Oral liquid preparation and preparation method thereof

Abstract

According to the oral liquid preparation and the preparation method thereof provided by the invention, the defects of the existing perilla-Huang cough-relieving capsules in the aspect of taking medicines for children and adolescent patients are overcome, the oral liquid preparation has the characteristics of convenience in administration, safety, effectiveness, better preparation stability and the like, the taking compliance of children and the clarity of the oral liquid preparation are improved, and the whole preparation method is simple and easy to implement. The method is suitable for industrial mass production.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine preparations, and in particular relates to an oral liquid preparation and a preparation method thereof. Background Art

[0002] With the changes in the natural and social environment, the incidence of cough has increased significantly. The prevalence of chronic cough with various causes is 9.6% in the general population worldwide and as high as 10% to 38% in specialist clinics.

[0003] There is no nationwide epidemiological survey data in China, but based on research reports from various parts of the country, the prevalence of chronic cough is 2.0% to 28.3%. In domestic specialist outpatient clinics, chronic cough patients account for more than one-third.

[0004] Studies have shown that more than 75% of children visit the doctor more than 5 times a year for cough, and 14% of children visit the doctor more than 15 times. The causes of cough in children are different from those in adults. Common causes of chronic cough in Chinese children are cough variant asthma (CVA), upper airway cough syndrome (UACS) and post-cold cough (also known as post-infectious cough, PIC); a national multicenter study published in 2012 suggested that the top three causes of chronic cough in Chinese children are: CVA (41.95%), UACS (24.71%) and PIC (21.73%).

[0005] At present, there are many adult-related drugs in this disease field, and the clinical needs are basically met; however, there are fewer children's cough medicines, especially those with clear indications for children's CVA and PIC, which have not yet been found, and there are some unmet clinical needs.

[0006] Suhuang Cough Capsules are a major Chinese medicine product produced by Beijing Haiyan Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group. They are mainly used to relieve wind and lung function, relieve cough and sore throat in adults. They can be taken by patients with symptoms of CVA and PIC with the same indications. There is no research data to support their use in patients under 18 years old. In clinical practice, Suhuang Cough Capsules have been widely used in children. According to clinical observations and studies, Suhuang Cough Capsules alone or in combination with Western medicine can relieve the clinical symptoms of cough in children with CVA and PIC, but children have poor compliance during medication and have difficulty swallowing.

[0007] Considering the high incidence of CVA and PIC in children, and the fact that children have higher requirements for medication compliance and safety, it is planned to research and develop oral liquid preparations that are easy to administer, require less daily crude drugs, and have equivalent or even better efficacy to meet the clinical demand for children's cough medication. At the same time, it is necessary to solve the problems of liquid preparation stability and clarity. Summary of the invention

[0008] The purpose of the present invention is to provide an oral liquid preparation based on the existing technology to solve the shortcomings of the existing Suhuang cough-relieving capsules in the medication of children and adolescent patients. The invention has the characteristics of convenient administration, safety and effectiveness, better preparation stability, etc., and improves the compliance of children's medication and the clarity of the oral liquid preparation.

[0009] Another object of the present invention is to provide a method for preparing the above oral liquid preparation.

[0010] The technical solution of the present invention is as follows:

[0011] An oral liquid preparation, comprising an extract, and / or volatile oil or its inclusion compound, and an antibacterial agent;

[0012] Wherein, the extract and / or volatile oil are prepared from the following components in parts by weight:

[0013] 2-6 parts of ephedra, 2-6 parts of perilla leaves, 2-6 parts of earthworms, 2-6 parts of loquat leaves, 1-4 parts of perilla seeds, 1-4 parts of cicada shells, 1-4 parts of peucedanum, 2-6 parts of burdock seeds, and 1-4 parts of schisandra chinensis.

[0014] Considering that the original dosage form has been on the market for many years with significant efficacy and is also widely used in children clinically, in order to expand the pediatric indication population and increase compliance, the present invention provides an oral liquid preparation.

[0015] In a preferred embodiment, the extract and / or volatile oil are prepared from the following components in parts by weight: 5 parts of ephedra, 5 parts of perilla leaves, 5 parts of earthworms, 5 parts of loquat leaves, 3 parts of perilla seeds, 4 parts of cicada shells, 4 parts of peucedanum, 5 parts of burdock seeds, and 4 parts of schisandra chinensis.

[0016] The present invention provides a method for preparing the above-mentioned oral liquid preparation, comprising the following steps:

[0017] (1) Preparation of volatile oil: soak perilla leaves and peucedanum chinense in water for 0.5-1.5 hours, extract volatile oil by distillation for 4-10 hours, and collect the obtained volatile oil;

[0018] (2) Preparation of volatile oil inclusion compound: hydroxypropyl-β-cyclodextrin and purified water are mixed evenly, and the volatile oil obtained in step (1) is slowly added and ground to prepare a volatile oil inclusion compound;

[0019] (3) Preparation of the extract, comprising the following steps:

[0020] I) adding 80% ethanol aqueous solution to ephedra and schisandra chinensis, refluxing and extracting three times, each time for 1-2 hours, filtering, combining the filtrates, recovering ethanol, and concentrating to a thick paste having a relative density of 1.08-1.11 measured at 50° C., and setting aside;

[0021] II) boiling earthworm, loquat leaf, perilla seed, cicada shell and burdock seed with water for three times, each time for 0.5-1h, filtering, concentrating the filtrate to a thick paste with a relative density of 1.08-1.11 measured at 50°C, adding ethanol to make the alcohol content reach 65-75%, refrigerating for the first time, filtering, recovering ethanol, and concentrating to a thick paste with a relative density of 1.15-1.22 measured at 50°C, combining with the thick paste obtained in step I), refrigerating again, filtering, and obtaining an extract;

[0022] (4) Preparation of oral liquid preparations, comprising the following steps:

[0023] a) water precipitation and alkali adjustment: filtering the extract obtained in step (3), adding purified water for water precipitation, stirring evenly to obtain a water precipitation liquid, adjusting the pH value thereof to 7.5-8.5, and refrigerating at 2-10° C. to obtain a water precipitation alkali adjustment liquid;

[0024] b) initial preparation: filtering the water-precipitated alkali solution obtained in step a), collecting the filtrate, adding an antibacterial agent, a sweetener and part of purified water to the filtrate, stirring evenly, adjusting the pH value to 4.5-6.5, heating and boiling for 20-40 minutes, cooling to 50-60° C. to obtain a drug solution, adding a solubilizing agent, the volatile oil inclusion compound obtained in step (2) and a flavor to the obtained drug solution, stirring evenly, and refrigerating at 2-10° C. to obtain an initial preparation solution;

[0025] c) Fine preparation and sterilization: The obtained preliminary preparation solution is centrifuged, the centrifuged solution is collected, purified water is added to make up the volume, filtered, filled and sterilized to obtain the oral liquid preparation.

[0026] In the present invention, in step (1), the soaking time is 1 hour; and the extraction time is 8 hours.

[0027] For the present invention, in step (2), the weight ratio of hydroxypropyl-β-cyclodextrin to purified water is 1:0.2-1.5, which can be but not limited to 1:0.2, 1:0.3, 1:0.5, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.9, 1:1.0, 1:1.3 or 1:1.5. Preferably, the weight ratio of hydroxypropyl-β-cyclodextrin to purified water is 1:0.5-1.0; more preferably, the weight ratio of hydroxypropyl-β-cyclodextrin to purified water is 1:0.7-0.8.

[0028] In step (2), the volume weight ratio of volatile oil to hydroxypropyl-β-cyclodextrin is 1:5-15 mL / g, which may be but is not limited to 1:5 mL / g, 1:7 mL / g, 1:8 mL / g, 1:9 mL / g, 1:10 mL / g, 1:11 mL / g, 1:12 mL / g, 1:13 mL / g, 1:14 mL / g or 1:15 mL / g. Preferably, the volume weight ratio of volatile oil to hydroxypropyl-β-cyclodextrin is 1:5-15 mL / g; more preferably, the volume weight ratio of volatile oil to hydroxypropyl-β-cyclodextrin is 1:10-12 mL / g.

[0029] In the present invention, in step (3), in step I), each extraction time is 1.5 hours.

[0030] In step II), each decoction time is 1 hour; ethanol is added until the alcohol content reaches 70%.

[0031] In step II), the initial refrigeration time is up to 24 hours or more.

[0032] In step II), the product is initially refrigerated, filtered, ethanol is recovered, and concentrated to a thick paste having a relative density of 1.18-1.20 measured at 50°C.

[0033] In step II), the temperature during the re-refrigeration is 2-10° C. and the refrigeration time is up to 48 hours or more.

[0034] For the present invention, in step (4), in step a), the weight ratio of the extract to the purified water is 1:0.2-1.5, which may be but not limited to 1:0.2, 1:0.3, 1:0.5, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.9, 1:1.0, 1:1.3 or 1:1.5, preferably, the weight ratio of the extract to the purified water is 1:1.0;

[0035] In step b), the pH value is adjusted to 7.5-8.5, and the pH value may be but is not limited to 7.5, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3 or 8.5. Preferably, the pH value is adjusted to 7.8-8.2.

[0036] In step b), the antibacterial agent is potassium sorbate and / or sodium benzoate, preferably potassium sorbate. Based on the total amount of the oral liquid preparation as 100%, the added amount is 0.1%-1.0%, which can be but not limited to 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.25%, 0.30%, 0.50%, 0.70%, 0.90% or 1.0%, preferably 0.15-0.25%, more preferably 0.2%.

[0037] In step b), the sweetener is sucralose and / or steviol glycoside, preferably sucralose. Based on the total amount of the oral liquid preparation as 100%, the added amount is 0.1%-1.0%, which may be but not limited to 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.25%, 0.30%, 0.50%, 0.70%, 0.90% or 1.0%, preferably 0.10-0.20%, more preferably 0.15%.

[0038] In step b), the pH value is adjusted to 5.5-6.0.

[0039] In step b), heating is performed and boiling is performed for 20 minutes.

[0040] In step b), the solubilizer is one or more of polysorbate 80, glycerol, propylene glycol, polyethylene glycol 400 or sodium citrate, preferably polysorbate 80. Based on the total amount of the oral liquid preparation as 100%, the added amount is 0.4%-0.8%, which may be but is not limited to 0.40%, 0.50%, 0.70% or 0.80%, preferably 0.5-0.7%, and more preferably 0.6%.

[0041] In step b), the flavor is strawberry flavor, orange flavor or pineapple flavor, preferably strawberry flavor; the added amount is 0.05-0.2%, preferably 0.15%.

[0042] In step c), during the centrifugal treatment, the rotation speed is 9400-9800 r / min, preferably 9600 r / min.

[0043] In step c), during filtration, the filter membrane is 0.45 μm.

[0044] In step c), during sterilization, the sterilization temperature is 100-110° C., preferably 104-106° C., more preferably 105° C.; the sterilization time is 20-40 minutes, preferably 30 minutes.

[0045] Adopt the technical scheme of the present invention, the advantages are as follows:

[0046] The oral liquid preparation provided by the present invention solves the shortcomings of the existing Suhuang cough-relieving capsules in terms of medication for children and adolescent patients. It has the characteristics of convenient administration, safety and effectiveness, better preparation stability, etc., improves the compliance of children in taking the medicine and the clarity of the oral liquid preparation. The entire preparation method is simple and suitable for industrial mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The number of coughs of guinea pigs in each group changed compared with the Control group. ##P<0.01; compared with the Model group, **P<0.01.

[0048] Figure 2 It is a picture of the product in Example 1 and Comparative Examples 1-2. DETAILED DESCRIPTION

[0049] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0050] Example 1

[0051] An oral liquid preparation, wherein the extract and / or volatile oil is prepared from the following components: 5g of ephedra, 5g of perilla leaf, 5g of earthworm, 5g of loquat leaf, 3g of perilla seed, 4g of cicada slough, 4g of peucedanum, 5g of arctium fruit, and 4g of schisandra chinensis;

[0052] The preparation method thereof comprises the following steps:

[0053] (1) Preparation of volatile oil: soak perilla leaves and peucedanum chinense in water for 1 hour, extract volatile oil by distillation for 8 hours, and collect the obtained volatile oil;

[0054] (2) Preparation of volatile oil inclusion compound: hydroxypropyl-β-cyclodextrin and purified water are uniformly mixed, and a volatile oil-ethanol solution prepared by dispersing the volatile oil obtained in step (1) in ethanol is slowly added, wherein the volume ratio of volatile oil to ethanol is 1:1, and the mixture is ground for 20 minutes to prepare a volatile oil inclusion compound; wherein the weight ratio of hydroxypropyl-β-cyclodextrin to purified water is 1:0.75, and the volume weight ratio of volatile oil to hydroxypropyl-β-cyclodextrin is 1:12 mL / g;

[0055] (3) Preparation of the extract, comprising the following steps:

[0056] 1) adding 80% ethanol aqueous solution to ephedra and schisandra chinensis, refluxing and extracting three times, each time for 1.5 hours, filtering, combining the filtrates, recovering ethanol, and concentrating to a thick paste having a relative density of 1.08-1.11 at 50° C., and setting aside;

[0057] II) boiling earthworm, loquat leaf, perilla seed, cicada shell and burdock seed with water for three times, each time for 0.5-1h, filtering, concentrating the filtrate to a thick paste with a relative density of 1.08-1.11 measured at 50°C, adding ethanol to make the alcohol content reach 70%, refrigerating for the first time for 24 hours, filtering, recovering ethanol, and concentrating to a thick paste with a relative density of 1.20 measured at 50°C, combining with the thick paste obtained in step I), refrigerating again, filtering, and obtaining an extract;

[0058] (4) Preparation of oral liquid preparations, comprising the following steps:

[0059] a) water precipitation and alkali adjustment: filtering the extract obtained in step (3), adding purified water for water precipitation, the weight ratio of the extract to the purified water being 1:1, stirring evenly to obtain a water precipitation liquid, adjusting the pH value thereof to 7.8-8.2 with 20% NaOH solution, and refrigerating at 2-10° C. to obtain a water precipitation alkali adjustment liquid;

[0060] b) initial preparation: the water-precipitated alkali solution obtained in step a) is filtered through a 5 μm filter membrane, the filtrate is collected into an initial preparation tank, 0.2% potassium sorbate, 0.15% sucralose and part of purified water are added, the mixture is stirred evenly, the pH value is adjusted to 5.5-6.0 with dilute hydrochloric acid, the mixture is heated and boiled for 20 minutes, and the mixture is cooled to 50-60° C. to obtain a liquid medicine; 0.6% polysorbate 80 is dispersed in purified water, the volatile oil inclusion compound obtained in step (2) and 0.15% strawberry essence are added, the mixture is stirred evenly, the mixture is slowly transferred to an initial preparation tank, the mixture is stirred evenly, and the mixture is refrigerated at 2-10° C. for more than 48 hours to obtain an initial preparation solution;

[0061] c) Fine preparation and sterilization: The obtained preliminary preparation liquid is centrifuged using a butterfly centrifuge at a speed of 9600 r / min. The slag is discharged once every 10 minutes, and the centrifuge liquid is collected and transferred to a fine preparation tank. Purified water is added to make up the volume, filtered through a 0.45 μm filter membrane, filled and sterilized at a sterilization temperature of 105°C and a sterilization time of 30 minutes to obtain an oral liquid preparation.

[0062] Example 2 Investigation of the preparation method of volatile oil inclusion

[0063] Testing and evaluation methods

[0064] Take the volatile oil inclusion solution, extract it with petroleum ether (30-60°C) for 3 times, 50 ml each time, collect the lower layer and weigh it. The volatile oil inclusion rate is used as the evaluation index (volatile oil inclusion rate determination method: weigh about 20g of the inclusion compound, put it into a round-bottom flask, add 300ml of water to dilute, connect the volatile oil extraction device, heat, keep it slightly boiling for 2 hours, collect the volatile oil, cool it down, and read the volume of the volatile oil. Blank recovery rate: transfer 1.5ml of volatile oil to a round-bottom flask, add 300ml of water to dilute, connect the volatile oil extraction device, heat, keep it slightly boiling for 2 hours, collect the volatile oil, cool it down, and read the volume of the volatile oil. Calculation formula: (1) Blank recovery rate = recovered volatile oil reading / volatile oil addition amount × 100%; (2) Volatile oil inclusion rate = (volatile oil reading × total weight of inclusion compound) / (4 × inclusion compound sampling amount × blank recovery rate) × 100%).

[0065] Study on the ratio of volatile oil to hydroxypropyl-β-cyclodextrin

[0066] The grinding method was used to examine the ratios of volatile oil (mL) to hydroxypropyl-β-cyclodextrin (g) of 1:8, 1:10, and 1:12 to prepare inclusion complexes. The volatile oil inclusion rates were measured and calculated. The results are shown in Table 1 below.

[0067] Table 1 Effect of the ratio of volatile oil (ml) to hydroxypropyl-β-CD (g) on ​​the inclusion process

[0068] Volatile oil: Hydroxypropyl-β-cyclodextrin (mL:g) Volatile oil inclusion rate / % 1:8 72.62 1:10 89.57 1:12 95.07

[0069] It can be seen from Table 1 above that as the proportion of hydroxypropyl-β-cyclodextrin added increases, the volatile oil inclusion rate also increases. When the ratio of volatile oil (mL) to hydroxypropyl-β-cyclodextrin (g) is 1:12, the inclusion rate is the highest. Finally, the ratio of volatile oil (ml) to hydroxypropyl-β-cyclodextrin (g) is determined to be 1:12.

[0070] Investigation on the grinding time of volatile oil inclusion

[0071] The volatile oil inclusion time has a certain influence on the volatile oil inclusion rate, so the volatile oil inclusion time was investigated. The ratio of volatile oil (ml) to hydroxypropyl-β-cyclodextrin (g) was 1:12, and the investigation time was 10 minutes, 20 minutes, and 30 minutes.

[0072] Table 2 Investigation of volatile oil inclusion grinding time

[0073] Grinding time / min Volatile oil inclusion rate / % 10 81.96 20 85.32 30 74.97

[0074] It can be seen from Table 2 above that the inclusion time has a certain influence on the inclusion process. When the inclusion time is 20 minutes, the inclusion rate of the inclusion compound is relatively high. After comprehensive consideration, the inclusion time is tentatively set to 20 minutes.

[0075] Water dosing test

[0076] The amount of water added to hydroxypropyl-β-cyclodextrin has a certain influence on the volatile oil inclusion rate, so the amount of water added was investigated. The ratio of volatile oil (ml) to hydroxypropyl-β-cyclodextrin (g) was 1:12, the volatile oil inclusion time was 20 minutes, and the amount of water added was 0.5 times, 0.75 times, 1.0 times, and 1.5 times. The volatile oil inclusion rates were measured and calculated respectively. The results of the investigation are shown in the table below.

[0077] Table 3 Water addition times

[0078]

[0079]

[0080] As shown in Table 3 above, when the water addition ratio is 0.75, the volatile oil inclusion rate is higher. Finally, the water addition ratio of hydroxypropyl-β-cyclodextrin is determined to be 0.75.

[0081] Inclusion Process Validation

[0082] In order to verify the stability of the inclusion process, according to the process parameters determined above: the ratio of volatile oil (ml) to hydroxypropyl-β-cyclodextrin (g) is 1:12, 0.75 times the amount of water is added to hydroxypropyl-β-cyclodextrin to make a hydroxypropyl-β-cyclodextrin solution, the inclusion time is 20 minutes, and three parallel verification tests are carried out to determine and calculate the volatile oil inclusion rate. The results are shown in the table below.

[0083] Table 4 Validation of volatile oil inclusion process

[0084] batch Volatile oil inclusion rate (%) 1 90.04 2 91.59 3 91.39

[0085] The results of three batches of small-scale volatile oil inclusion process verification showed that the volatile oil inclusion rate was stable and the process was feasible. Therefore, the ratio of volatile oil (ml) to hydroxypropyl-β-cyclodextrin (g) was determined to be 1:12, and 0.75 times the amount of water was added to hydroxypropyl-β-cyclodextrin to prepare a hydroxypropyl-β-cyclodextrin solution, and the inclusion time was 20 minutes.

[0086] Example 3 Preparation Forming Process Study

[0087] Water dosing test

[0088] After the liquid extract is precipitated, the water-insoluble components in the extract can be removed to increase the stability of the finished product. Therefore, the water addition times of the extract were investigated, and the water addition times were 0.75 times, 1 times, 1.25 times, and 1.5 times. The transfer rate of ephedrine hydrochloride, pseudoephedrine hydrochloride and arctiin, solid content, and solid content loss rate were used as evaluation indicators to determine the water addition times of the extract.

[0089] Table 5 Investigation of different water addition times

[0090]

[0091] Note: When adding 0.75 times the amount of water, the liquid is difficult to filter, so replace 2 filter papers

[0092] The results of the water addition process investigation show that, with increasing water addition, the solid content and solid loss rate decrease; there is no significant difference in the transfer rates of ephedrine hydrochloride, pseudoephedrine and arctiin at 1.0 times, 1.25 times and 1.5 times the water addition; the transfer rate of the index components at 0.75 times the water addition is slightly lower than that at other times, and the water addition amount is tentatively set to be no less than 1.0 times.

[0093] Water subsidence time investigation

[0094] The refrigeration time of the extract was investigated for 24 hours, 48 ​​hours, and 72 hours, with the transfer rate of ephedrine hydrochloride, pseudoephedrine hydrochloride, and arctiin, solid content, and solid loss rate as evaluation indicators. The process investigation results are as follows.

[0095] Table 6 Investigation of different sinking times

[0096]

[0097] The process investigation results show that as the water precipitation time increases, there is no significant difference in the transfer rate of each component, solid content and solid loss rate. Considering factors such as production time, the water precipitation time is tentatively set to be more than 24 hours.

[0098] Investigation on the initial refrigeration time

[0099] Heat treatment and refrigeration are common ways to remove impurities from liquid preparations, which also affect the stability of the finished product. Therefore, the refrigeration time of the initial preparation was investigated, and the investigation time was 24 hours, 48 ​​hours, 72 hours, 96 hours, and 120 hours. The transfer rate of ephedrine hydrochloride, pseudoephedrine hydrochloride, and arctiin, solid content, and solid loss rate were used as evaluation indicators to evaluate the initial preparation refrigeration time. The results of the process investigation are as follows.

[0100] Table 7 Investigation of different refrigeration time

[0101]

[0102] The results of the process investigation on the initial refrigeration time showed that there was no difference in the evaluation indicators of different refrigeration times. The initial refrigeration time is tentatively set to be more than 24 hours.

[0103] Sweetener dosage survey

[0104] ZYY-772 extract tastes sour and bitter, so sweeteners need to be added to correct the flavor. Considering the safety of sweeteners, the natural sweetener stevioside was selected for investigation. The proportions of stevioside investigated were 0.2%, 0.4%, 0.6%, 0.8%, and 1.0%, and the proportion of stevioside was determined based on the taste of the finished product.

[0105] Five volunteers were selected to evaluate the taste from seven aspects: sweetness, bitterness, sourness, spiciness, fishy smell, saltiness, and volatile oil taste.

[0106] Sweetness: Total score is 10 points, too sweet, not sweet (1) → moderately sweet (10)

[0107] Bitterness: Total score is 10, bitter (1) → not bitter (10)

[0108] Sourness: Total score is 10 points, strong sourness (1) → moderate sourness (10)

[0109] Spiciness: Total score is 10, strong spiciness (1) → no spiciness (10)

[0110] Fishy smell: total score is 10 points, strong fishy smell (1) → no fishy smell (10)

[0111] Saltiness: Total score is 10, strong saltiness (1) → no saltiness (10)

[0112] Volatile oil smell: total score is 10 points, strong volatile oil smell (1) → no volatile oil smell (10)

[0113] Table 8 Stevioside addition assessment score table

[0114]

[0115]

[0116] Table 9 Investigation of the amount of stevioside added

[0117]

[0118] Note: It is generally reported that the taste is sour and salty, and the sweetness is not obvious (after-sweetness). The sweetener sucralose is added. According to the score sheet and the taste of the finished product, the proportion of stevioside is tentatively set at 0.8%.

[0119] Table 10 Score table for investigation of sucralose addition amount

[0120]

[0121]

[0122] Table 11 Investigation of the amount of sucralose added

[0123]

[0124] Note: Adding the sweetener sucralose makes it sweet at first, followed by a sour and salty taste, which significantly increases the sweetness and tastes better than stevioside

[0125] According to the scoring table and the taste of the finished product, the tentative sweetener is sucralose, and the addition ratio is 0.20%.

[0126] Fragrance dosage investigation

[0127] The volatile components of this product have a strong irritating odor, so flavors need to be added to improve the odor and increase children's compliance. In the preliminary experiment, orange flavor, pineapple flavor, and strawberry flavor were compared respectively, and it was found that the addition of strawberry flavor had a better masking effect, so the amount of strawberry flavor added was investigated, and the addition ratios were 0.09%, 0.12%, 0.15%, and 0.18%. The taste of the finished product was used as the evaluation index to assess the amount of strawberry flavor used.

[0128] Five volunteers were selected to evaluate the taste from seven aspects: sweetness, bitterness, sourness, spiciness, fishy smell, saltiness, and volatile oil taste.

[0129] Sweetness: Total score is 10 points, too sweet, not sweet (1) → moderately sweet (10)

[0130] Bitterness: Total score is 10, bitter (1) → not bitter (10)

[0131] Sourness: Total score is 10 points, strong sourness (1) → moderate sourness (10)

[0132] Spiciness: Total score is 10, strong spiciness (1) → no spiciness (10)

[0133] Fishy smell: total score is 10 points, strong fishy smell (1) → no fishy smell (10)

[0134] Saltiness: Total score is 10, strong saltiness (1) → no saltiness (10)

[0135] Volatile oil smell: total score is 10 points, strong volatile oil smell (1) → no volatile oil smell (10)

[0136] Table 12 Evaluation table of flavor dosage

[0137]

[0138]

[0139] Table 13 Investigation of flavor dosage

[0140] Amount of strawberry flavor added (%) Finished product taste 0.09 Salty, sour, bitter, sweet, not very spicy, no fishy smell or volatile oil smell 0.12 Salty, sour, bitter, sweet, not very spicy, no fishy smell or volatile oil smell 0.15 Salty, slightly sour, bitter, sweet, not very spicy, no fishy smell or volatile oil smell 0.18 It has the smell of volatile oil, sour, bitter, slightly sweet, salty, not very spicy, no fishy smell

[0141] According to the scoring table and the taste of the finished product, the proportion of strawberry flavor added is tentatively set at 0.15%.

[0142] Adjust pH back to acidic state

[0143] The adjusted back pH was investigated at pH values ​​of 4.5, 5.0, 5.5, 6.0, and 6.5. The adjusted back pH was evaluated using the ephedrine hydrochloride, pseudoephedrine hydrochloride, and arctiin content transfer rates, solid content, solid content transfer rate, and finished product properties as evaluation indicators.

[0144] Table 14 pH adjustment investigation

[0145]

[0146]

[0147] The results of the process investigation of adjusting the pH back to acidic during fine mixing showed that there was no difference in the evaluation indicators at different pH values ​​and the properties were all qualified. The pH value was temporarily adjusted back to 4.5-6.5.

[0148] Example 4

[0149] By establishing a cough variant asthma guinea pig model, we observed the effects of cough variant asthma on airway inflammation in guinea pigs.

[0150] 1.1 Experimental animals

[0151] Guinea pigs, 6-8 weeks old, half male and half female, weighing approximately 200-250 g, were housed in a constant temperature laboratory at 20°C-22°C and 30%-70% humidity, with a 12-h light-dark cycle, during which they had free access to food and water.

[0152] 1.2 Experimental drugs

[0153] Oral liquid preparation (route A), route D and positive drug in Example 1. Wherein, the sources of route D and positive drug are as follows:

[0154] Route D

[0155] The formula is consistent with that in Example 1, and the preparation method refers to the preparation method disclosed in Example 1 in the patent with application number 202310058408.3 and the invention name is Suhuang cough relieving granules and their preparation method and quality standard.

[0156] Positive Drug

[0157] The formula is consistent with that in Example 1, and the preparation method is prepared with reference to the "Suhuang Cough Capsules" [Preparation Method] in the 2020 edition of the "Chinese Pharmacopoeia", which includes the formula preparations and single-ingredient preparations.

[0158] 2. Experimental Methods

[0159] 2.1 Model establishment

[0160] First, the guinea pigs were adaptively fed for 3 days. On the 4th day, each guinea pig except the blank group was intraperitoneally injected with 1 mL of 0.2% ovalbumin solution (actual dose: 1 / 16), and the blank group was intraperitoneally injected with 1 mL of NS; on the 11th day, each guinea pig in the OVA-sensitized group was intraperitoneally injected with 1 mL of sensitized ovalbumin solution (actual dose: 1 / 16), and the blank group was intraperitoneally injected with 1 mL of NS; from the 18th to the 24th day, each guinea pig in the OVA-sensitized group was challenged with 1.0% ovalbumin aerosol (actual dose: 1 / 2), 60 seconds each time every day. During the aerosol challenge, the guinea pigs showed symptoms such as coughing, sneezing, restlessness, and abdominal cramps.

[0161] 2.2 Animal grouping and drug administration

[0162] Blank group, model group, line A (each group has high and low dose groups), line D (each group has high and low dose groups) / positive drug group. Each group has 8 mice, and the drug is administered by gavage before atomization according to the grouping. According to "Pharmacological Experimental Methodology": Conversion of equivalent doses between humans and animals, the conversion factor for adults / guinea pigs is 5.4.

[0163] 0.2% ovalbumin solution: 2 mg OVA and 100 mg aluminum hydroxide were dissolved in 1 mL normal saline (NS); ovalbumin sensitization solution: 0.01 mg OVA and 100 mg aluminum hydroxide were dissolved in 1 mL NS; 1.0% ovalbumin solution: 100 mg OVA was dissolved in 10 mL NS.

[0164] 2.3 Guinea pig airway sensitivity assay

[0165] Capsaicin was used as a stimulus to induce cough reflex in guinea pigs. One hour after the last administration, the guinea pigs were placed in a sealed transparent box for 10 -4 mol / L capsaicin aerosol was mixed with 600mL / min airflow for atomization inhalation. The administration time was 60 seconds, and then the nebulizer was turned off. The guinea pig continued to stay in the multifunctional cough and wheeze inducing instrument for 60 seconds, and then the number of coughs of each guinea pig within two minutes of inhaling capsaicin was recorded. The observer could make statistics based on the guinea pig's coughing posture (neck extended forward and front legs extended forward), and the number of coughs and cough delay time of the guinea pig were recorded as indicators for judging airway sensitivity.

[0166] 2.4 Statistical analysis

[0167] All data were processed using SPSS 22.0 statistical software. Continuity was expressed as "mean ± standard deviation". One-way analysis of variance was used for comparison of multiple groups. LSD test was used for comparison of pairs of groups when variance was equal, and Dunnett's test was used for unequal variance. P < 0.05 was considered to be different, indicating statistical significance.

[0168] Guinea pig airway sensitivity test results Figure 1 Compared with the Control group, the cough frequency in the Model group was significantly increased (P<0.01), indicating that the model was successfully established. Group A was superior to Group D in improving the airway sensitivity of guinea pigs, which was equivalent to the positive drug.

[0169] Comparative Example 1

[0170] The difference from Example 1 is that in step a) water precipitation and alkali adjustment, the pH value is adjusted to 6.8-7.2 with 20% NaOH solution.

[0171] Comparative Example 2

[0172] The difference from Example 1 is that in step b) of initial preparation, the amount of polysorbate 80 is reduced to 0.2%.

[0173] The oral liquid preparations prepared in Example 1 and Comparative Examples 1-2 were subjected to a finished product property test. Figure 2 shown.

[0174] Depend on Figure 2 It can be seen that the oral liquid preparation prepared in Example 1 has a clear and transparent solution, no precipitation at the bottom, and good clarity; while the product in Comparative Example 1 has a clear and transparent solution, precipitation at the bottom, which does not disperse when shaken lightly, and poor clarity; the product in Comparative Example 2 has a turbid solution and very poor clarity.

[0175] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An oral liquid preparation, characterized in that: Including extracts, and / or volatile oils or their inclusion compounds, antibacterial agents; The extract and / or volatile oil are prepared from the following components in parts by weight: 2-6 parts of ephedra, 2-6 parts of perilla leaves, 2-6 parts of earthworms, 2-6 parts of loquat leaves, 1-4 parts of perilla seeds, 1-4 parts of cicada shells, 1-4 parts of peucedanum, 2-6 parts of burdock seeds, and 1-4 parts of schisandra chinensis.

2. The oral liquid preparation according to claim 1, characterized in that: The preparation method of the oral liquid preparation comprises the following steps: (1) Preparation of volatile oil: soak perilla leaves and peucedanum chinense in water for 0.5-1.5 hours, extract volatile oil by distillation for 4-10 hours, and collect the obtained volatile oil; (2) Preparation of volatile oil inclusion compound: hydroxypropyl-β-cyclodextrin and purified water are mixed evenly, and the volatile oil obtained in step (1) is slowly added and ground to prepare a volatile oil inclusion compound; (3) Preparation of the extract, comprising the following steps: I) adding 80% ethanol aqueous solution to ephedra and schisandra chinensis, refluxing and extracting three times, each time for 1-2 hours, filtering, combining the filtrates, recovering ethanol, and concentrating to a thick paste having a relative density of 1.08-1.11 measured at 50° C., and setting aside; II) boiling earthworm, loquat leaf, perilla seed, cicada shell and burdock seed with water for three times, each time for 0.5-1h, filtering, concentrating the filtrate to a thick paste with a relative density of 1.08-1.11 measured at 50°C, adding ethanol to make the alcohol content reach 65-75%, refrigerating for the first time, filtering, recovering ethanol, and concentrating to a thick paste with a relative density of 1.15-1.22 measured at 50°C, combining with the thick paste obtained in step I), refrigerating again, filtering, and obtaining an extract; (4) Preparation of oral liquid preparations, comprising the following steps: a) water precipitation and alkali adjustment: filtering the extract obtained in step (3), adding purified water for water precipitation, stirring evenly to obtain a water precipitation liquid, adjusting the pH value thereof to 7.5-8.5, and refrigerating at 2-10° C. to obtain a water precipitation alkali adjustment liquid; b) initial preparation: filtering the water-precipitated alkali solution obtained in step a), collecting the filtrate, adding an antibacterial agent, a sweetener and part of purified water to the filtrate, stirring evenly, adjusting the pH value to 4.5-6.5, heating and boiling for 20-40 minutes, cooling to 50-60° C. to obtain a drug solution, adding a solubilizing agent, the volatile oil inclusion compound obtained in step (2) and a flavor to the obtained drug solution, stirring evenly, and refrigerating at 2-10° C. to obtain an initial preparation solution; c) Fine preparation and sterilization: The obtained preliminary preparation solution is centrifuged, the centrifuged solution is collected, purified water is added to the fixed volume, filtered, filled and sterilized to obtain the oral liquid preparation.

3. The oral liquid preparation according to claim 2, characterized in that: The extract and / or volatile oil is prepared from the following components in parts by weight: 5 parts of ephedra, 5 parts of perilla leaves, 5 parts of earthworms, 5 parts of loquat leaves, 3 parts of perilla seeds, 4 parts of cicada shells, 4 parts of peucedanum peucedanum, 5 parts of burdock seeds, and 4 parts of schisandra chinensis.

4. The oral liquid preparation according to claim 3, characterized in that: In step (1), the soaking time is 1 hour; the extraction time is 8 hours; in step (2), the weight ratio of hydroxypropyl-β-cyclodextrin to purified water is 1:0.2-1.5, preferably 1:0.5-1.0; more preferably 1:0.7-0.8; the volume weight ratio of volatile oil to hydroxypropyl-β-cyclodextrin is 1:5-15mL / g, preferably 1:5-15mL / g; more preferably 1:10-12mL / g.

5. The oral liquid preparation according to claim 3, characterized in that: In step (3): in step I), each extraction time is 1.5 hours; in step II), each decoction time is 1 hour; ethanol is added until the alcohol content reaches 70%; the initial refrigeration time is up to 24 hours or more; the temperature during the second refrigeration is 2-10°C, and the refrigeration time is up to 48 hours or more.

6. The oral liquid preparation according to claim 3, characterized in that: In step (4): In step a), the weight ratio of the extract to purified water is 1:0.2-1.5, preferably 1:1.0; the pH value is adjusted to 7.8-8.2; In step b), the antibacterial agent is potassium sorbate and / or sodium benzoate, preferably potassium sorbate; the sweetener is sucralose and / or steviol glycoside, preferably sucralose; the pH value is adjusted to 5.5-6.0; heated and boiled for 20 minutes; the solubilizer is one or more of polysorbate 80, glycerol, propylene glycol, polyethylene glycol 400 or sodium citrate, preferably polysorbate 80; the flavor is strawberry flavor, orange flavor or pineapple flavor, preferably strawberry flavor; In step c), during centrifugation, the rotation speed is 9400-9800 r / min, preferably 9600 r / min; during filtration, the filter membrane is 0.45 μm; during sterilization, the sterilization temperature is 100-110° C., preferably 105° C.; the sterilization time is 20-40 minutes, preferably 30 minutes.

7. The method for preparing the oral liquid preparation according to claim 1, characterized in that: The steps include: (1) Preparation of volatile oil: soak perilla leaves and peucedanum chinense in water for 0.5-1.5 hours, extract volatile oil by distillation for 4-10 hours, and collect the obtained volatile oil; (2) Preparation of volatile oil inclusion compound: hydroxypropyl-β-cyclodextrin and purified water are mixed evenly, and the volatile oil obtained in step (1) is slowly added and ground to prepare a volatile oil inclusion compound; (3) Preparation of the extract, comprising the following steps: I) adding 80% ethanol aqueous solution to ephedra and schisandra chinensis, refluxing and extracting three times, each time for 1-2 hours, filtering, combining the filtrates, recovering ethanol, and concentrating to a thick paste having a relative density of 1.08-1.11 measured at 50° C., and setting aside; II) boiling earthworm, loquat leaf, perilla seed, cicada shell and burdock seed with water for three times, each time for 0.5-1h, filtering, concentrating the filtrate to a thick paste with a relative density of 1.08-1.11 measured at 50°C, adding ethanol to make the alcohol content reach 65-75%, refrigerating for the first time, filtering, recovering ethanol, and concentrating to a thick paste with a relative density of 1.15-1.22 measured at 50°C, combining with the thick paste obtained in step I), refrigerating again, filtering, and obtaining an extract; (4) Preparation of oral liquid preparations, comprising the following steps: a) water precipitation and alkali adjustment: filtering the extract obtained in step (3), adding purified water for water precipitation, stirring evenly to obtain a water precipitation liquid, adjusting the pH value thereof to 7.5-8.5, and refrigerating at 2-10° C. to obtain a water precipitation alkali adjustment liquid; b) initial preparation: filtering the water-precipitated alkali solution obtained in step a), collecting the filtrate, adding an antibacterial agent, a sweetener and part of purified water to the filtrate, stirring evenly, adjusting the pH value to 4.5-6.5, heating and boiling for 20-40 minutes, cooling to 50-60° C. to obtain a drug solution, adding a solubilizing agent, the volatile oil inclusion compound obtained in step (2) and a flavor to the obtained drug solution, stirring evenly, and refrigerating at 2-10° C. to obtain an initial preparation solution; c) Fine preparation and sterilization: The obtained preliminary preparation solution is centrifuged, the centrifuged solution is collected, purified water is added to the fixed volume, filtered, filled and sterilized to obtain the oral liquid preparation.

8. The method for preparing an oral liquid preparation according to claim 7, characterized in that: In step (1), the soaking time is 1 hour; the extraction time is 8 hours; in step (2), the weight ratio of hydroxypropyl-β-cyclodextrin to purified water is 1:0.2-1.5, preferably 1:0.5-1.0; more preferably 1:0.75; the volume weight ratio of volatile oil to hydroxypropyl-β-cyclodextrin is 1:5-15mL / g, preferably 1:5-15mL / g; more preferably 1:10-12mL / g.

9. The method for preparing an oral liquid preparation according to claim 7, characterized in that: In step (3): in step I), each extraction time is 1.5 hours; in step II), each decoction time is 1 hour; ethanol is added until the alcohol content reaches 70%; the initial refrigeration time is up to 24 hours or more; the temperature during the second refrigeration is 2-10°C, and the refrigeration time is up to 48 hours or more.

10. The method for preparing an oral liquid preparation according to claim 7, characterized in that: In step a), the weight ratio of the extract to purified water is 1:0.2-1.5, preferably 1:1.0; the pH value is adjusted to 7.8-8.2; In step b), the antibacterial agent is potassium sorbate and / or sodium benzoate, preferably potassium sorbate; the sweetener is sucralose and / or steviol glycoside; the pH value is adjusted to 5.5-6.0; heated and boiled for 20 minutes; the solubilizer is one or more of polysorbate 80, glycerol, propylene glycol, polyethylene glycol 400 or sodium citrate, preferably polysorbate 80; the flavor is strawberry flavor, orange flavor or pineapple flavor, preferably strawberry flavor; In step c), during centrifugation, the rotation speed is 9400-9800 r / min, preferably 9600 r / min; during filtration, the filter membrane is 0.45 μm; during sterilization, the sterilization temperature is 100-110° C., preferably 104-106° C.; the sterilization time is 20-40 minutes, preferably 30 minutes.

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