Preparation method of oral drops of pediatric lung-clearing composition

Abstract

The present invention discloses a preparation method for oral drops of a pediatric lung-clearing composition, belonging to the field of pharmaceutical technology. The method comprises the following steps: pulverizing ephedra and subjecting it to heated ultrasonic alcohol extraction to obtain a concentrated solution; pulverizing the remaining drugs, adding water, heating to 70-85°C, and subjecting it to ultrasonic extraction; adding ethanol to the concentrated solution extracted from the remaining drugs, stirring and layering, and obtaining a supernatant; combining the supernatants of the ephedra concentrated solutions and treating them with a clarifier to obtain an impurity-removed concentrated solution; and encapsulating the impurity-removed concentrated solution with cyclodextrin to obtain the pediatric lung-clearing oral drops. The method solves the problems of low extraction rate of effective substances, high impurities, and difficulty in removing impurities in the extraction and preparation of existing traditional Chinese medicines.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceuticals, and in particular to a method for preparing oral drops of a pediatric lung-clearing composition. Background Art

[0002] The statements herein merely provide background information related to the present invention and do not necessarily constitute prior art.

[0003] Children's colds are a common and frequent disease among children, but children are young and have difficulty taking medicine. Currently, the common traditional Chinese medicines for treating children's colds and coughs are mostly granules, oral liquids, and syrups. In order to achieve the effect of treating the disease, a large dosage is often required. Granules need to be taken with a large amount of water. The common specifications of oral liquids are 5-10 ml. Syrups have the side effect of causing tooth decay, and the dosage is generally more than 5 ml. In addition, traditional Chinese medicine preparations have a special taste, which is poorly accepted by children and difficult to take.

[0004] Patent No. CN 102302647A discloses a traditional Chinese medicine composition for clearing away lung heat and resolving phlegm in children, and its preparation method. It is used for clearing away lung heat and resolving phlegm, and has good effects on treating children's exogenous cough, cough with excessive phlegm, yellow and sticky phlegm, and uncomfortable phlegm caused by phlegm-heat blocking the lungs. The preparation method of this scheme is used to prepare granules, oral liquids, syrups, etc. of this prescription by reflux extraction.

[0005] The dosage of drops is small, children have a high acceptance rate, and they are easy to swallow. However, the inventors found that existing Chinese medicine drops are often used externally, and the inventors did not retrieve the preparation of oral Chinese medicine drops. This is because the extraction and preparation of Chinese medicines have many impurities, the concentration of active ingredients is reduced after impurities are removed, and a large dosage is required to achieve an effective concentration. In addition, there are problems such as the density of the extract increases after concentration, it is difficult to control the amount of drops to be added, the mouth feels sticky, and the compliance of the mouth is poor after the drug load is increased. Summary of the Invention

[0006] In view of the deficiencies in the prior art, the purpose of the embodiments of the present invention is to provide a method for preparing oral drops of a pediatric Xuanfei composition, which at least solves one of the above problems.

[0007] In order to achieve the above objectives, the embodiments of the present invention provide the following technical solutions:

[0008] A preparation method of oral drops of a pediatric lung-clearing composition,

[0009] The composition of the pediatric lung-clearing composition is composed of ephedra, saposhnikovia root, scutellaria baicalensis, platycodon grandiflorum, mustard seeds, bitter almonds, scutellaria baicalensis seeds, amaranth, astragalus root, yam, hawthorn and liquorice;

[0010] The method comprises:

[0011] Step 1: Powder ephedra, add ethanol water solution, heat to 75-85°C, perform ultrasonic extraction, filter, and concentrate to obtain concentrated solution A;

[0012] Step 2: Powder the remaining drugs, add water, heat to 70-85°C, perform ultrasonic extraction, filter, and concentrate to obtain concentrated solution B1;

[0013] Step 3: Add ethanol to the concentrated solution B1, stir thoroughly, and allow to stand for stratification to obtain a supernatant, thereby obtaining the concentrated solution B2;

[0014] Step 4: Combine the concentrate A and the concentrate B2 to obtain a concentrate C1, treat the concentrate C1 with a clarifier, let it stand, centrifuge, and collect the supernatant to obtain the impurity-removed concentrate C2;

[0015] Step 5: Use cyclodextrin to encapsulate the impurity-removed concentrated solution C2 to obtain pediatric Xuanfei oral drops.

[0016] The technical solution of the present invention improves the extraction rates of ephedrine hydrochloride and pseudoephedrine hydrochloride by performing ultrasonic alcohol extraction on ephedra, and performs ultrasonic water extraction on other drugs at a temperature of 70-85°C. Under the premise of reducing the dissolution of impurities, the transfer rate of effective substances such as baicalin is improved, and the dry paste rate is reduced. At the same time, at the above temperature, the dissolution of impurities in the medicinal materials can also be reduced, which is more conducive to subsequent impurity removal and improves the retention rate of effective substances in the impurity removal process.

[0017] In some embodiments, in step 1, the volume fraction of ethanol in the ethanol aqueous solution is 70-85%, preferably 80%.

[0018] In some embodiments, in step 1, ultrasonic extraction is performed twice, with 8-9 times of water added for the first time and ultrasonic extraction for 1 hour to 1.5 hours, and 5-6 times of water added for the second time and ultrasonic extraction for 45 minutes to 1 hour.

[0019] In some embodiments, in step 1, the density of the concentrated solution A obtained by concentration is 1.05-1.10.

[0020] In some embodiments, in step 2, ultrasonic extraction is performed twice, with 5-6 times water added and ultrasonication performed for 1 hour to 1.5 hours for the first extraction, and 5-6 times water added and ultrasonication performed for 45 minutes to 1 hour for the second extraction.

[0021] In some embodiments, in step 2, the southwestern scutellaria baicalensis is added when the mixture is heated to 70-85°C.

[0022] In some embodiments, in step 1, the density of the concentrated solution B1 obtained by concentration is 1.05-1.10.

[0023] In some embodiments, the ultrasonic extraction power in step 1 and step 2 is 280-320W, preferably 300W.

[0024] In some embodiments, in step 3, ethanol is added to the concentrated solution B1 until the ethanol volume fraction reaches 50-70%, preferably 60%, for alcohol precipitation.

[0025] In some embodiments, the clarifier is a ZTC1+1 clarifier, and the ZTC1+1 clarifier is mixed evenly with the concentrated solution C1, allowed to stand, centrifuged, and the supernatant is collected to obtain the impurity-removed concentrated solution C2.

[0026] In some embodiments, the ZTC1+1 clarifier includes component A and component B, and is prepared by the following steps: the mass concentration of component A and component B is 1%.

[0027] In some embodiments, in step 4, the temperature of the concentrated solution C1 is maintained at 75-85° C., and a 1% by mass concentration of ZTC1+1 clarifier component B is added to the concentrated solution C1, where the volume of component B is 4% of the volume of the concentrated solution C1. The mixture is mixed evenly and allowed to stand at 75-85° C. for 2-2.5 hours. Then, a 1% by mass concentration of ZTC1+1 clarifier component A is added, where the volume of component A is 2.0-3.0% of the volume of the concentrated solution C1. The mixture is mixed evenly and allowed to stand at room temperature for 2-2.5 hours.

[0028] In some embodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0029] In some embodiments, 2% to 4% by mass of hydroxypropyl-β-cyclodextrin is added to the impurity-removed concentrated solution C2 for inclusion.

[0030] In some embodiments, strawberry flavor, orange flavor, or lemon flavor is added after inclusion.

[0031] In some embodiments, the pediatric lung-clearing composition is 56.18g of ephedra, 112.36g of saposhnikovia divaricata, 112.36g of southwestern scutellaria, 56.18g of platycodon, 56.18g of mustard seeds, 56.18g of bitter almonds, 56.18g of scutellaria baicalensis, 112.36g of amaranth, 112.36g of astragalus, 56.18g of yam, 112.36g of hawthorn, and 56.18g of licorice.

[0032] One or more technical solutions provided in the embodiments of the present invention have at least the following technical effects or advantages:

[0033] 1. The technical solution of the present invention improves the extraction rate of effective substances such as baicalin and ephedrine while reducing the dissolution of impurities, thereby reducing the dry paste rate, reducing the dosage and consistency of the drops, and lowering the extraction temperature, which can also reduce the dissolution of impurities in the medicinal materials. This temperature can also reduce starch gelatinization, facilitating subsequent impurity removal. Combined with the impurity removal process, the drops remain clear, the retention rate of effective substances during the impurity removal process is improved, and the density of effective substances in the drops is increased. The obtained drops have fewer impurities and poor compliance in children.

[0034] 2. Compared with granules, oral liquids, etc., the oral drops used in the present invention have a small dosage and are easy to take. The increased density allows the drug to stay in the lesion longer and has a better cough-relieving effect. Only 1ml-3ml of drops are needed each time to achieve the effective drug loading amount, solving the problem of difficulty in children taking medicine.

[0035] 3. The present invention determines the optimal extraction process through pharmacological experimental screening; in the preparation process, the cyclodextrin inclusion technology is used to overcome the problems of turbid solution and large component loss after the alcohol sediment is added with water, so that the obtained drops are clear and transparent, with a sweet and sour taste and a fresh and fragrant smell. DETAILED DESCRIPTION

[0036] It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0037] As described in the background, existing pediatric Xuanfei granules are available in granules, oral liquids, and syrups. These formulations, however, suffer from high dosage requirements and poor taste, making them difficult for children to accept and take. The following issues arise when using existing extraction methods for pediatric Xuanfei granules to prepare drops: The original extraction process contains numerous impurities, making it difficult to maintain clarity in the drops. After impurity removal, the active ingredient level is reduced, preventing the cough suppressant effect. The high density makes it difficult to control the dosage, resulting in a sticky taste. Furthermore, increasing the drug loading results in a bitter taste, leading to poor compliance in children.

[0038] In order to solve the above technical problems, the present invention proposes a preparation method of pediatric Xuanfei oral drops, wherein the pediatric Xuanfei composition is composed of 561.8g of ephedra, 1123.6g of bamboo leaf siler, 1123.6g of southwestern scutellaria, 561.8g of platycodon, 561.8g of mustard seeds, 561.8g of bitter almonds, 561.8g of scutellaria seeds, 1123.6g of amaranth, 1123.6g of astragalus, 561.8g of yam, 1123.6g of hawthorn, and 561.8g of liquorice;

[0039] The method comprises:

[0040] Ephedra was pulverized and extracted with ultrasound at 80°C for two times. For the first extraction, 80% ethanol aqueous solution was added in 8-9 times the amount and ultrasound was applied at 300W for 1h-1.5h. For the second extraction, 5-6 times the amount of water was added and ultrasound was applied for 45min-1h. The extract was filtered, the filtrates were combined, and the extract was concentrated to a density of 1.05-1.10 (80°C) to obtain concentrated solution A. The remaining eleven medicinal materials were pulverized, drinking water was added, and ultrasound was applied at 80°C and 300W for two times. Among them, southwestern scutellaria was added after the temperature was raised to 80°C. For the first extraction, 5-6 times the amount of water was added and ultrasound was applied for 1h-1.5h. For the second extraction, 5-6 times the amount of water was added and ultrasound was applied for 45min-1h. The extract was filtered, the filtrates were combined, and the extract was concentrated to a density of 1.05-1.10 (80°C) to obtain concentrated solution B1 for later use.

[0041] Add ethanol to the concentrated solution B1 to make the volume fraction of ethanol reach 60%, stir thoroughly, let it stand for 24 hours, take the supernatant and concentrate it under reduced pressure to a density of 1.10-1.15 (80℃), and obtain the concentrated solution B2 for use.

[0042] Combine the concentrated solutions A and B2, keep warm at 80°C, then add 1% ZTC1+1 clarifier component B, stir until the mixture is uniformly mixed, and let it stand at a constant temperature of 80°C for 2-2.5 hours; wherein, the volume amount of 1% ZTC1+1 clarifier component B is 4% of the volume of the liquid; after the standing is completed, add 1% ZTC1+1 clarifier component A, stir until the mixture is uniformly mixed, and let it stand at room temperature for 2-2.5 hours; wherein, the volume amount of 1% ZTC1+1 clarifier component A is 2.0-3.0% of the volume of the liquid; after the standing is completed, cool to room temperature, centrifuge, and collect the supernatant.

[0043] Take the above-mentioned impurity-removed concentrated paste, add 2% to 4% by weight of hydroxypropyl-β-cyclodextrin, incorporate at 60°C for 2 hours, add 2g of strawberry essence / 1.5g of orange essence / 1g of lemon essence, 4g of stevioside, and 0.3g of ethyl hydroxybenzoate, add 90°C hot water to 1000ml, refrigerate for 72 hours, and take the supernatant to obtain the finished product.

[0044] In order to enable those skilled in the art to more clearly understand the technical solution of the present disclosure, the technical solution of the present disclosure will be described in detail below in combination with specific embodiments and comparative examples, and the present invention will be further described in detail in combination with specific embodiments. It should be pointed out that the specific embodiments are for explanation rather than limitation of the present invention.

[0045] Example 1

[0046] The pediatric lung-clearing prescription used in this embodiment is 56.18g of ephedra, 112.36g of saposhnikovia divaricata, 112.36g of southwestern scutellaria, 56.18g of platycodon, 56.18g of mustard seeds, 56.18g of bitter almonds, 56.18g of scutellaria baicalensis, 112.36g of amaranth, 112.36g of astragalus, 56.18g of yam, 112.36g of hawthorn, and 56.18g of liquorice.

[0047] The inventors analyzed the chemical components of the Chinese medicinal materials in the prescription and combined existing literature to identify ephedrine, chromones from fangfeng, platycodon polysaccharides, astragalus polysaccharides, yam polysaccharides, flavonoids from hawthorn, baicalin, sinigrin, amygdalin, flavonoids from scutellaria baicalensis seeds, and flavonoids from amaranth as the main active ingredients. Based on the physicochemical properties and pharmacological effects of the active ingredients in each herb, an extraction process was studied and the following process was designed:

[0048] Process 1: Powder the whole medicinal materials and extract with water for 3 times, each time for 1 hour, with the amount of water added being 8 times, 7 times, and 7 times. The extract is concentrated under reduced pressure, and ethanol is added to make the alcohol content reach 60%. Alcohol precipitation is carried out, and the extract is allowed to stand for 24 hours and filtered. The three filtrates are combined to obtain an extract. The extract is concentrated under reduced pressure at 80℃ to obtain a thick paste, and the relative density is controlled to be 1.08.

[0049] Process 2: Grind the whole medicinal materials into powder and extract with 70% ethanol, extract for 3 times, each time for 1 hour, add 8 times, 7 times and 7 times the amount of alcohol, filter, and concentrate the alcohol extract at 70℃ under reduced pressure to obtain a thick paste, add 3 times the amount of water of the thick paste, precipitate with water, let it stand for 24 hours, filter, combine the three filtrates to obtain an extract, and concentrate the extract under reduced pressure to obtain a thick paste, and control the relative density to be 1.08.

[0050] Process 3: Powder ephedra and extract with 80% ethanol under reflux twice, first with 8x water for 1 hour, then with 6x water for 45 minutes. Collect the filtrates, combine the two filtrates to obtain Extract A, and concentrate to a density of 1.08 (80°C). The remaining eleven herbs are extracted with warm water at 90°C, first with 5x water for 1 hour, then with 5x water for 45 minutes. Filter the aqueous extracts, combine the filtrates, and obtain an extract. This extract is concentrated under reduced pressure to a density of 1.08 (80°C). Ethanol is added to bring the alcohol content to 60%, followed by alcohol precipitation. The mixture is allowed to stand for 24 hours and filtered. The precipitate is then concentrated under reduced pressure to a thick paste with a density of 1.08 (80°C). The two concentrates are combined to obtain a mixed concentrated paste.

[0051] Process 4: Pulverize ephedra and extract with ultrasonic wave at 80℃, extract twice, add 8 times of water for the first time, ultrasonic wave at 300w for 1h, add 5 times of water for the second time, ultrasonic wave for 45min, filter the extract, combine the filtrate to obtain the extract, and concentrate the extract under reduced pressure to a density of 1.08 (80℃) to obtain concentrated solution A.

[0052] Powder the remaining eleven herbs, add drinking water, and extract twice at 80°C using 300W ultrasonic technology. For the first extraction, add 5x more water and ultrasonicate for 1 hour. For the second extraction, add 5x more water and ultrasonicate for 45 minutes. Filter the extracts, combine the filtrates, and obtain an extract. Concentrate the extract under reduced pressure to a density of 1.08 (80°C). This concentrate, B1, is set aside.

[0053] Add ethanol to the concentrated solution B1 to make the volume fraction of ethanol 60%, stir thoroughly, let it stand for 24 hours, take the supernatant and concentrate it under reduced pressure to a density of 1.08 (80℃), and obtain the concentrated solution B2 for use.

[0054] The concentrated solution A and the concentrated solution B2 are mixed to obtain a concentrated paste C.

[0055] Process 5: Pulverize ephedra and extract with ultrasonic wave at 80℃, extract twice, add 8 times of water for the first time, ultrasonic wave at 300w for 1h, add 5-6 times of water for the second time, ultrasonic wave for 45min, filter the extract, combine the filtrate to obtain the extract, and concentrate the extract under reduced pressure to a density of 1.08 (80℃) to obtain concentrated solution A.

[0056] The remaining eleven herbs were ground into powder and extracted twice with drinking water at 80°C and 300W ultrasonication. The southwestern scutellaria baicalensis was added after the temperature reached 80°C. The first extraction was performed with 5x water and ultrasonication for 1 hour. The second extraction was performed with 5x water and ultrasonication for 45 minutes. The extracts were filtered, and the filtrates were combined to obtain an extract. The extract was then concentrated under reduced pressure to a density of 1.08 (80°C). This concentrate, B1, was set aside.

[0057] Add ethanol to the concentrated solution B1 to make the volume fraction of ethanol 60%, stir thoroughly, let it stand for 24 hours, take the supernatant and concentrate it under reduced pressure to a density of 1.08 (80℃), and obtain the concentrated solution B2 for use.

[0058] The concentrated solution A and the concentrated solution B2 are mixed to obtain a concentrated paste C.

[0059] The extracts obtained from processes 1 to 5 above were tested

[0060] The following measurements were performed on the extracts obtained by the above four processes, using the transfer rates of baicalin, ephedrine hydrochloride, pseudoephedrine hydrochloride, and the dry-to-paste ratio of the extracts as evaluation criteria:

[0061] 1. The finished product is quantitatively analyzed for baicalin in accordance with the content determination under the item of Xiaoer Xuanfei Zhike Granules in the "National Drug Standard" issued by the State Food and Drug Administration.

[0062] The determination method of Scutellaria baicalensis is based on the high performance liquid chromatography method (Appendix VID of Part I of the 2010 edition of the Chinese Pharmacopoeia), specifically:

[0063] (1) Chromatographic conditions and system suitability test

[0064] Octadecylsilane bonded silica gel was used as the filler, and acetonitrile-0.05 mol / L potassium dihydrogen phosphate buffer solution (pH 3.5) was used to accurately weigh 6.8050 g of potassium dihydrogen phosphate powder dried to a constant weight, placed in a 1000 ml volumetric flask, dissolved with an appropriate amount of water and diluted to nearly the scale, added 0.5 ml of phosphoric acid, added water to the scale, shook well, and stored in a refrigerator for later use (24:76) as the mobile phase; the detection wavelength was 275 nm.

[0065] (2) Preparation of reference solution

[0066] Accurately weigh an appropriate amount of Scutellaria baicalensis reference substance and add 50% ethanol to make a solution containing 0.1 mg per 1 ml.

[0067] (3) Preparation of test solution

[0068] Take 1 ml of each of the extracts prepared by the above five processes, accurately add 25 ml of 50% ethanol, ultrasonically treat (power 250 W, frequency 20 kHz) for 20 minutes, filter, and take the filtrate to obtain the product.

[0069] (4) Determination method

[0070] Accurately pipette 10 ml of reference solution and test solution respectively, inject into liquid chromatograph, and measure to obtain the result.

[0071] 2. The finished product shall be quantitatively analyzed for ephedrine hydrochloride and pseudoephedrine hydrochloride in accordance with the content determination under the item of Children's Xuanfei Zhike Granules in the "National Drug Standard" issued by the State Food and Drug Administration.

[0072] The determination method of Ephedra is based on the high performance liquid chromatography method (Appendix VID of Part I of the Chinese Pharmacopoeia 2010 Edition), specifically:

[0073] (1) Chromatographic conditions and system suitability test

[0074] Polar ether-linked phenyl-bonded silica gel was used as the filler; the mobile phase was methanol-0.092% phosphoric acid solution (containing 0.04% triethylamine and 0.02% di-n-butylamine) (1.5:98.5); the detection wavelength was 210 nm. The theoretical plate number, calculated based on the ephedrine hydrochloride peak, should be no less than 3000.

[0075] (2) Preparation of reference solution

[0076] Take appropriate amounts of ephedrine hydrochloride reference substance and pseudoephedrine hydrochloride reference substance, accurately weigh them, and add methanol to prepare mixed solutions containing 40 μg of each per 1 ml.

[0077] (3) Preparation of test solution

[0078] Take 1 ml of each of the extracts prepared by the above five processes, plug them into conical flasks respectively, accurately add 50 ml of 1.44% phosphoric acid solution, weigh the weight, ultrasonically treat (power 600 W, frequency 50 kHz) for 20 minutes, let cool, weigh again, make up the lost weight with 1.44% phosphoric acid solution, shake well, filter, and take the filtrate to obtain.

[0079] (4) Determination method

[0080] Accurately pipette 10 μl of reference solution and test solution respectively, inject into liquid chromatograph and measure to obtain the result.

[0081] 3. Determination of the dry paste rate of process 3 to process 5 extracts

[0082] Accurately measure 50 ml of the extracts from process three to process five, place them in an evaporating dish that has been dried to constant weight, evaporate to dryness on a water bath, dry at 105°C for 3 hours, transfer to a desiccator, cool for 30 minutes, and quickly and accurately weigh.

[0083] Dry cream rate calculation formula: Dry cream rate (%) = (weighed dry cream weight 50 Extract volume / herbal material weight) 100%

[0084] Table 1 Effective substance transfer rates obtained from the extracts of different processes

[0085]

[0086] Table 2 Dry paste rate of extracts from different processes

[0087]

[0088] According to Table 1 and Table 2, compared with other processes, the concentrated plaster liquid extracted by process four and process five has a high content of active ingredients, a low dry paste rate, and a greatly improved clarity. Among them, process four and process five are the best. This may be because the ultrasonic water extraction and alcohol extraction of the medicinal materials increase the extraction rate of the active ingredients in the medicinal materials. At the same time, by lowering the temperature, the dissolution of impurities such as protein, tannic acid, and polysaccharides in the medicinal materials is prevented, which also facilitates subsequent impurity removal.

[0089] In process five, southwestern scutellaria baicalensis is added after the predetermined temperature is reached in order to effectively kill the relevant enzymes in southwestern scutellaria baicalensis and prevent the enzymes from decomposing baicalin and causing the reduction of the effective ingredients.

[0090] Example 2

[0091] To explore the optimal extraction temperature and time for medicinal herbs other than ephedra, this example compared the temperature and extraction efficiency of ultrasonic water extraction for each medicinal herb in process 4. This example compared the ultrasonic water extraction temperatures and extraction efficiency of 11 medicinal herbs other than ephedra at 65-90°C. The baicalin transfer rate, the total ephedrine transfer rate (ephedrine hydrochloride + pseudoephedrine hydrochloride transfer rate), and the dry extract yield were measured according to the method in Example 1. Specific process parameters and data are as follows.

[0092] The above data were weighted and evaluated to obtain the best extraction process. Weighted score calculation formula: Weighted score = Baicalin transfer rate 0.25+ total ephedrine transfer rate 0.25+ (100-Ephedra dry paste rate) 0.25+ (100-dry paste rate of eleven medicinal herbs) 0.25

[0093] Table 3

[0094] The effective substance transfer rate and dry cream rate of the extract obtained under different extraction parameters in Example 2

[0095]

[0096] From the data in Table 3, it can be seen that when the extraction temperature of the other medicinal materials except ephedra is 75-85℃, they have a better extraction rate, a low dry paste rate, and better impurity control, among which the best temperature is 80℃.

[0097] Example 2

[0098] This example compares the antitussive effects of concentrated pastes prepared by process three, process four, and process five, and further screens the preparation processes.

[0099] Pharmacological screening

[0100] 1. Objective: To compare the antitussive effects of pediatric lung-expelling and cough-relieving compositions with different preparation processes on coughing mice.

[0101] 2. Instruments and Materials

[0102] 2.1 Animals

[0103] 80 SPF KM mice aged 8-9 weeks, half male and half female, weighing 20-22 g.

[0104] 2.2 Medicinal materials and reagents

[0105] The mixed concentrated paste prepared by process three, the mixed concentrated paste prepared by process four, the mixed concentrated paste prepared by process five, ammonia water, physiological saline, absorbent cotton and plastic wrap.

[0106] 3. Methods:

[0107] 3.1 Grouping and processing

[0108] After the mice were adaptively cultured for 7 days, they were randomly divided into a control group, a treatment group 1, a treatment group 2, and a treatment group 3, with 20 mice in each group. The treatment group 1 was treated with the concentrated cream obtained by process 3 in Example 1, the treatment group 2 was treated with the concentrated cream C obtained by process 4 in Example 1, and the treatment group 3 was treated with the concentrated cream C obtained by process 5 in Example 1. Specifically, the drug was administered orally daily at a dose of 1 g / kg. -1 The mice were gavaged with the same amount of saline for 7 consecutive days.

[0109] 3.2 Ammonia-induced cough test

[0110] Mice were fasted for 12 hours but not water. One hour after the last oral gavage, mice from each group were placed one by one into a 1000 mL beaker. A 1 mL syringe was used to draw 0.2 mL of ammonia solution at a time and injected into a cotton ball. The bottle was closed and a stopwatch was used to time the number of coughs (times) and cough latency (s) within 60 seconds.

[0111] The symptoms of coughing are: coughing sounds when opening the mouth wide or narrow, and abdominal muscle contraction can be seen.

[0112] 4 Results

[0113] Table 4 Number of coughs and cough latency within 60 seconds in mice treated with different methods

[0114]

[0115] Table 4 shows the effects of different preparation processes of the pediatric lung-clearing and cough-relieving composition on the ammonia-induced cough test in mice. The results show that compared with the blank control group, the medicinal solutions obtained by different preparation processes of the pediatric lung-clearing and cough-relieving composition were able to significantly prolong the cough latency period of mice and significantly reduce the number of coughs in mice (P<0.05). Compared with treatment group 1, the cough latency period of mice in treatment groups 2 and 3 was prolonged and the number of coughs was reduced, with significant differences (P<0.05), indicating that the concentrated ointments obtained by processes 4 and 5 were significantly more effective than those obtained by process 3.

[0116] Example 3

[0117] The preparations obtained by process 4 and process 5 have the best pharmacological effects, but there are still problems with the concentrated paste being turbid in color and a large amount of precipitation appearing after long-term storage. In addition, the chlorophyll brought by the ephedra extract makes the liquid system unstable and prone to discoloration, and the viscous drop mixed precipitate is difficult for children to accept. To solve the above problems, the concentrated paste needs to be cleaned for the next step of preparation. Therefore, taking process 5 of Example 1 as an example, the concentrated paste C obtained by process 5 was subjected to impurity removal.

[0118] As a new type of food additive, ZTC1+1 natural clarifier is a natural high molecular compound that mainly removes unstable colloid components such as tannins, proteins, and waxes. It has no effect on the effective ingredients of traditional Chinese medicine such as flavonoids, alkaloids, saponins, polysaccharides, vitamins, and minerals. It has good thermal stability and is safe and non-toxic. In the impurity removal process, the use of natural clarifier is compared with the traditional impurity removal process.

[0119] The concentrated pastes in the following comparative examples are all concentrated paste C obtained by process five of Example 1.

[0120] Comparative Example 1: 2% by weight of activated carbon was added to the concentrated paste, and the mixture was decolorized by ultrasonication at 60° C. for 2 h, and the supernatant was filtered.

[0121] Comparative Example 2: The concentrated paste was centrifuged at 10,000 rpm for 10 minutes to obtain the supernatant.

[0122] Comparative Example 3: The concentrated paste was kept warm at 80°C, and then 1% of ZTC1+1 clarifier component B was added, stirred until mixed, and then allowed to stand at a constant temperature of 80°C for 2 hours; wherein, the volume dosage of 1% of ZTC1+1 clarifier component B was 4% of the volume of the liquid; after standing, 1% of ZTC1+1 clarifier component A was added, stirred until mixed, and allowed to stand at room temperature for 2 hours; wherein, the volume dosage of 1% of ZTC1+1 clarifier component A was 3.0% of the volume of the liquid. After standing, the mixture was cooled to room temperature, centrifuged, and the supernatant was collected.

[0123] Table 5 Effect of ZTC1+1 clarifier on concentrated paste

[0124]

[0125] As shown in Table 5, the use of activated carbon will cause the loss of active ingredients. Simple centrifugation can retain the active ingredients, but cannot completely remove impurities in the liquid medicine. The combination of ZTC1+1 and centrifugation can effectively remove impurities and retain active ingredients.

[0126] Example 4

[0127] The supernatant obtained in Example 3 needs to be replenished with water. Due to the alcohol precipitation process, precipitates will be produced after replenishment, making the medicine turbid and bitter. This is because the concentration causes the low water-soluble components in the aqueous solution to be supersaturated and precipitated. To solve the above problem, the inventors chose to use hydroxypropyl-β-cyclodextrin inclusion alcohol precipitation concentrated paste to increase solubility and mask part of the bitterness.

[0128] The specific steps are as follows:

[0129] The supernatant obtained in Example 3 was added with hydroxypropyl-β-cyclodextrin and stirred at 60° C. for 2 h. The amount of cyclodextrin used is shown in Table 6. The mixture was then filled with water to 100 ml and allowed to stand to collect the supernatant.

[0130] Table 6 Screening of hydroxypropyl-β-cyclodextrin dosage

[0131]

[0132] As shown in Table 6, the inclusion effect of hydroxypropyl-β-cyclodextrin added at 2%-4% by weight of the concentrated paste on the supernatant is better and the taste is acceptable.

[0133] Example 5

[0134] The medicine prepared according to Example 4 has a distinct sour taste in the mouth. Therefore, the inventors chose flavors to correct the taste. After research, the inventors found that the pediatric Xuanfei oral liquid was prepared with orange, strawberry, and lemon flavors, and stevioside was added to improve the sour taste and improve children's compliance with the medicine.

[0135] The two groups of medicine obtained in Example 4 were treated as follows: 3 groups of the above medicine were set up, each group had 10 ml, and the following treatments were performed and tasted. The treatments and results were as follows:

[0136] Group 1: Add 0.15% orange flavor, 0.4% stevioside, and 0.03% ethylparaben and stir until completely dissolved. Smell the orange fragrance and taste sweet and sour.

[0137] Group 2: Add 0.1% orange flavor, 0.4% stevioside, and 0.03% ethylparaben and stir until completely dissolved. The lemon scent is lighter and the taste is sweet and sour and refreshing.

[0138] Group 3: Add 0.2% strawberry essence, 0.4% stevioside, and 0.03% ethylparaben and stir until completely dissolved. The strawberry flavor is stronger when you smell it, but it is lighter in the mouth with a more obvious sour taste.

[0139] Conclusion: From the above, it can be seen that orange flavor and lemon flavor are more suitable for children's Xuanfei oral liquid because they are sweet and sour, refreshing and fragrant.

[0140] The above describes the specific implementation methods of the present invention, but does not limit the scope of protection of the present invention. Those skilled in the art should understand that various modifications or variations that can be made by those skilled in the art on the basis of the technical solution of the present invention without creative work are still within the scope of protection of the present invention.

Claims

1. A method for preparing oral drops of a pediatric lung-clearing composition, wherein the pediatric lung-clearing composition is composed of ephedra, saposhnikovia root, scutellaria baicalensis, platycodon, mustard seeds, bitter almonds, scutellaria baicalensis seeds, amaranth, astragalus root, yam, hawthorn and liquorice, characterized in that: The method comprises: Step 1: Powder ephedra, add ethanol water solution, heat to 75-85°C, perform ultrasonic extraction, filter, and concentrate to obtain concentrated solution A; Ultrasonic extraction was performed twice, with 8-9 times the amount of water added for the first extraction and 1 h-1.5 h of ultrasonic extraction, and 5-6 times the amount of water added for the second extraction and 45 min-1 h of ultrasonic extraction. Step 2: Powder the remaining drugs, add water, heat to 70-85°C, perform ultrasonic extraction, filter, and concentrate to obtain concentrated solution B1; Step 3: Add ethanol to the concentrated solution B1, stir thoroughly, and allow to stand for stratification to obtain a supernatant, thereby obtaining the concentrated solution B2; Step 4: Combine the concentrate A and the concentrate B2 to obtain a concentrate C1, treat the concentrate C1 with a clarifier, let it stand, centrifuge, and collect the supernatant to obtain the impurity-removed concentrate C2; The clarifier is ZTC1+1 clarifier; Step 5: using cyclodextrin to include the impurity-removed concentrated solution C2 to obtain pediatric Xuanfei oral drops; The cyclodextrin is hydroxypropyl-β-cyclodextrin; the mass fraction is 2% to 4%; The pediatric lung-clearing composition comprises 56.18g of ephedra, 112.36g of saposhnikovia divaricata, 112.36g of scutellaria baicalensis, 56.18g of platycodon grandiflorum, 56.18g of mustard seeds, 56.18g of bitter almonds, 56.18g of scutellaria baicalensis seeds, 112.36g of amaranth, 112.36g of astragalus, 56.18g of yam, 112.36g of hawthorn, and 56.18g of liquorice.

2. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: In step 1, the volume fraction of ethanol in the ethanol aqueous solution is 70-85%.

3. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: In step 2, ultrasonic extraction is performed twice. The first time, 5-6 times water is added and ultrasonicated for 1 h-1.5 h. The second time, 5-6 times water is added and ultrasonicated for 45 min-1 h.

4. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: In step 2, the southwestern scutellaria baicalensis is added when the temperature is heated to 70-85°C.

5. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: The density of the concentrate A or the concentrate B1 is 1.05-1.

10.

6. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: The ultrasonic extraction power of step 1 and step 2 is 280-320W.

7. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: The ultrasonic extraction power in step 1 and step 2 is 300W.

8. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: In step 3, ethanol is added to the concentrated solution B1 until the ethanol volume fraction reaches 50-70% for alcohol precipitation.

9. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: In step 3, ethanol is added to the concentrated solution B1 until the ethanol volume fraction reaches 60% for alcohol precipitation.

10. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: The ZTC1+1 clarifier includes component A and component B, and is prepared by the following steps: the mass concentration of component A and component B is 1%.

11. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: In step 4, the temperature of the concentrated solution C1 is maintained at 75-85° C., and a 1% mass concentration of ZTC1+1 clarifier component B is added to the concentrated solution C1, where the volume of component B is 4% of the volume of the concentrated solution C1. The mixture is mixed evenly and allowed to stand at 75-85° C. for 2-2.5 hours. Then, a 1% mass concentration of ZTC1+1 clarifier component A is added, where the volume of component A is 2.0-3.0% of the volume of the concentrated solution C1. The mixture is mixed evenly and allowed to stand at room temperature for 2-2.5 hours.

12. The method for preparing the oral drops of the pediatric Xuanfei composition according to claim 1, wherein: Add strawberry essence, orange essence or lemon essence after inclusion.

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