A traditional Chinese medicine nasal spray for treating allergic rhinitis and a preparation method thereof

Abstract

The present application relates to the technical field of traditional Chinese medicine preparation, and discloses a traditional Chinese medicine nasal spray for treating allergic rhinitis and a preparation method thereof. The traditional Chinese medicine nasal spray comprises a water extraction and clarification liquid and an aromatic water concentrate. The water extraction and clarification liquid is prepared from water-extracted medicinal materials including honeysuckle, forsythia, radix scutellariae, kochia and periostracum cygni through water extraction and clarification treatment. The aromatic water concentrate is obtained by steam distillation of mint to obtain a condensate, and free oil phase is removed and concentrated to obtain. The water extraction and clarification liquid is kept at 2-8 DEG C, and the aromatic water concentrate is added step by step. The unit critical compatible volume is determined according to the turbidity change, and the production compounding volume of the aromatic water concentrate is determined according to 55%-80% of the unit critical compatible volume. The obtained traditional Chinese medicine nasal spray does not contain ethanol and polysorbate surfactant, and has no visible free oil phase, good low-temperature stability and consistent continuous spray dose.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, specifically to a traditional Chinese medicine nasal spray for treating allergic rhinitis and its preparation method. Background Technology

[0002] Allergic rhinitis is a non-infectious inflammatory disease of the nasal mucosa triggered by allergens, often manifesting as sneezing, nasal itching, increased nasal secretions, and nasal congestion. Traditional Chinese medicine nasal sprays can deliver the medication directly to the nasal cavity. Current traditional Chinese medicine nasal sprays typically add volatile oils or extracts containing aromatic components to aqueous extracts of traditional Chinese medicine, and disperse the aromatic components in the solution using ethanol, polysorbate surfactants, or other solubilizing excipients.

[0003] However, different batches of Chinese herbal extracts have different actual compatibility with aromatic components. When the existing technology adds aromatic components in a fixed proportion, it is difficult to adjust the amount of aromatic components added according to the actual compatibility of the Chinese herbal extracts, which can easily lead to insufficient low-temperature stability of the resulting Chinese herbal nasal spray. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a traditional Chinese medicine nasal spray for treating allergic rhinitis and its preparation method. This invention solves the problem that existing traditional Chinese medicine nasal sprays, which use a fixed proportion of aromatic components, are difficult to adjust the amount of aromatic components added according to the actual compatibility of the aqueous extract of the traditional Chinese medicine, resulting in insufficient low-temperature stability of the obtained traditional Chinese medicine nasal spray.

[0005] To achieve the above objectives, the present invention is implemented through the following technical solution: a traditional Chinese medicine nasal spray for treating allergic rhinitis, comprising a water-extracted clarified liquid and an aromatic water concentrate.

[0006] The water-extracted clarified liquid is obtained by water extraction and clarification of water-extracted medicinal materials, including honeysuckle, forsythia, scutellaria, kochia, and cicada molting.

[0007] The aromatic water concentrate is obtained by steam distillation of peppermint to obtain condensate, oil-water separation of the condensate to remove the free oil phase, and concentration of the aqueous phase after removal of the free oil phase.

[0008] The volume of the aromatic water concentrate added is 55% to 80% of the critical compatibility volume of the production batch. The critical compatibility volume of the production batch is calculated by proportionally converting the unit critical compatibility volume with the volume of the water-extracted clarified liquid to be compounded.

[0009] The critical compatibility volume is determined as follows: a quantitative amount of the water-extracted clarified liquid is maintained at 2–8°C, and the aromatic water concentrate is added to the water-extracted clarified liquid in stages. After each addition, the mixture is stirred and allowed to stand. When the turbidity of the mixture reaches a preset turbidity increment threshold for the first time relative to the turbidity without the addition of the aromatic water concentrate, the cumulative volume of the aromatic water concentrate added is determined as the critical compatibility volume. The preset turbidity increment threshold is 10–20 NTU.

[0010] The herbal nasal spray contains no ethanol or polysorbate surfactants and has no visible free oil phase.

[0011] Furthermore, the water-extracted medicinal material comprises the following raw materials in parts by weight:

[0012] Honeysuckle 8-16 parts, Forsythia 5-12 parts, Scutellaria baicalensis 8-16 parts, Kochia scoparia 4-10 parts, and Cicadae periostracum 3-8 parts;

[0013] The amount of peppermint is 5 to 12 parts by weight.

[0014] Furthermore, the water-extracted medicinal material comprises the following raw materials in parts by weight:

[0015] Honeysuckle 12 parts, forsythia 8 parts, scutellaria 12 parts, kochia 6 parts and cicada molting 6 parts;

[0016] The amount of peppermint is 9 parts by weight.

[0017] Furthermore, the clarified water extract is obtained by sequentially centrifuging, coarse filtration, and ultrafiltration of the original water extract, wherein the ultrafiltration process uses an ultrafiltration membrane with a molecular weight cutoff of 10 to 50 kilodaltons.

[0018] Furthermore, the pH value of the traditional Chinese medicine nasal spray is 5.8-6.5, the osmotic pressure is 270-330 milliohms per kilogram, and the total amount of raw material corresponding to each milliliter of the traditional Chinese medicine nasal spray is 80-180 mg.

[0019] Furthermore, the volume of the aromatic water concentrate added is 60% to 75% of the critical compatibility volume of the production batch.

[0020] This invention also provides a method for preparing the traditional Chinese medicine nasal spray for treating allergic rhinitis, comprising the following steps:

[0021] S1. The water-extracted medicinal materials, including honeysuckle, forsythia, scutellaria, kochia and cicada molting, are crushed and mixed to obtain a mixture of water-extracted medicinal materials;

[0022] S2. The water-extracted medicinal material mixture is subjected to fractional water extraction using purified water, and the extracts obtained from each water extraction are combined to obtain the original water extract.

[0023] S3. The water extract stock solution is clarified and concentrated to obtain a clarified water extract solution;

[0024] S4. The peppermint is subjected to steam distillation, the condensate produced by distillation is collected, the condensate is subjected to oil-water separation to remove the free oil phase, and the aqueous phase after the removal of the free oil phase is concentrated to obtain an aromatic water concentrate.

[0025] S5. Maintain a quantitative amount of the water-extracted clarified liquid at 2-8°C, and add the aromatic water concentrate to the water-extracted clarified liquid step by step. Stir and let stand after each addition. When the turbidity of the mixture reaches the preset turbidity increment threshold for the first time relative to the turbidity without the addition of the aromatic water concentrate, the cumulative volume of the aromatic water concentrate added is determined as the unit critical compatibility volume. The preset turbidity increment threshold is 10-20 NTU.

[0026] S6. Based on the critical compatibility volume of the unit and the volume of the water-extracted clarified liquid to be compounded, the critical compatibility volume of the production batch is obtained by proportional conversion. The production compounding volume of the aromatic water concentrate is determined according to 55% to 80% of the critical compatibility volume of the production batch. The aromatic water concentrate of the production compounding volume is added to the water-extracted clarified liquid to obtain the compounded drug solution.

[0027] S7. Adjust the pH value and osmotic pressure of the compound medicine solution, and filter and fill the compound medicine solution to obtain the traditional Chinese medicine nasal spray.

[0028] Further, step S2 includes:

[0029] Add 8 to 12 times the total mass of purified water to the water-extracted medicinal material mixture, extract at 65 to 80°C for 50 to 90 minutes, and filter to obtain the first extract and the first residue;

[0030] Add 6 to 10 times the weight of purified water to the first residue, extract at 85 to 95°C for 30 to 60 minutes, and filter to obtain the second extract;

[0031] The first extract and the second extract are combined to obtain the water extract stock solution.

[0032] Further, in step S3, the clarification process includes sequentially centrifuging, coarse filtration, and ultrafiltration of the water extract, wherein the ultrafiltration process uses an ultrafiltration membrane with a molecular weight cutoff of 10 to 50 kilodaltons.

[0033] The concentration process is carried out at a temperature not exceeding 60°C, so that the concentration of the active pharmaceutical ingredient corresponding to the water extract reaches 0.10 to 0.30 grams per milliliter.

[0034] Further, in step S4, the condensate is divided into front-stage condensate, middle-stage condensate and rear-stage condensate. The front-stage condensate, which accounts for 5% to 10% of the total volume of the condensate, is discarded, and the middle-stage condensate, which accounts for 40% to 70% of the total volume of the condensate, is collected. The middle-stage condensate is subjected to oil-water separation, and the aqueous phase after the removal of the free oil phase is concentrated at a temperature not exceeding 45°C.

[0035] Further, in step S6, the aromatic water concentrate is added to the water-extracted clarified liquid at a temperature of 10-25°C in 3-8 portions, and stirred for 3-10 minutes after each addition. After all the additions are completed, stirring continues for 10-30 minutes.

[0036] Further, in step S7, the pH value of the compound drug solution is adjusted to 5.8-6.5, the osmotic pressure of the compound drug solution is adjusted to 270-330 milliohms per kilogram, and then filtered sequentially using filter membranes with pore sizes of 0.45 micrometers and 0.22 micrometers.

[0037] This invention provides a traditional Chinese medicine nasal spray for treating allergic rhinitis and its preparation method. It has the following beneficial effects:

[0038] 1. This invention involves adding aromatic water concentrate to a quantitative amount of water-extracted clarified liquid at 2–8°C in stages. The critical compatibility volume per unit is determined based on the turbidity change of the mixture. The critical compatibility volume of the production batch is obtained by proportionally converting the unit critical compatibility volume with the actual volume of the water-extracted clarified liquid to be compounded. The production compounding volume of the aromatic water concentrate is then determined according to 55%–80% of the critical compatibility volume of the production batch. This allows the production compounding volume of the aromatic water concentrate to be adjusted according to the actual compatibility of different batches of water-extracted clarified liquid, avoiding the addition of aromatic water concentrate at a fixed ratio, which would result in the amount added approaching or exceeding the upper limit of compatibility of the water-extracted clarified liquid. This improves the low-temperature stability of the traditional Chinese medicine nasal spray.

[0039] 2. This invention involves steam distilling peppermint and separating the condensate into oil and water to remove the free oil phase. Only the aqueous phase after removing the free oil phase is used to prepare an aromatic water concentrate. This allows the aromatic components to be added to the water-extracted clarifying liquid in an aqueous phase-compatible state. Without using ethanol and polysorbate surfactants, the formation of visible free oil phase is reduced, and the dosage consistency of aromatic components during continuous spraying is improved.

[0040] 3. The present invention sequentially performs centrifugation, coarse filtration and ultrafiltration on the water extract, which can reduce the impact of suspended impurities and macromolecular colloids in the water extract on the compatibility of the aromatic water concentrate, reduce the initial turbidity of the Chinese herbal nasal spray and the risk of forming non-redispersible precipitates during storage.

[0041] 4. This invention uses a graded water extraction method to prepare the water extract stock solution, and performs two water extractions at a limited temperature. This can extract the water-soluble components from the water-extracted medicinal materials while controlling the impurity content introduced by high-temperature and long-term extraction, thus providing a stable water extract stock solution for subsequent clarification treatment and compounding of aromatic water concentrate.

[0042] 5. The present invention adjusts the pH value of the compound medicine solution to 5.8-6.5 and the osmotic pressure of the compound medicine solution to 270-330 milliomol per kilogram, so that the resulting Chinese medicine nasal spray has a pH value and osmotic pressure suitable for local nasal administration.

[0043] 6. The present invention uses honeysuckle, forsythia, scutellaria, kochia and cicada molting to prepare a water-based clarified liquid, and peppermint to prepare an aromatic water concentrate. The resulting Chinese herbal nasal spray can reduce sneezing, nose scratching and nasal secretions caused by allergic rhinitis, and reduce the serum total immunoglobulin E content. Attached Figure Description

[0044] Figure 1 This is a flowchart illustrating the preparation method of the traditional Chinese medicine nasal spray for treating allergic rhinitis according to the present invention.

[0045] Figure 2 A comparison chart showing the increase in turbidity of traditional Chinese medicine nasal sprays obtained by determining the production compounding volume based on 70% of the critical compatibility volume of the production batch under different raw material batches and by using a fixed production compounding volume.

[0046] Figure 3 The graph shows a comparison of the increase in turbidity of the traditional Chinese medicine nasal sprays prepared in Examples 1-5 and Comparative Examples 1-6 after five temperature cycles.

[0047] Figure 4 This is a comparison chart showing the deviation of menthol content in continuous sprays of the traditional Chinese medicine nasal sprays prepared in Examples 1-5 and Comparative Examples 1-6;

[0048] Figure 5 A comparison chart of efficacy indicators for different groups of allergic rhinitis medications. Detailed Implementation

[0049] The present application will be further described in detail below with reference to the embodiments. It should be understood that the following embodiments are only used to illustrate the technical solutions of the present application, and are not intended to limit the scope of protection of the present application.

[0050] Current traditional Chinese medicine nasal sprays typically involve directly adding the volatile oils of Chinese herbs to an aqueous extract and using ethanol or polysorbate surfactants for solubilization. However, the composition and solid content of the aqueous extract vary between different batches. When volatile components are added in a fixed ratio, the volatile components may exceed the actual compatibility of the aqueous extract, leading to problems such as increased turbidity, precipitation of free oil phase, and uneven spray dosage during low-temperature storage or continuous spraying.

[0051] The applicant's research found that the compatibility of the aqueous extract with the aromatic water concentrate is related to the batch of the aqueous extract and the composition of the aqueous extract. The amount of aromatic water concentrate added cannot be determined solely based on a fixed amount of peppermint. Therefore, this application involves steam distilling peppermint to remove the free oil phase from the condensate, obtaining an aromatic water concentrate. The aqueous extract is then maintained at 2–8°C, and the aromatic water concentrate is added stepwise to a fixed quantity of the aqueous extract. The critical compatibility volume per unit is determined based on the change in turbidity. This critical compatibility volume is then proportionally converted to the volume of the aqueous extract in the actual production batch to obtain the critical compatibility volume for the production batch. The production compounding volume of the aromatic water concentrate is then determined to be 55%–80% of the critical compatibility volume of the production batch.

[0052] like Figure 1 As shown, the production volume of the aromatic water concentrate can be adjusted according to the actual compatibility of the water-extracted clarified liquid, thereby reducing the risk of increased turbidity and free oil phase precipitation in the traditional Chinese medicine nasal spray during low-temperature storage without adding ethanol and polysorbate surfactants, and improving the dosage consistency of aromatic components during continuous spraying.

[0053] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0054] The water-extracted medicinal materials include honeysuckle, forsythia, scutellaria, kochia, and cicada molting. The water-extracted medicinal materials and peppermint were purchased from Beijing Tongrentang (Bozhou) Pharmaceutical Co., Ltd., and were identified and tested to meet the requirements of the corresponding Chinese herbal medicines in Part I of the 2025 edition of the Pharmacopoeia of the People's Republic of China.

[0055] Among them, honeysuckle is the dried flower bud or newly opened flower of Lonicera japonica Thunb. (family Caprifoliaceae); forsythia is the dried fruit of Forsythia suspensa Thunb. Vahl (family Oleaceae); scutellaria is the dried root of Scutellaria baicalensis Georgi (family Lamiaceae); kochia is the dried mature fruit of Kochia scoparia L. Schrad. (family Chenopodiaceae); cicada molt is the exoskeleton shed by the nymph of Cryptotympana pustulata Fabricius (family Cicadae); and peppermint is the dried aerial part of Mentha haplocalyx Briq. (family Lamiaceae). The water-extracted medicinal materials and peppermint are cleaned separately before use to remove impurities and stored in a sealed container under cool, dry conditions.

[0056] The purified water was prepared by a laboratory pure water preparation system and complies with the requirements for purified water in the 2025 edition of the Pharmacopoeia of the People's Republic of China.

[0057] Sodium chloride was purchased from Sinopharm Chemical Reagent Co., Ltd., analytical grade, CAS number 7647-14-5, and was used to adjust the osmotic pressure of the compound drug solution.

[0058] Citric acid monohydrate was purchased from Sinopharm Chemical Reagent Co., Ltd., analytical grade, CAS No. 5949-29-1; trisodium citrate dihydrate was purchased from Sinopharm Chemical Reagent Co., Ltd., analytical grade, CAS No. 6132-04-3; citric acid monohydrate and trisodium citrate dihydrate were used to adjust the pH value of the compound drug solution.

[0059] L-menthol reference standard was purchased from Sigma-Aldrich. It is an analytical standard with a purity of not less than 99.0% and CAS number 2216-51-5. It is used as a qualitative and quantitative reference standard for the analysis of volatile marker components in aromatic water concentrate.

[0060] Formalazine turbidity standard solution was purchased from Tanmo Quality Inspection Technology Co., Ltd., with a nominal turbidity of 4000 NTU, and was used for the calibration of turbidity detectors and the detection of preset turbidity increment thresholds.

[0061] The polyethersulfone ultrafiltration membranes were purchased from Merck Millipore, with molecular weight cutoffs of 10,000 Daltons, 20,000 Daltons, 30,000 Daltons, 40,000 Daltons, and 50,000 Daltons, respectively; the filter membranes with pore sizes of 0.45 μm and 0.22 μm were both polyethersulfone filter membranes, purchased from Merck Millipore.

[0062] The metered nasal spray pump bottle was purchased from Zhejiang Zhengzhuang Industrial Co., Ltd. The nominal single-puff spray volume of the spray pump is 0.10 ml, and the bottle volume is 15 ml.

[0063] Example 1

[0064] This embodiment provides a method for preparing a traditional Chinese medicine nasal spray for treating allergic rhinitis, including the following steps.

[0065] S1. Weigh out 80g of honeysuckle, 50g of forsythia, 80g of scutellaria, 40g of kochia, and 30g of cicada slough as water-extractable medicinal materials, and weigh out 50g of peppermint. Crush the honeysuckle, forsythia, scutellaria, kochia, and cicada slough separately to a particle size of 2mm, mix them evenly, and obtain a mixture of water-extractable medicinal materials.

[0066] In this embodiment, the weight parts of honeysuckle, forsythia, scutellaria, kochia, cicada molting and mint are 8 parts, 5 parts, 8 parts, 4 parts, 3 parts and 5 parts respectively.

[0067] S2. Add 2240 ml of purified water to 280 g of the aqueous extract mixture, extract at 65°C for 50 minutes, and filter to obtain the first extract and the first residue. Filter the first residue by pressure; the mass of the filtered residue is 400 g. Add 2400 ml of purified water to the first residue, extract at 85°C for 30 minutes, and filter to obtain the second extract. Combine the first and second extracts to obtain the original aqueous extract.

[0068] S3. Cool the water extract to 15°C and centrifuge at 4000 rpm for 15 minutes. Collect the supernatant and perform coarse filtration through a 5-micron pore size filter, followed by ultrafiltration using a polyethersulfone membrane with a molecular weight cutoff of 10 kilodaltons. Concentrate the ultrafiltration liquid under reduced pressure at 55°C to obtain 2800 mL of clarified water extract. The concentration of the active pharmaceutical ingredient in the clarified water extract is 0.10 g / mL.

[0069] S4. Crush 50 grams of peppermint to a particle size of 2 mm, add 300 ml of purified water for steam distillation, and add purified water during the distillation process to keep the liquid level in the distillation container stable. Collect a total of 1000 ml of condensate.

[0070] According to the collection order of the condensate, the condensate is divided into front-stage condensate, middle-stage condensate, and rear-stage condensate. 50 ml of the front-stage condensate (5% of the total condensate volume) is discarded, and 400 ml of the middle-stage condensate (40% of the total condensate volume) is collected. The remaining condensate is used as the rear-stage condensate and is not used in this embodiment.

[0071] The intermediate-stage condensate was transferred to an oil-water separator and allowed to stand for 60 minutes. The free oil phase that formed on the surface was removed, and the aqueous phase after removing the free oil phase was retained. The aqueous phase after removing the free oil phase was concentrated under reduced pressure at 45°C to obtain 350 mL of aromatic water concentrate. The aromatic water concentrate contained no visible free oil phase.

[0072] S5. Take 100 ml of the water-extracted clarified liquid as the base sample and keep the base sample at 2℃. While stirring, add 0.5 ml of aromatic water concentrate to the base sample each time, stirring for 1 minute after each addition and letting it stand for 20 minutes, and then measure the turbidity of the resulting mixture.

[0073] When the cumulative volume of the aromatic water concentrate added reaches 20 ml, the turbidity of the mixture increases by 10 NTU for the first time compared to the turbidity without the addition of aromatic water concentrate. Therefore, the 20 ml aromatic water concentrate corresponding to every 100 ml of water extract clarification is defined as the unit critical compatibility volume.

[0074] S6. Calculate the critical compatibility volume (CCM) proportionally to the volume of the water-extracted clarified liquid to be compounded. Each 100 ml of water-extracted clarified liquid corresponds to a CCM of 20 ml of aromatic water concentrate. The volume of the water-extracted clarified liquid to be compounded is 2800 ml. After proportional conversion, the CCM of the production batch is calculated to be 560 ml. The production compounding volume of the aromatic water concentrate is determined to be 308 ml, which is 55% of the CCM of the production batch.

[0075] The temperature of the water extract was controlled at 10℃. 308 ml of aromatic water concentrate was added to the water extract in three equal portions, stirring for 3 minutes after each addition. After all the water extract was added, stirring was continued for 10 minutes to obtain the compound drug solution.

[0076] S7. The pH of the compound solution was adjusted to 5.8 using citric acid monohydrate and trisodium citrate dihydrate, and the osmotic pressure of the compound solution was adjusted to 270 mOsmol per kilogram using sodium chloride. Purified water was added to adjust the total volume to 4125 ml, so that the total amount of raw material drug corresponding to each milliliter of traditional Chinese medicine nasal spray is 80 mg.

[0077] The compounded medicinal solution was filtered sequentially through polyethersulfone filter membranes with pore sizes of 0.45 micrometers and 0.22 micrometers, and then filled into quantitative nasal spray pump bottles, with each bottle containing 15 ml, to obtain a traditional Chinese medicine nasal spray.

[0078] The obtained traditional Chinese medicine nasal spray is free of ethanol and polysorbate surfactants, and has no visible free oil phase. After five temperature cycles at 2℃ and 20℃, the increase in turbidity of the obtained traditional Chinese medicine nasal spray does not exceed 10 NTU.

[0079] Example 2

[0080] This embodiment provides a method for preparing a traditional Chinese medicine nasal spray for treating allergic rhinitis, including the following steps.

[0081] S1. Weigh out 100g of honeysuckle, 60g of forsythia, 100g of scutellaria, 50g of kochia, and 40g of cicada slough as water-extractable medicinal materials, and weigh out 70g of peppermint. Crush the honeysuckle, forsythia, scutellaria, kochia, and cicada slough separately to a particle size of 3mm, mix them evenly, and obtain a mixture of water-extractable medicinal materials.

[0082] In this embodiment, the weight parts of honeysuckle, forsythia, scutellaria, kochia, cicada molting and mint are 10 parts, 6 parts, 10 parts, 5 parts, 4 parts and 7 parts respectively.

[0083] S2. Add 3150 ml of purified water to 350 g of the aqueous extract mixture, extract at 68°C for 60 minutes, and filter to obtain the first extract and the first residue. Filter the first residue by pressure; the mass of the filtered residue is 500 g. Add 3500 ml of purified water to the first residue, extract at 88°C for 40 minutes, and filter to obtain the second extract. Combine the first and second extracts to obtain the original aqueous extract.

[0084] S3. Cool the water extract to 18°C, centrifuge at 4500 rpm for 15 minutes, collect the supernatant for coarse filtration, and then perform ultrafiltration using a polyethersulfone ultrafiltration membrane with a molecular weight cutoff of 20 kilodaltons. Concentrate the ultrafiltration liquid under reduced pressure at 55°C to obtain 2333 ml of clarified water extract, corresponding to a raw material concentration of 0.15 g / ml.

[0085] S4. Crush 70g of peppermint to a particle size of 3mm, add 490ml of purified water and steam distill, collecting a total of 1200ml of condensate.

[0086] Discard the 72 ml of initial condensate (6% of the total condensate volume) and collect the 600 ml of intermediate condensate (50% of the total condensate volume). After allowing the intermediate condensate to stand, perform oil-water separation, remove the free oil phase, and retain the aqueous phase after removing the free oil phase.

[0087] The aqueous phase after removing the free oil phase was concentrated under reduced pressure at 43°C to obtain 450 mL of aromatic water concentrate. No free oil phase was visible to the naked eye in the aromatic water concentrate.

[0088] S5. Take 100 ml of the water extract as the base sample and keep the base sample at 4℃. Add 1 ml of aromatic water concentrate to the base sample each time, stirring for 2 minutes and letting it stand for 30 minutes after each addition.

[0089] When the cumulative volume of the aromatic water concentrate added reaches 22 ml, the turbidity of the mixture increases by 12 NTU for the first time compared to the turbidity without the addition of aromatic water concentrate. Therefore, the 22 ml aromatic water concentrate corresponding to every 100 ml of water extract clarification is defined as the unit critical compatibility volume.

[0090] S6. Calculate the critical compatibility volume (CCM) proportionally to the volume of the water extract to be compounded. Each 100 ml of water extract corresponds to a CCM of 22 ml of aromatic water concentrate. The volume of the water extract to be compounded is 2333 ml. After proportional conversion, the CCM for the production batch is calculated to be 513.26 ml. Determine the production compounding volume of the aromatic water concentrate as 60% of the CCM for the production batch. The calculated production compounding volume is 307.96 ml, which is rounded up to 308 ml.

[0091] The temperature of the water extract was controlled at 15℃. 308 ml of aromatic water concentrate was added to the water extract in four equal portions. After each addition, the mixture was stirred for 5 minutes. After all the extracts were added, the mixture was stirred for another 15 minutes to obtain the compound drug solution.

[0092] S7. Adjust the pH of the compound solution to 6.0, adjust the osmotic pressure of the compound solution to 285 mOsmol per kilogram, add purified water to adjust the total volume to 4200 ml, so that the total amount of raw material drug corresponding to each ml of Chinese herbal nasal spray is 100 mg.

[0093] The compounded medicinal solution was filtered sequentially through polyethersulfone filter membranes with pore sizes of 0.45 micrometers and 0.22 micrometers, and then filled into a metered nasal spray pump bottle to obtain a traditional Chinese medicine nasal spray.

[0094] The obtained traditional Chinese medicine nasal spray is free of ethanol and polysorbate surfactants, and has no visible free oil phase. After five temperature cycles at 4℃ and 25℃, the increase in turbidity of the obtained traditional Chinese medicine nasal spray does not exceed 10 NTU.

[0095] Example 3

[0096] This embodiment provides a method for preparing a traditional Chinese medicine nasal spray for treating allergic rhinitis, including the following steps.

[0097] S1. Weigh out 120g of honeysuckle, 80g of forsythia, 120g of scutellaria, 60g of kochia, and 60g of cicada slough as water-extractable medicinal materials, and weigh out 90g of peppermint. Crush the honeysuckle, forsythia, scutellaria, kochia, and cicada slough separately to a particle size of 4mm, mix them evenly, and obtain a mixture of water-extractable medicinal materials.

[0098] In this embodiment, the weight parts of honeysuckle, forsythia, scutellaria, kochia, cicada molting and mint are 12 parts, 8 parts, 12 parts, 6 parts, 6 parts and 9 parts respectively.

[0099] S2. Add 4400 ml of purified water to 440 g of the aqueous extract mixture, extract at 72°C for 70 minutes, and filter to obtain the first extract and the first residue. Filter the first residue by pressure; the mass of the filtered residue is 620 g. Add 4960 ml of purified water to the first residue, extract at 90°C for 45 minutes, and filter to obtain the second extract. Combine the first and second extracts to obtain the original aqueous extract.

[0100] S3. Cool the water extract to 20°C and centrifuge at 5000 rpm for 20 minutes. Take the supernatant and perform coarse filtration and ultrafiltration in sequence. The ultrafiltration process uses a polyethersulfone ultrafiltration membrane with a molecular weight cutoff of 30 kilodaltons.

[0101] The liquid obtained by ultrafiltration was concentrated under reduced pressure at 50°C to obtain 2200 ml of water extract clarified solution, with a raw material concentration of 0.20 g / ml.

[0102] S4. Crush 90 grams of peppermint to a particle size of 5 mm, add 810 ml of purified water and steam distill, collecting a total of 1500 ml of condensate.

[0103] Discard 120 ml of the initial condensate (8% of the total condensate volume) and collect 900 ml of the intermediate condensate (60% of the total condensate volume). Let the intermediate condensate stand for 60 minutes, remove the free oil phase that forms on the surface, and retain the aqueous phase after removing the free oil phase.

[0104] The aqueous phase after removing the free oil phase was concentrated under reduced pressure at 40°C to obtain 600 mL of aromatic water concentrate. The aromatic water concentrate contained no visible free oil phase.

[0105] S5. Take 100 ml of the water extract as the base sample and keep the base sample at 5°C. While continuously stirring, add 1 ml of aromatic water concentrate to the base sample each time, stirring for 3 minutes after each addition and letting it stand for 40 minutes.

[0106] When the cumulative volume of the aromatic water concentrate added reaches 25 ml, the turbidity of the mixture increases by 15 NTU for the first time compared to the turbidity without the addition of aromatic water concentrate. Therefore, 25 ml of aromatic water concentrate corresponding to 100 ml of water extract clarification is defined as the unit critical compatibility volume.

[0107] S6. Calculate the critical compatibility volume (CCM) proportionally to the volume of the water extract to be compounded. Each 100 ml of water extract corresponds to 25 ml of aromatic water concentrate. The volume of the water extract to be compounded is 2200 ml. After proportional conversion, the CCM for the production batch is calculated to be 550 ml. Determine the production compounding volume of the aromatic water concentrate as 70% of the production batch's CCM, resulting in a production compounding volume of 385 ml.

[0108] The temperature of the water extract was controlled at 20℃. 385 ml of aromatic water concentrate was added to the water extract in 5 equal portions. After each addition, the mixture was stirred for 6 minutes. After all the extracts were added, the mixture was stirred for another 20 minutes to obtain the compound drug solution.

[0109] S7. The pH of the compound solution was adjusted to 6.2 using citric acid monohydrate and trisodium citrate dihydrate, and the osmotic pressure of the compound solution was adjusted to 300 mOsmol per kilogram using sodium chloride. Purified water was added to adjust the total volume to 4240 ml, so that the total amount of raw material drug corresponding to each milliliter of traditional Chinese medicine nasal spray is 125 mg.

[0110] The compounded medicinal solution was filtered sequentially through polyethersulfone filter membranes with pore sizes of 0.45 micrometers and 0.22 micrometers, and then filled into quantitative nasal spray pump bottles, with each bottle containing 15 ml, to obtain a traditional Chinese medicine nasal spray.

[0111] The obtained traditional Chinese medicine nasal spray is free of ethanol and polysorbate surfactants, and has no visible free oil phase. After five temperature cycles at 5℃ and 25℃, the increase in turbidity of the obtained traditional Chinese medicine nasal spray does not exceed 10 NTU.

[0112] Example 4

[0113] This embodiment provides a method for preparing a traditional Chinese medicine nasal spray for treating allergic rhinitis, including the following steps.

[0114] S1. Weigh out 140g of honeysuckle, 100g of forsythia, 140g of scutellaria, 80g of kochia, and 70g of cicada slough as water-extractable medicinal materials, and weigh out 100g of peppermint. Crush the honeysuckle, forsythia, scutellaria, kochia, and cicada slough separately to a particle size of 5mm, mix them evenly, and obtain a mixture of water-extractable medicinal materials.

[0115] In this embodiment, the weight parts of honeysuckle, forsythia, scutellaria, kochia, cicada molting and mint are 14 parts, 10 parts, 14 parts, 8 parts, 7 parts and 10 parts respectively.

[0116] S2. Add 5830 ml of purified water to 530 g of the aqueous extract mixture, extract at 78°C for 80 minutes, and filter to obtain the first extract and the first residue. Filter the first residue by pressure; the mass of the filtered residue is 740 g. Add 6660 ml of purified water to the first residue, extract at 93°C for 55 minutes, and filter to obtain the second extract. Combine the first and second extracts to obtain the original aqueous extract.

[0117] S3. Cool the water extract to 22°C and centrifuge at 5500 rpm for 20 minutes. Take the supernatant and perform coarse filtration and ultrafiltration in sequence. The ultrafiltration treatment uses a polyethersulfone ultrafiltration membrane with a molecular weight cutoff of 40 kilodaltons.

[0118] The liquid obtained by ultrafiltration was concentrated under reduced pressure at 48°C to obtain 2120 ml of water extract clarified solution, with a corresponding raw material concentration of 0.25 g / ml.

[0119] S4. Crush 100g of peppermint to a particle size of 6mm, add 1000ml of purified water and steam distill, collecting a total of 1600ml of condensate.

[0120] Discard the 144 mL initial condensate (9% of the total condensate volume) and collect the 1040 mL intermediate condensate (65% of the total condensate volume). Perform oil-water separation on the intermediate condensate, removing the free oil phase and retaining the aqueous phase after removing the free oil phase.

[0121] The aqueous phase after removing the free oil phase was concentrated under reduced pressure at 42°C to obtain 600 mL of aromatic water concentrate. The aromatic water concentrate contained no visible free oil phase.

[0122] S5. Take 100 ml of the water extract as the base sample and keep the base sample at 7°C. Add 1 ml of aromatic water concentrate to the base sample each time, stirring for 4 minutes and letting it stand for 50 minutes after each addition.

[0123] When the cumulative volume of the aromatic water concentrate added reaches 28 ml, the turbidity of the mixture increases by 18 NTU for the first time compared to the turbidity without the addition of aromatic water concentrate. Therefore, the 28 ml aromatic water concentrate corresponding to every 100 ml of water extract clarification is defined as the unit critical compatibility volume.

[0124] S6. Calculate the critical compatibility volume (CCM) proportionally to the volume of the water extract to be compounded. Each 100 ml of water extract corresponds to 28 ml of aromatic water concentrate. The volume of the water extract to be compounded is 2120 ml. After proportional conversion, the CCM for the production batch is calculated to be 593.6 ml. Determine the production compounding volume of the aromatic water concentrate as 75% of the production batch's CCM, resulting in a production compounding volume of 445.2 ml.

[0125] The temperature of the water extract was controlled at 22℃. 445.2 ml of aromatic water concentrate was added to the water extract in 6 equal portions. After each addition, the mixture was stirred for 8 minutes. After all the extracts were added, the mixture was stirred for another 25 minutes to obtain the compound drug solution.

[0126] S7. Adjust the pH of the compound solution to 6.4, adjust the osmotic pressure of the compound solution to 315 mOsmol per kilogram, add purified water to adjust the total volume to 3937.5 ml, so that the total amount of raw material drug corresponding to each ml of Chinese herbal nasal spray is 160 mg.

[0127] The compounded medicinal solution was filtered sequentially through polyethersulfone filter membranes with pore sizes of 0.45 micrometers and 0.22 micrometers, and then filled into a metered nasal spray pump bottle to obtain a traditional Chinese medicine nasal spray.

[0128] The obtained traditional Chinese medicine nasal spray is free of ethanol and polysorbate surfactants, and has no visible free oil phase. After five temperature cycles at 7°C and 28°C, the increase in turbidity of the obtained traditional Chinese medicine nasal spray does not exceed 10 NTU.

[0129] Example 5

[0130] This embodiment provides a method for preparing a traditional Chinese medicine nasal spray for treating allergic rhinitis, including the following steps.

[0131] S1. Weigh out 160g of honeysuckle, 120g of forsythia, 160g of scutellaria, 100g of kochia, and 80g of cicada slough as water-extractable medicinal materials, and weigh out 120g of peppermint. Crush the honeysuckle, forsythia, scutellaria, kochia, and cicada slough separately to a particle size of 6mm, mix them evenly, and obtain a mixture of water-extractable medicinal materials.

[0132] In this embodiment, the weight parts of honeysuckle, forsythia, scutellaria, kochia, cicada molting and mint are 16 parts, 12 parts, 16 parts, 10 parts, 8 parts and 12 parts respectively.

[0133] S2. Add 7440 ml of purified water to 620 g of the aqueous extract mixture, extract at 80°C for 90 minutes, and filter to obtain the first extract and the first residue. Filter the first residue by pressure; the mass of the filtered residue is 870 g. Add 8700 ml of purified water to the first residue, extract at 95°C for 60 minutes, and filter to obtain the second extract. Combine the first and second extracts to obtain the original aqueous extract.

[0134] S3. Cool the water extract to 25°C and centrifuge at 6000 rpm for 30 minutes. Take the supernatant and perform coarse filtration and ultrafiltration in sequence. The ultrafiltration process uses a polyethersulfone ultrafiltration membrane with a molecular weight cutoff of 50 kilodaltons.

[0135] The liquid obtained by ultrafiltration was concentrated under reduced pressure at 60°C to obtain 2066.7 mL of water extract clarified solution, and the concentration of the active pharmaceutical ingredient corresponding to the water extract clarified solution was 0.30 g / mL.

[0136] S4. Crush 120g of peppermint to a particle size of 8mm, add 1440ml of purified water and steam distill, collecting a total of 2000ml of condensate.

[0137] Discard 200 ml of the initial condensate (10% of the total condensate volume) and collect 1400 ml of the intermediate condensate (70% of the total condensate volume). Let the intermediate condensate stand for 90 minutes to separate the oil and water phases, remove the free oil phase, and retain the aqueous phase after removing the free oil phase.

[0138] The aqueous phase after removing the free oil phase was concentrated under reduced pressure at 45°C to obtain 800 mL of aromatic water concentrate. No free oil phase was visible to the naked eye in the aromatic water concentrate.

[0139] S5. Take 100 ml of the water extract as the base sample and keep the base sample at 8°C. Add 2 ml of aromatic water concentrate to the base sample each time, stirring for 5 minutes and letting it stand for 60 minutes after each addition.

[0140] When the cumulative volume of the aromatic water concentrate added reaches 30 ml, the turbidity of the mixture increases by 20 NTU for the first time compared to the turbidity without the addition of aromatic water concentrate. Therefore, the 30 ml of aromatic water concentrate corresponding to every 100 ml of water extract clarification is defined as the unit critical compatibility volume.

[0141] S6. Calculate the critical compatibility volume (CCM) proportionally to the volume of the water extract to be compounded. Each 100 ml of water extract corresponds to a CCM of 30 ml of aromatic water concentrate. The volume of the water extract to be compounded is 2066.7 ml. After proportional conversion, the CCM for the production batch is calculated to be 620 ml. Determine the production compounding volume of the aromatic water concentrate as 80% of the production batch's CCM. The calculated production compounding volume is 496 ml, which is then rounded up.

[0142] The temperature of the water extract was controlled at 25℃. 496 ml of aromatic water concentrate was added to the water extract in 8 equal portions. After each addition, the mixture was stirred for 10 minutes. After all the extracts were added, the mixture was stirred for another 30 minutes to obtain the compound drug solution.

[0143] S7. The pH of the compound solution was adjusted to 6.5 using citric acid monohydrate and trisodium citrate dihydrate, and the osmotic pressure of the compound solution was adjusted to 330 mOsmol per kilogram using sodium chloride. Purified water was added to adjust the total volume to 4111.1 ml, so that the total amount of raw materials corresponding to each milliliter of traditional Chinese medicine nasal spray was 180 mg.

[0144] The compounded medicinal solution was filtered sequentially through polyethersulfone filter membranes with pore sizes of 0.45 micrometers and 0.22 micrometers, and then filled into quantitative nasal spray pump bottles, with each bottle containing 15 ml, to obtain a traditional Chinese medicine nasal spray.

[0145] The obtained traditional Chinese medicine nasal spray is free of ethanol and polysorbate surfactants, and has no visible free oil phase. After five temperature cycles at 8℃ and 30℃, the increase in turbidity of the obtained traditional Chinese medicine nasal spray does not exceed 10 NTU.

[0146] Comparative Example 1

[0147] The only difference between this comparative example and Example 3 is that, in step S6, the production compounding volume of the aromatic water concentrate is determined according to 100% of the critical compatibility volume of the production batch, instead of 70% of the critical compatibility volume of the production batch.

[0148] Specifically, in step S5, the critical compatibility volume corresponding to 100 ml of water-extracted clarified liquid is measured to be 25 ml of aromatic water concentrate. Based on the proportional conversion between the critical compatibility volume and the volume of the 2200 ml water-extracted clarified liquid to be compounded, the critical compatibility volume for the production batch is calculated to be 550 ml. The production compounding volume of the aromatic water concentrate is determined to be 100% of the critical compatibility volume of the production batch, resulting in a production compounding volume of 550 ml.

[0149] The temperature of the water extract was controlled at 20℃. 550 ml of aromatic water concentrate was added to the water extract in 5 equal portions. After each addition, the mixture was stirred for 6 minutes. After all the extracts were added, the mixture was stirred for another 20 minutes to obtain the compound drug solution.

[0150] Subsequently, the pH value and osmotic pressure of the compound medicine solution were adjusted according to step S7 of Example 3, and purified water was added to adjust the total volume so that the total amount of raw materials corresponding to each milliliter of traditional Chinese medicine nasal spray was 125 mg. The solution was filtered through polyethersulfone filter membranes with pore sizes of 0.45 μm and 0.22 μm and then filled to obtain the traditional Chinese medicine nasal spray of Comparative Example 1.

[0151] Comparative Example 2

[0152] The only difference between this comparative example and Example 3 is that in step S5, the critical compatibility volume is determined at 25°C instead of maintaining the water-extracted clarified liquid at 5°C to determine the critical compatibility volume.

[0153] Specifically, 100 ml of the water-extracted clarified liquid was used as the base sample, and the base sample was kept at 25°C. Under continuous stirring, 1 ml of aromatic water concentrate was added to the base sample each time, and the mixture was stirred for 3 minutes and allowed to stand for 40 minutes after each addition.

[0154] When the cumulative volume of the aromatic water concentrate added reaches 32 ml, the turbidity of the mixture increases by 15 NTU for the first time compared to the turbidity without the addition of aromatic water concentrate. Therefore, the 32 ml aromatic water concentrate corresponding to every 100 ml of water extract clarification is defined as the unit critical compatibility volume.

[0155] In step S6, the critical compatibility volume per unit measured at 25°C is proportionally converted to the volume of the water extract to be compounded. Each 100 ml of water extract corresponds to a critical compatibility volume of 32 ml of aromatic water concentrate. The volume of the water extract to be compounded is 2200 ml. After proportional conversion, the critical compatibility volume for the production batch is calculated to be 704 ml. The production compounding volume of the aromatic water concentrate is determined to be 70% of the critical compatibility volume of the production batch, resulting in a production compounding volume of 492.8 ml.

[0156] Subsequently, following the method of adding the aromatic water concentrate in step S6 of Example 3 and step S7, low-temperature compounding, pH adjustment, osmotic pressure adjustment, filtration and filling were carried out to obtain the traditional Chinese medicine nasal spray of Comparative Example 2.

[0157] Comparative Example 3

[0158] The only difference between this comparative example and Example 3 is that the free oil phase in the intermediate condensate is not removed in step S4.

[0159] Specifically, 90 grams of peppermint were crushed to a particle size of 5 mm, and 810 ml of purified water was added for steam distillation, collecting a total of 1500 ml of condensate; 120 ml of the initial condensate was discarded, and 900 ml of the middle condensate was collected.

[0160] After the mid-section condensate was allowed to stand for 60 minutes, without oil-water separation, the mid-section condensate containing the free oil phase was directly concentrated under reduced pressure at 40°C to obtain an aromatic water concentrate.

[0161] Subsequently, the critical compatibility volume was determined according to step S5 of Example 3. The critical compatibility volume of the production batch was obtained by proportionally converting the critical compatibility volume of the unit critical compatibility volume to the volume of the water-extracted clarified liquid to be compounded. The production compounding volume of the aromatic water concentrate was determined according to 70% of the critical compatibility volume of the production batch. Then, the compounding, pH adjustment, osmotic pressure adjustment, filtration and filling were carried out according to steps S6 and S7 of Example 3 to obtain the traditional Chinese medicine nasal spray of Comparative Example 3.

[0162] Comparative Example 4

[0163] The only difference between this comparative example and Example 3 is that the water extract stock solution is not subjected to ultrafiltration in step S3.

[0164] Specifically, the water extract was cooled to 20°C and centrifuged at 5000 rpm for 20 minutes. The supernatant was then coarsely filtered, without using a polyethersulfone ultrafiltration membrane with a molecular weight cutoff of 30 kilodaltons for ultrafiltration.

[0165] The liquid obtained from coarse filtration was concentrated under reduced pressure at 50°C to obtain 2200 ml of water extract clarified solution, with a corresponding raw material concentration of 0.20 g / ml.

[0166] Subsequently, the aromatic water concentrate was prepared according to step S4 of Example 3, and the unit critical compatibility volume was determined according to step S5 of Example 3. The unit critical compatibility volume was proportionally converted to the volume of the water-extracted clarified liquid to be compounded to obtain the critical compatibility volume of the production batch. The production compounding volume of the aromatic water concentrate was determined according to 70% of the critical compatibility volume of the production batch. Then, the compounding, pH adjustment, osmotic pressure adjustment, filtration and filling were carried out according to steps S6 and S7 of Example 3 to obtain the traditional Chinese medicine nasal spray of Comparative Example 4.

[0167] Comparative Example 5

[0168] The only difference between this comparative example and Example 3 is that the determination process of the unit critical compatibility volume in step S5 is not performed, nor is the critical compatibility volume of the production batch obtained by proportionally converting the unit critical compatibility volume with the volume of the water-extracted clarified liquid to be compounded. Instead, the production compounding volume of the aromatic water concentrate is determined by a fixed addition volume.

[0169] Specifically, based on the weight ratio of peppermint to water-extracted medicinal materials, the production compound volume of aromatic water concentrate is fixed at 20 ml of aromatic water concentrate for every 100 ml of water-extracted clarified liquid, and the production compound volume of aromatic water concentrate corresponding to 2200 ml of water-extracted clarified liquid is 440 ml.

[0170] The temperature of the water extract was controlled at 20℃. 440 ml of aromatic water concentrate was added to the water extract in 5 equal portions. After each addition, the mixture was stirred for 6 minutes. After all the extracts were added, the mixture was stirred for another 20 minutes to obtain the compound drug solution.

[0171] Subsequently, the pH value and osmotic pressure of the compound medicine solution were adjusted according to step S7 of Example 3, and purified water was added to adjust the total volume so that the total amount of raw materials corresponding to each milliliter of traditional Chinese medicine nasal spray was 125 mg. The solution was filtered through polyethersulfone filter membranes with pore sizes of 0.45 μm and 0.22 μm and then filled to obtain the traditional Chinese medicine nasal spray of Comparative Example 5.

[0172] Comparative Example 6

[0173] The only difference between this comparative example and Example 3 is that in step S6, the production compounding volume of the aromatic water concentrate is determined according to 40% of the critical compatibility volume of the production batch, instead of 70% of the critical compatibility volume of the production batch.

[0174] Specifically, in step S5, the critical compatibility volume corresponding to 100 ml of water-extracted clarified liquid is measured to be 25 ml of aromatic water concentrate. Based on the proportional conversion between the critical compatibility volume and the volume of the 2200 ml water-extracted clarified liquid to be compounded, the critical compatibility volume for the production batch is calculated to be 550 ml. The production compounding volume of the aromatic water concentrate is determined to be 220 ml, which is 40% of the critical compatibility volume for the production batch.

[0175] The temperature of the water extract was controlled at 20℃. 220 ml of aromatic water concentrate was added to the water extract in 5 equal portions. After each addition, the mixture was stirred for 6 minutes. After all the extracts were added, the mixture was stirred for another 20 minutes to obtain the compound drug solution.

[0176] Subsequently, the pH value and osmotic pressure of the compound medicine solution were adjusted according to step S7 of Example 3, and purified water was added to adjust the total volume so that the total amount of raw materials corresponding to each milliliter of traditional Chinese medicine nasal spray was 125 mg. The solution was filtered through polyethersulfone filter membranes with pore sizes of 0.45 μm and 0.22 μm and then filled to obtain the traditional Chinese medicine nasal spray of Comparative Example 6.

[0177] Test Example 1: Low Temperature Stability and Batch Adaptability Test

[0178] 1.1 Low-temperature stability test method

[0179] Take three bottles of each of the traditional Chinese medicine nasal sprays prepared in Examples 1-5 and Comparative Examples 1-6, and take 10 ml from each bottle as a parallel sample.

[0180] The initial turbidity of each sample was determined using a turbidity detector calibrated with formalin turbidity standard solution. Subsequently, each sample underwent five temperature cycles, each cycle comprising the following steps:

[0181] First, place the sample in an environment of 4°C for 24 hours, and then place the sample in an environment of 25°C for 24 hours.

[0182] After completing five temperature cycles, the sample was restored to 25°C and allowed to stand for 2 hours. The turbidity of the sample after the cycle was measured, and the presence of visible free oil phase, continuous oil ring, or non-redispersible precipitate was observed in the sample.

[0183] The increase in turbidity is the difference between the turbidity after cycling and the initial turbidity. The test results are the average of three parallel samples, and the results are shown in Table 1.

[0184] Table 1. Low-temperature stability test results of various traditional Chinese medicine nasal sprays

[0185] Example 1 5.1 11.4 6.3 No visible free oil phase, no non-redispersible precipitate Example 2 5.8 11.0 5.2 No visible free oil phase, no non-redispersible precipitate Example 3 4.6 9.4 4.8 No visible free oil phase, no non-redispersible precipitate Example 4 6.3 13.1 6.8 No visible free oil phase, no non-redispersible precipitate Example 5 7.0 15.7 8.7 No visible free oil phase, no non-redispersible precipitate Comparative Example 1 4.8 21.6 16.8 Slight continuous oil rings appeared Comparative Example 2 4.9 24.7 19.8 Continuous oil rings and opalescence appear Comparative Example 3 8.6 38.4 29.8 Visible free oil phase appears Comparative Example 4 22.5 48.9 26.4 Non-redispersible precipitate appears Comparative Example 5 5.0 13.9 8.9 No visible free oil phase Comparative Example 6 4.1 7.0 2.9 No visible free oil phase, no non-redispersible precipitate

[0186] Depend on Figure 3 As shown in Table 1, after five temperature cycles, the turbidity increase of the traditional Chinese medicine nasal sprays prepared in Examples 1 to 5 did not exceed 10 NTU, and there were no visible free oil phases or non-redispersible precipitates.

[0187] Comparative Example 1 determined the production compounding volume of the aromatic water concentrate according to 100% of the unit critical compatibility volume. After circulation, the turbidity increased significantly and a slight continuous oil ring appeared, indicating that when the aromatic water concentrate was added to the unit critical compatibility volume, the resulting Chinese medicine nasal spray lacked the compatibility margin to resist temperature changes.

[0188] Comparative Example 2 determined the unit critical compatibility volume at 25℃. The measured unit critical compatibility volume was greater than that measured at 2-8℃, resulting in a larger production compounding volume of the aromatic water concentrate. The resulting traditional Chinese medicine nasal spray exhibited opalescence and continuous oil rings after low-temperature cycling.

[0189] Comparative Example 3 did not remove the free oil phase, and after circulation, a visible free oil phase appeared. Comparative Example 4 did not undergo ultrafiltration treatment, and its initial turbidity and turbidity after circulation both increased significantly, and non-redispersible precipitates appeared.

[0190] Although Comparative Example 6 showed a lower increase in turbidity, its production and compounding volume of aromatic water concentrate was only 40% of the unit critical compatibility volume. It is necessary to combine efficacy testing to evaluate whether it can provide sufficient therapeutic effect.

[0191] 1.2 Batch Adaptability Testing Method

[0192] Three other batches of honeysuckle, forsythia, scutellaria, kochia, cicada molting, and peppermint were selected and designated as batch A, batch B, and batch C, respectively. Aqueous extracts and aromatic water concentrates were prepared according to steps S1-S5 of Example 3, and the critical compatibility volume per 100 ml of aqueous extract was determined.

[0193] For each batch, the production blending volume of the aromatic water concentrate is determined using the following two methods:

[0194] In the first method, following the method in Example 3, the production and compounding volume of the aromatic water concentrate is determined to be 70% of the unit critical compatibility volume;

[0195] The second method follows the method of Comparative Example 5, without determining the critical compatibility volume, and fixes the addition of 20 ml of aromatic water concentrate to every 100 ml of water extract clarified liquid.

[0196] Five temperature cycles were performed according to the method in Test Example 1.1, and the results are as follows: Figure 2 As shown in Table 2.

[0197] Table 2. Adaptability of unit critical compatibility volume control to different raw material batches

[0198] Batch A 21.0 14.7 20.0 4.6 13.7 Batch B 25.0 17.5 20.0 4.8 8.9 Batch C 29.0 20.3 20.0 5.1 5.4

[0199] When batch A uses the fixed production compounding volume of Comparative Example 5, the added volume of aromatic water concentrate reaches 95.2% of the unit critical compatibility volume, and the turbidity increase after temperature cycling reaches 13.7 NTU.

[0200] When batch C uses the same fixed production compounding volume, the added volume of aromatic water concentrate is only 69.0% of the unit critical compatibility volume. This indicates that the actual compatibility of different batches of water-extracted clarified liquid with aromatic water concentrate varies, and using a fixed production compounding volume cannot guarantee that different batches of traditional Chinese medicine nasal spray have the same compatibility margin.

[0201] After determining the production compounding volume using 70% of the unit critical compatibility volume, the turbidity increase of the three raw material batches did not exceed 5.1 NTU, indicating that the unit critical compatibility volume can convert the differences between raw material batches into the adjustment amount of the production compounding volume of the aromatic water concentrate.

[0202] Test Example 2: Continuous Spray Dosage Consistency Test

[0203] 2.1 Test Method

[0204] Six bottles of each of the traditional Chinese medicine nasal sprays prepared in Examples 1-5 and Comparative Examples 1-6 were taken and placed at 25°C for 24 hours before testing. The spray bottles were not shaken before the test.

[0205] Each bottle of herbal nasal spray is first pre-pressed 3 times to achieve a stable spray state. Then, following the spray sequence, the spray solution is divided into the first 10 presses, the middle 10 presses, and the last 10 presses.

[0206] The volume of each spray was determined by weighing. After each spray was completed, the change in mass of the spray bottle was weighed, and the volume of each spray was calculated based on the density of the herbal nasal spray.

[0207] The menthol content in the first 10 sprays, the middle 10 sprays, and the last 10 sprays was determined by gas chromatography. Gas chromatography was performed using a polyethylene glycol stationary capillary column with an injection port temperature of 220℃ and a detector temperature of 250℃. Nitrogen was used as the carrier gas, and a flame ionization detector was employed. A standard curve was established using L-menthol as a reference standard.

[0208] The average menthol content of the first ten, middle ten, and last ten sprays of each bottle of Chinese herbal nasal spray was set as 100%, and the relative menthol content of the first ten, middle ten, and last ten sprays was calculated respectively.

[0209] The deviation of menthol content in continuous spraying was obtained by dividing the difference between the highest and lowest relative menthol content in the three spraying stages by the average relative menthol content in the three spraying stages. The test results are shown in Table 3.

[0210] Table 3 Consistency of continuous spray dosage for various traditional Chinese medicine nasal sprays

[0211] Example 1 0.100 2.9 97.2 101.3 98.4 4.1 Example 2 0.101 2.7 96.8 101.7 98.9 4.9 Example 3 0.100 2.6 97.5 102.1 98.2 4.6 Example 4 0.099 3.1 95.8 102.7 99.1 7.0 Example 5 0.101 3.4 94.9 103.8 98.6 9.0 Comparative Example 1 0.100 3.8 89.4 100.8 112.6 22.7 Comparative Example 2 0.101 4.1 86.7 101.9 115.4 28.3 Comparative Example 3 0.098 5.2 72.6 93.8 133.7 63.5 Comparative Example 4 0.096 6.1 88.9 103.6 107.5 18.2 Comparative Example 5 0.100 3.7 90.8 100.5 109.7 18.8 Comparative Example 6 0.100 2.5 98.4 100.8 99.1 2.4

[0212] Depend on Figure 4 As shown in Table 3, the average single-press spray volume of Examples 1 to 5 is close to the nominal single-press spray volume of the metered nasal spray pump bottle, and the deviation of menthol content in continuous spray does not exceed 10%.

[0213] The amount of aromatic water concentrate added in Comparative Examples 1 and 2 was close to or exceeded the stable compatibility range of the water-extracted clarified liquid under low temperature conditions, which caused changes in the distribution of aromatic components during continuous spraying.

[0214] In Comparative Example 3, where the free oil phase was not removed, the relative content of menthol in the first ten sprays was significantly lower than that in the last ten sprays, indicating that the free oil phase could not maintain a uniform distribution throughout the spraying process.

[0215] Comparative Example 4, which did not undergo ultrafiltration treatment, showed an increased relative standard deviation in single-press spray volume and a deviation of 18.2% in menthol content during continuous spraying. This indicates that colloidal and suspended impurities in the water extract can affect the stability of spray output and the distribution of aromatic components.

[0216] The deviation in menthol content of continuous spray in Comparative Example 6 was small, but this result only indicates that it has good physical stability when the amount of aromatic water concentrate added is low, and does not indicate that it can achieve the same therapeutic effect as Examples 1 to 5.

[0217] Test Example 3: Efficacy Test of Allergic Rhinitis Medication

[0218] 3.1 Establishment and grouping of animal models

[0219] Seventy healthy male SD rats, weighing 180–220 g, were selected and randomly divided into six groups (n=10 each) after 7 days of acclimatization: blank group, model group, positive control group, Example 1 group, Example 3 group, Example 5 group, and comparative example group 6.

[0220] Except for the control group, all other groups underwent basic sensitization with ovalbumin and aluminum hydroxide, and nasal provocation was performed with ovalbumin solution to establish an animal model of allergic rhinitis.

[0221] After basic sensitization, ovalbumin solution was administered into the nasal cavity of rats for 7 consecutive days to challenge the nasal cavity. Successful model establishment was determined upon the appearance of increased sneezing frequency, increased nose-scratching frequency, and increased nasal secretions.

[0222] After successful model establishment, the medication was administered continuously for 7 days, with the following administration methods for each group:

[0223] The control group and the model group were given equal volumes of physiological saline.

[0224] The positive control group was given commercially available budesonide nasal spray;

[0225] Groups 1, 3, and 5 were administered the traditional Chinese medicine nasal sprays prepared in the corresponding examples.

[0226] Comparative group 6 was given the traditional Chinese medicine nasal spray prepared in comparative group 6.

[0227] The total volume of each dose for each group was 0.05 ml, with 0.025 ml administered to each nostril, once daily.

[0228] 3.2 Symptom Evaluation

[0229] One hour after the last administration, except for the control group, all other groups underwent nasal provocation again with ovalbumin solution. The number of sneezes and nose scratches for each rat were recorded within 30 minutes after provocation, and the rats were scored according to the amount of nasal secretions.

[0230] The scoring criteria for nasal secretions are as follows:

[0231] A score of 0 indicates no nasal discharge;

[0232] A score of 1 indicates the presence of a small amount of nasal secretions around the nostrils;

[0233] A score of 2 indicates that nasal secretions extend beyond the nostrils but do not reach the upper lip;

[0234] A score of 3 indicates that nasal secretions flow to or below the upper lip.

[0235] 3.3 Serum total immunoglobulin E detection

[0236] After symptom evaluation, rat blood was collected, serum was separated, and the total immunoglobulin E content in the serum was detected by enzyme-linked immunosorbent assay (ELISA).

[0237] Statistical software was used to analyze the test data, which are expressed as mean ± standard deviation. One-way ANOVA was used for comparisons among multiple groups, and post-hoc tests were used for pairwise comparisons between groups. A p-value < 0.05 was considered statistically significant. Results are as follows: Figure 5 As shown in Table 4.

[0238] Table 4. Results of drug efficacy tests for allergic rhinitis in each group

[0239] Blank group 1.8±0.8 2.5±1.0 0.2±0.4 32.6±5.7 Model group 22.4±3.5 30.1±4.2 2.6±0.5 155.8±18.6 Positive control group 6.3±1.7 8.0±2.1 0.8±0.4 69.4±10.2 Example 1 Group 8.4±2.0 10.9±2.6 1.1±0.3 82.7±11.8 Example 3 Group 6.9±1.8 8.7±2.2 0.8±0.4 72.1±9.6 Example 5 group 7.2±1.9 9.1±2.3 0.9±0.3 74.8±10.4 Comparative Example 6 Groups 12.7±2.8 16.4±3.1 1.6±0.5 105.3±13.7

[0240] The number of sneezes, nose scratching, nasal secretion scores, and serum total immunoglobulin E levels in the model group were significantly higher than those in the control group, indicating that the animal model of allergic rhinitis was successfully established.

[0241] The number of sneezes, the number of times the nose was scratched, the nasal secretion score, and the serum total immunoglobulin E content in the Example 1, Example 3, and Example 5 groups were all lower than those in the model group, indicating that the traditional Chinese medicine nasal spray prepared within the limits of Examples 1 to 5 can improve the symptoms of allergic rhinitis.

[0242] Comparative Example 6 determined the production compounding volume of the aromatic water concentrate to be 40% of the unit critical compatibility volume. Although the traditional Chinese medicine nasal spray prepared in Comparative Example 6 had a lower increase in turbidity and a smaller deviation in menthol content during continuous spraying, its improvement on sneezing, nose scratching, nasal secretions, and serum total immunoglobulin E was weaker than that of Example 1, Example 3, and Example 5.

[0243] The results of tests 1-3 show that limiting the production volume of the aromatic water concentrate to 55%-80% of the unit critical compatibility volume can ensure that the aromatic components are added in an appropriate amount while maintaining the low-temperature stability and continuous spray dosage consistency of the traditional Chinese medicine nasal spray, thereby achieving the effect of improving allergic rhinitis.

[0244] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A traditional Chinese medicine nasal spray for treating allergic rhinitis, characterized in that, Including water-extracted clarified liquid and aromatic water concentrate; The water-extracted clarified liquid is obtained by water extraction and clarification of water-extracted medicinal materials, including honeysuckle, forsythia, scutellaria, kochia, and cicada molting. The aromatic water concentrate is obtained by steam distillation of peppermint to obtain condensate, oil-water separation of the condensate to remove free oil phase, and concentration of the aqueous phase after removal of free oil phase. The volume of the aromatic water concentrate added is 55% to 80% of the critical compatibility volume of the production batch. The critical compatibility volume of the production batch is calculated by proportionally converting the unit critical compatibility volume with the volume of the water-extracted clarified liquid to be compounded. The unit critical compatibility volume is determined as follows: a quantitative amount of the water-extracted clarified liquid is maintained at 2-8°C, and the aromatic water concentrate is added to the water-extracted clarified liquid step by step. After each addition, the mixture is stirred and allowed to stand. When the turbidity of the mixture relative to the turbidity without the addition of the aromatic water concentrate first reaches a preset turbidity increment threshold, the cumulative volume of the aromatic water concentrate added is determined as the unit critical compatibility volume. The preset turbidity increment threshold is 10-20 NTU. The herbal nasal spray contains no ethanol or polysorbate surfactants and has no visible free oil phase.

2. The traditional Chinese medicine nasal spray for treating allergic rhinitis according to claim 1, characterized in that, The water-extracted medicinal material comprises the following raw materials in parts by weight: Honeysuckle 8-16 parts, Forsythia 5-12 parts, Scutellaria baicalensis 8-16 parts, Kochia scoparia 4-10 parts, and Cicadae periostracum 3-8 parts; The amount of peppermint is 5 to 12 parts by weight.

3. The traditional Chinese medicine nasal spray for treating allergic rhinitis according to claim 2, characterized in that, The water-extracted medicinal material comprises the following raw materials in parts by weight: Honeysuckle 12 parts, forsythia 8 parts, scutellaria 12 parts, kochia 6 parts and cicada molting 6 parts; The amount of peppermint is 9 parts by weight.

4. A traditional Chinese medicine nasal spray for treating allergic rhinitis according to claim 1, characterized in that, The clarified water extract is obtained by sequentially centrifuging, coarse filtration and ultrafiltration of the original water extract. The ultrafiltration process uses an ultrafiltration membrane with a molecular weight cutoff of 10 to 50 kilodaltons.

5. A traditional Chinese medicine nasal spray for treating allergic rhinitis according to claim 1, characterized in that, The pH value of the traditional Chinese medicine nasal spray is 5.8-6.5, the osmotic pressure is 270-330 milliohms per kilogram, and the total amount of raw material corresponding to each milliliter of the traditional Chinese medicine nasal spray is 80-180 mg.

6. A traditional Chinese medicine nasal spray for treating allergic rhinitis according to claim 1, characterized in that, The volume of the aromatic water concentrate added is 60% to 75% of the critical compatibility volume of the production batch.

7. A method for preparing a traditional Chinese medicine nasal spray for treating allergic rhinitis according to any one of claims 1 to 6, characterized in that, Includes the following steps: S1. The water-extracted medicinal materials, including honeysuckle, forsythia, scutellaria, kochia and cicada molting, are crushed and mixed to obtain a mixture of water-extracted medicinal materials; S2. The water-extracted medicinal material mixture is subjected to fractional water extraction using purified water, and the extracts obtained from each water extraction are combined to obtain the original water extract. S3. The water extract stock solution is clarified and concentrated to obtain a clarified water extract solution; S4. The peppermint is subjected to steam distillation, the condensate produced by distillation is collected, the condensate is subjected to oil-water separation to remove the free oil phase, and the aqueous phase after the removal of the free oil phase is concentrated to obtain an aromatic water concentrate. S5. Maintain a quantitative amount of the water-extracted clarified liquid at 2-8°C, and add the aromatic water concentrate to the water-extracted clarified liquid step by step. Stir and let stand after each addition. When the turbidity of the mixture reaches the preset turbidity increment threshold for the first time relative to the turbidity without the addition of the aromatic water concentrate, the cumulative volume of the aromatic water concentrate added is determined as the unit critical compatibility volume. The preset turbidity increment threshold is 10-20 NTU. S6. Based on the critical compatibility volume of the unit and the volume of the water-extracted clarified liquid to be compounded, the critical compatibility volume of the production batch is obtained by proportional conversion. The production compounding volume of the aromatic water concentrate is determined according to 55% to 80% of the critical compatibility volume of the production batch. The aromatic water concentrate of the production compounding volume is added to the water-extracted clarified liquid to obtain the compounded drug solution. S7. Adjust the pH value and osmotic pressure of the compound medicine solution, and filter and fill the compound medicine solution to obtain the traditional Chinese medicine nasal spray.

8. The preparation method according to claim 7, characterized in that, Step S2 includes: Add 8 to 12 times the total mass of purified water to the water-extracted medicinal material mixture, extract at 65 to 80°C for 50 to 90 minutes, and filter to obtain the first extract and the first residue; Add 6 to 10 times the weight of purified water to the first residue, extract at 85 to 95°C for 30 to 60 minutes, and filter to obtain the second extract; The first extract and the second extract are combined to obtain the water extract stock solution.

9. The preparation method according to claim 7, characterized in that, In step S3, the clarification process includes centrifugation, coarse filtration and ultrafiltration of the water extract in sequence, wherein the ultrafiltration process uses an ultrafiltration membrane with a molecular weight cutoff of 10 to 50 kilodaltons. The concentration process is carried out at a temperature not exceeding 60°C, so that the concentration of the active pharmaceutical ingredient corresponding to the water extract reaches 0.10 to 0.30 grams per milliliter.

10. The preparation method according to claim 7, characterized in that, In step S4, the condensate is divided into front-stage condensate, middle-stage condensate and rear-stage condensate. The front-stage condensate, which accounts for 5% to 10% of the total volume of the condensate, is discarded. The middle-stage condensate, which accounts for 40% to 70% of the total volume of the condensate, is collected. The middle-stage condensate is subjected to oil-water separation. The aqueous phase after the removal of the free oil phase is concentrated at a temperature not exceeding 45°C. In step S6, the aromatic water concentrate is added to the water extract clarified solution at a temperature of 10-25°C in 3 to 8 portions, and the mixture is stirred for 3 to 10 minutes after each addition. After all the additions are completed, the mixture is stirred for another 10 to 30 minutes. In step S7, the pH value of the compound drug solution is adjusted to 5.8-6.5, the osmotic pressure of the compound drug solution is adjusted to 270-330 milliohms per kilogram, and then filtered sequentially using filter membranes with pore sizes of 0.45 micrometers and 0.22 micrometers.

Images