25 MPa, carbon dioxide flow rate 20-30 L / h, and extraction time 1.0-2.0 h.

4. The preparation method according to claim 1, characterized in that In step (4), in the mixture of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin, the weight ratio of beta-cyclodextrin to hydroxypropyl-beta-cyclodextrin is 1:1-2.

5. The preparation method according to claim 1, characterized in that In step (4), the vacuum degree in the self-circulating vacuum concentrator is controlled at -0.05 to -0.09 MPa, and the vapor pressure is adjusted to maintain the concentration temperature at 60 to 70° C. During the concentration process, the drug solution is kept in a continuous circulation state to promote continued inclusion of the components.

6. The preparation method according to claim 1, characterized in that In step (6), the drying treatment conditions include: the air outlet temperature is set to 60-70° C., and the drying time is 15-30 minutes.

7. The preparation method according to claim 1, characterized in that In step (6), magnesium stearate and talc are added after granulation, and tableting is completed after mixing.

8. A compound preparation of Herba Cynanchifoliae prepared by the method according to any one of claims 1 to 7.

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