Azelastine hydrochloride nasal spray and preparation method thereof

Abstract

The invention provides an azelastine hydrochloride nasal spray and a preparation method of the azelastine hydrochloride nasal spray, and belongs to the technical field of nasal sprays. The azelastine hydrochloride oral liquid is prepared from the following components: 0.1 percent of azelastine hydrochloride, 0.3 to 0.4 percent of chamomile-herba houttuyniae-peony flower composite water extraction fermentation product, 0.005 to 0.01 percent of stabilizer, 0.002 to 0.01 percent of preservative, 0.95 to 1.05 percent of thickening agent, 0.7 to 0.8 percent of pH regulator, 0.45 to 0.48 percent of sodium chloride and the balance of purified water, the chamomile-heartleaf houttuynia herb-peony flower composite water extraction fermented product is prepared by extracting a mixture of chamomile, heartleaf houttuynia herb and peony flower with water to obtain a water extract and then fermenting the water extract with compound enzyme, wherein the compound enzyme comprises cellulase, pectate lyase and laccase. According to the invention, the irritation to eyes in the use process can be effectively reduced, and the use is safer and trustworry-free.

Description

Technical Field

[0001] The invention belongs to the technical field of nasal sprays, and particularly relates to an azelastine hydrochloride nasal spray and a preparation method thereof. Background Art

[0002] Azelastine hydrochloride, Chinese alias: 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4-yl)-1-(2H)-phthalazine hydrochloride, has strong anti-histamine pharmacological activity and comprehensive anti-inflammatory mediator effects. It is suitable for allergic patients and can be used to treat allergic rhinitis and allergic perennial rhinitis, such as excessive nasal discharge, sneezing and nasal itching.

[0003] The existing azelastine hydrochloride nasal spray is a colorless transparent liquid. When the valve is pressed, the medicine is sprayed out in a mist. Animal experimental data show that high concentrations of azelastine hydrochloride can prevent the synthesis and release of certain chemical mediators in allergic reactions (such as leukotrienes, histamine, and 5-hydroxytryptamine) and can prevent the upregulation of I-CAMI and the migration of eosinophils to exert a wide range of anti-inflammatory effects. When the nasal spray is administered, no local toxic reactions or organ-specific toxic reactions are detected at the maximum dose allowed.

[0004] The ingredients in azelastine hydrochloride nasal spray are designed for use in the nasal cavity, but because it is in a mist form when used, once sprayed, it is difficult to control the dispersion path of the mist liquid, and it can easily enter the eyes, which are very sensitive organs and can easily cause discomfort or injury. Even if the user is very cautious and strictly maintains the correct posture when using the nasal spray (head upright and slightly tilted forward), closes the eyes tightly, and waits for the drug to be released before opening the eyes, the anatomical structure between the nasal cavity and the eye is very close, especially the tear duct connecting the nasal cavity and the eye, so when the drug is sprayed into the nasal cavity, it may still enter the eye through this channel, irritating the eye and causing eye discomfort in the patient, such as burning sensation, redness, itching or tearing of the eye. Summary of the invention

[0005] In order to solve the problems existing in the background technology, the present invention provides an azelastine hydrochloride nasal spray and a preparation method thereof, which can effectively reduce the irritation to the eyes during use and ensure safer and more reliable use.

[0006] In order to achieve the above-mentioned object, in a first aspect, the present invention provides an azelastine hydrochloride nasal spray, which is composed of the following components by mass percentage: 0.1% azelastine hydrochloride, 0.3-0.4% chamomile-houttuynia-peony flower composite water extraction fermentation product, 0.005-0.01% stabilizer, 0.002-0.01% preservative, 0.95-1.05% thickener, 0.7-0.8% pH adjuster, 0.45-0.48% sodium chloride and the balance of purified water; The chamomile-houttuynia-peony composite water extraction fermentation product is prepared by first extracting a mixture of chamomile, houttuynia and peony with water to obtain a water extract and then fermenting it with a composite enzyme. The mass ratio of chamomile, houttuynia and peony is 5:(1-2):(3-5), and the mass of the composite enzyme is 0.2-0.3% of the mass of the mixture of chamomile, houttuynia and peony. The composite enzyme includes cellulase, pectate lyase and laccase, and the mass ratio of the three is 2:(0.7-1):(1.2-1.5). The viscosity of the azelastine hydrochloride nasal spray is 1.91-2.07 mPa.s; the pH value of the azelastine hydrochloride nasal spray is 6.75-6.90.

[0007] Furthermore, the preparation method of the chamomile-houttuynia-peony flower composite water extraction fermentation product is as follows: A1. Mix chamomile, houttuynia and peony to obtain a mixture, add water 3-4 times the mass of the mixture, heat to 80±5°C, soak for 1-1.5h, then add water 5-7 times the mass of the mixture, distill and reflux water for 5-7h, and concentrate to 2-3 times the mass of the mixture to obtain an aqueous extract; A2, adding complex enzyme to the water extract obtained in A1, continuously stirring, fermenting, inactivating, filtering, and obtaining chamomile-houttuynia-peony flower complex water extract fermentation product.

[0008] Furthermore, a water-soluble antioxidant is added to A1, and the mass of the water-soluble antioxidant is 2-3% of the mass of the mixture.

[0009] Furthermore, the water-soluble antioxidant includes vitamin C and / or tea polyphenols.

[0010] Furthermore, in A2, the continuous stirring speed is 80-100 r / min.

[0011] Furthermore, in A2, the fermentation temperature is 48-58°C and the fermentation time is 56-64h.

[0012] Furthermore, in A2, the inactivation temperature is 98±2°C and the inactivation time is 20-30 min.

[0013] Furthermore, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hydroxypropyl methylcellulose; the pH adjuster is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:(5-6).

[0014] In a second aspect, the present invention provides a method for preparing the above-mentioned azelastine hydrochloride nasal spray, comprising the following steps: placing a preservative, a stabilizer, a pH adjuster and sodium chloride in a beaker, adding 2 / 7 of the total amount of purified water at 80-90°C, stirring and dissolving; then adding a thickener, maintaining the temperature at 80-90°C, stirring at high speed for 15-20 minutes with an emulsifier to fully swell, cooling to room temperature, adding 4 / 7 of the total amount of purified water, stirring at high speed with an emulsifier, then adding azelastine hydrochloride and chamomile-houttuynia-peony composite water extraction fermentation product, stirring at high speed for 10 minutes, adding the remaining 1 / 7 of the total amount of purified water, and continuing to stir for 5 minutes to obtain the product.

[0015] This application has the following beneficial effects: 1. On the one hand, the ingredients such as azelastine hydrochloride in the raw materials of the present invention are irritating to the eyes to a certain extent. In the viscosity range of 1.1 mPa.s to 2.8 mPa.s, as the viscosity increases, the retention time of the pharmaceutical ingredients in the eyes will be prolonged, thereby increasing the irritation to the eyes.

[0016] On the other hand, the chamomile-houttuynia-peony flower composite water extraction and fermentation product in the raw materials of the present invention is prepared by combined water extraction and fermentation of chamomile, houttuynia and peony flowers, which takes into account the improvement of drug efficacy and drug efficacy release / action speed, so as to more quickly relieve / eliminate eye irritation; at the same time, the viscosity of the drug will also affect the drug efficacy release speed and action speed; When the viscosity is low (about 1.1mPa.s to 2.0mPa.S), the retention time of the drug in the eyes is too short, and the efficacy of the chamomile-houttuynia-peony flower composite water-extracted fermented product cannot be fully exerted. Therefore, as the viscosity increases, the retention time of the drug will be prolonged, and the efficacy of the chamomile-houttuynia-peony flower composite water-extracted fermented product will be more thoroughly exerted, thereby improving the effect of relieving / eliminating eye irritation; When the viscosity is high (about 2.0mPa.s to 2.8mPa.S), the drug stays in the eyes long enough to fully exert the efficacy of the chamomile-houttuynia-peony flower composite water extract and fermentation product. However, the high viscosity will lead to low fluidity of the drug, affecting the release / action rate of the efficacy of the chamomile-houttuynia-peony flower composite water extract and fermentation product. Therefore, with the increase of viscosity, the release / action rate of the efficacy of the chamomile-houttuynia-peony flower composite water extract and fermentation product decreases, resulting in a decrease in the effect of relieving / eliminating eye irritation.

[0017] The above two aspects work synergistically, when the amount of the thickener is 0.95-1.05%, the azelastine hydrochloride nasal spray prepared by adding the chamomile-houttuynia-peony flower composite water extraction fermentation product of the present invention is less irritating to the eyes and is safer and more reliable to use.

[0018] 2. In the preparation of the chamomile-houttuynia-peony composite water extraction fermentation product of the present invention, the mixed water extraction product of chamomile, houttuynia and peony is fermented with a composite enzyme prepared by cellulase, pectate lyase and laccase, which can not only produce secondary metabolites and mutually enhance the efficacy of the medicinal ingredients, thereby improving the efficacy, but also convert macromolecules into small molecules to make them easier to absorb, thereby increasing the release / action speed of the efficacy; ultimately, the effect of relieving / eliminating eye irritation is improved while improving the therapeutic effect on allergic rhinitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 , a comparative trend chart of the eye irritation score test data of the azelastine hydrochloride nasal spray prepared in Example 1 to Example 5 and Comparative Example 1 to Comparative Example 5 in Test Example 1 of the present invention; Figure 2 , a comparative trend chart of the test data of the therapeutic effect of azelastine hydrochloride nasal spray on rhinitis prepared in Example 1 and Comparative Example 2 of Test Example 2 of the present invention. DETAILED DESCRIPTION

[0020] The present application is further described in detail below with reference to the embodiments.

[0021] Unless otherwise specified, the raw materials used in the examples and comparative examples of the present application are all commercially available.

[0022] Example 1: (1) Preparation of chamomile-houttuynia-peony flower composite water extraction fermentation product, the preparation method is as follows: A1. Mix chamomile, houttuynia cordata and peony in a mass ratio of 5:1.5:4 to obtain a mixture; add water-soluble antioxidant vitamin C, the mass of which is 2.5% of the mass of the mixture; add water 3.5 times the mass of the mixture, heat to 80°C, soak for 1.2 hours, then add water 6 times the mass of the mixture, extract with distilled reflux water for 6 hours, and concentrate to 2.5 times the mass of the mixture to obtain a water extract.

[0023] A2. Add a composite enzyme to the water extract obtained in A1. The composite enzyme includes cellulase, pectate lyase and laccase, and the mass ratio of the three is 2:0.8:1.3; the mass of the composite enzyme is 0.25% of the mass of the mixture of chamomile, houttuynia and peony; continue stirring and fermenting at a stirring speed of 90r / min, the fermentation temperature is about 52°C, and the fermentation time is 60h. Then inactivate, the inactivation temperature is 98°C, and the inactivation time is 25min. Then filter, and the obtained filtrate is the chamomile-houttuynia-peony composite water extraction fermentation product.

[0024] Among them, cellulase (YT2466) was purchased from Beijing Ita Biotechnology Co., Ltd. Pectate lyase (MGZ-E-PCLYAN) was purchased from Shanghai Yubo Biotechnology Co., Ltd. Laccase (YT1218) was purchased from Beijing Ita Biotechnology Co., Ltd.

[0025] (2) Azelastine hydrochloride nasal spray is prepared as follows: The following components were weighed in percentage by mass: 0.1% azelastine hydrochloride, 0.35% chamomile-houttuynia-peony flower composite water extraction and fermentation product, 0.008% stabilizer, 0.005% preservative, 1.0% thickener, 0.75% pH adjuster, 0.46% sodium chloride and the balance purified water.

[0026] Among them, azelastine hydrochloride (R341445) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. The stabilizer is edetate disodium, which was purchased from Nanjing Chemical Reagent Co., Ltd. The preservative is benzalkonium bromide, which was purchased from Shandong Taiyu Chemical Co., Ltd. The thickener is hydroxypropyl methylcellulose, which was purchased from Guangdong Jianer Pharmaceutical Co., Ltd. The pH adjusters are citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid and disodium hydrogen phosphate is 1:5.5 (i.e. citric acid 0.115%, disodium hydrogen phosphate 0.63%); citric acid and disodium hydrogen phosphate were both purchased from Hunan Erkang Pharmaceutical Co., Ltd.

[0027] Preservatives, stabilizers, pH adjusters and sodium chloride are placed in a beaker, 2 / 7 of the total amount of purified water at 85°C is added, and the mixture is stirred at a constant speed of 240 r / min for 30 minutes to dissolve. Then, a thickener is added, the temperature is maintained at 85°C, and the mixture is stirred at high speed (3000 r / min) with an emulsifier for 15 minutes to fully swell, and the mixture is cooled to room temperature, 4 / 7 of the total amount of purified water is added, and the mixture is stirred at high speed with an emulsifier, and azelastine hydrochloride and chamomile-houttuynia-peony flower composite water extraction fermentation product are added, and the mixture is stirred at high speed for 10 minutes, and the remaining 1 / 7 of the total amount of purified water is added, and the mixture is stirred for 5 minutes to obtain azelastine hydrochloride nasal spray.

[0028] The viscosity of azelastine hydrochloride nasal spray is 1.99 mPa.s; the pH value of azelastine hydrochloride nasal spray is 6.83.

[0029] Example 2: The difference between this example and Example 1 is that: (1) The preparation method of the chamomile-houttuynia-peony flower composite water extraction fermentation product is as follows: A1. Mix chamomile, houttuynia cordata and peony in a mass ratio of 5:1:3 to obtain a mixture; add water-soluble antioxidant vitamin C, the mass of which is 2% of the mass of the mixture; add water 3 times the mass of the mixture, heat to 75°C, soak for 1.5 hours, then add water 5 times the mass of the mixture, extract with distilled reflux water for 7 hours, and concentrate to 2 times the mass of the mixture to obtain a water extract.

[0030] A2. Add a composite enzyme to the water extract obtained in A1. The composite enzyme includes cellulase, pectate lyase and laccase, and the mass ratio of the three is 2:0.7:1.2; the mass of the composite enzyme is 0.3% of the mass of the mixture of chamomile, houttuynia and peony; continue stirring and fermenting at a stirring speed of 80r / min, the fermentation temperature is about 52°C, and the fermentation time is 56h. Then inactivate, the inactivation temperature is 96°C, and the inactivation time is 30min. Then filter, and the obtained filtrate is the chamomile-houttuynia-peony composite water extraction fermentation product.

[0031] Example 3: The difference between this example and Example 1 is that: (1) The preparation method of the chamomile-houttuynia-peony flower composite water extraction fermentation product is as follows: A1. Mix chamomile, houttuynia cordata and peony in a mass ratio of 5:2:5 to obtain a mixture; add water-soluble antioxidant vitamin C, the mass of which is 3% of the mass of the mixture; add water 4 times the mass of the mixture, heat to 85°C, soak for 1 hour, then add water 7 times the mass of the mixture, extract with distilled reflux water for 5 hours, and concentrate to 3 times the mass of the mixture to obtain a water extract.

[0032] A2. Add a composite enzyme to the water extract obtained in A1, wherein the composite enzyme includes cellulase, pectate lyase and laccase, and the mass ratio of the three is 2:1:1.5; the mass of the composite enzyme is 0.2% of the mass of the mixture of chamomile, houttuynia and peony; stir and ferment continuously at a stirring speed of 100 r / min, the fermentation temperature is about 52°C, and the fermentation time is 64h. Then inactivate at a temperature of 98°C and a time of 20min. Then filter, and the obtained filtrate is the chamomile-houttuynia-peony composite water extraction fermentation product.

[0033] Example 4: This example differs from Example 1 in that: (2) Azelastine hydrochloride nasal spray is prepared by the following method: The following components were weighed by mass percentage: 0.1% azelastine hydrochloride, 0.3% chamomile-houttuynia-peony flower composite water extraction fermentation product, 0.005% stabilizer, 0.002% preservative, 0.95% thickener, 0.75% pH adjuster, 0.45% sodium chloride and the balance of purified water. Among them, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hydroxypropyl methylcellulose; the pH adjuster is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (i.e. 0.115% citric acid and 0.63% disodium hydrogen phosphate).

[0034] Preservatives, stabilizers, pH adjusters and sodium chloride are placed in a beaker, 2 / 7 of the total amount of purified water at 85°C is added, and the mixture is stirred at a constant speed of 240 r / min for 30 minutes to dissolve. Then, a thickener is added, the temperature is maintained at 85°C, and the mixture is stirred at high speed (3000 r / min) with an emulsifier for 15 minutes to fully swell, and the mixture is cooled to room temperature, 4 / 7 of the total amount of purified water is added, and the mixture is stirred at high speed with an emulsifier, and azelastine hydrochloride and chamomile-houttuynia-peony flower composite water extraction fermentation product are added, and the mixture is stirred at high speed for 10 minutes, and the remaining 1 / 7 of the total amount of purified water is added, and the mixture is stirred for 5 minutes to obtain azelastine hydrochloride nasal spray.

[0035] The viscosity of the azelastine hydrochloride nasal spray is 1.91 mPa.s; the pH value of the azelastine hydrochloride nasal spray is 6.81.

[0036] Example 5: This example differs from Example 1 in that: (2) Azelastine hydrochloride nasal spray is prepared by the following method: The following components were weighed by mass percentage: 0.1% azelastine hydrochloride, 0.4% chamomile-houttuynia-peony flower composite water extraction fermentation product, 0.01% stabilizer, 0.01% preservative, 1.05% thickener, 0.75% pH adjuster, 0.48% sodium chloride and the balance of purified water. Among them, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hydroxypropyl methylcellulose; the pH adjuster is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (i.e. 0.115% citric acid and 0.63% disodium hydrogen phosphate).

[0037] Preservatives, stabilizers, pH adjusters and sodium chloride are placed in a beaker, 2 / 7 of the total amount of purified water at 85°C is added, and the mixture is stirred at a constant speed of 240 r / min for 30 minutes to dissolve. Then, a thickener is added, the temperature is maintained at 85°C, and the mixture is stirred at high speed (3000 r / min) with an emulsifier for 15 minutes to fully swell, and the mixture is cooled to room temperature, 4 / 7 of the total amount of purified water is added, and the mixture is stirred at high speed with an emulsifier, and azelastine hydrochloride and chamomile-houttuynia-peony flower composite water extraction fermentation product are added, and the mixture is stirred at high speed for 10 minutes, and the remaining 1 / 7 of the total amount of purified water is added, and the mixture is stirred for 5 minutes to obtain azelastine hydrochloride nasal spray.

[0038] The viscosity of the azelastine hydrochloride nasal spray is 2.07 mPa.s; the pH value of the azelastine hydrochloride nasal spray is 6.87.

[0039] Comparative Example 1: The difference between this comparative example and Example 1 is that in the preparation of azelastine hydrochloride nasal spray, the chamomile-houttuynia-peony flower composite water extraction fermentation product is deleted, and the amount of the thickener is 0.6%.

[0040] Specifically, azelastine hydrochloride nasal spray is prepared, and its preparation method is as follows: The following components were weighed in percentage by mass: 0.1% azelastine hydrochloride, 0.008% stabilizer, 0.005% preservative, 0.6% thickener, 0.75% pH adjuster, 0.46% sodium chloride and the balance of purified water. Among them, the stabilizer was edetate disodium; the preservative was benzalkonium bromide; the thickener was hydroxypropyl methylcellulose; the pH adjuster was citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate was 1:5.5 (i.e. 0.115% citric acid and 0.63% disodium hydrogen phosphate).

[0041] Preservatives, stabilizers, pH adjusters and sodium chloride are placed in a beaker, and 2 / 7 of the total amount of purified water at 85°C is added, and stirred at a stirring speed of 240r / min for 30 minutes to dissolve. Then, a thickener is added, the temperature is maintained at 85°C, and an emulsifier is used to stir at high speed (3000r / min) for 15 minutes to fully swell, and the mixture is cooled to room temperature, and 4 / 7 of the total amount of purified water is added, and the mixture is stirred at high speed with an emulsifier, and azelastine hydrochloride is added, and the mixture is stirred at high speed for 10 minutes, and the remaining 1 / 7 of the total amount of purified water is added, and the mixture is stirred for 5 minutes to obtain azelastine hydrochloride nasal spray.

[0042] The viscosity of azelastine hydrochloride nasal spray is 1.11 mPa.s.

[0043] Comparative Example 2: The difference between this comparative example and Example 1 is that in the preparation of azelastine hydrochloride nasal spray, the chamomile-houttuynia-peony flower composite water extraction fermentation product is deleted (the amount of thickener remains unchanged, which is 1.0%).

[0044] Specifically, azelastine hydrochloride nasal spray is prepared, and its preparation method is as follows: The following components were weighed in percentage by mass: 0.1% azelastine hydrochloride, 0.008% stabilizer, 0.005% preservative, 1.0% thickener, 0.75% pH adjuster, 0.46% sodium chloride and the balance of purified water. Among them, the stabilizer was edetate disodium; the preservative was benzalkonium bromide; the thickener was hydroxypropyl methylcellulose; the pH adjuster was citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate was 1:5.5 (i.e. 0.115% citric acid and 0.63% disodium hydrogen phosphate).

[0045] Preservatives, stabilizers, pH adjusters and sodium chloride are placed in a beaker, and 2 / 7 of the total amount of purified water at 85°C is added, and stirred at a stirring speed of 240r / min for 30 minutes to dissolve. Then, a thickener is added, the temperature is maintained at 85°C, and an emulsifier is used to stir at high speed (3000r / min) for 15 minutes to fully swell, and the mixture is cooled to room temperature, and 4 / 7 of the total amount of purified water is added, and the mixture is stirred at high speed with an emulsifier, and azelastine hydrochloride is added, and the mixture is stirred at high speed for 10 minutes, and the remaining 1 / 7 of the total amount of purified water is added, and the mixture is stirred for 5 minutes to obtain azelastine hydrochloride nasal spray.

[0046] The viscosity of azelastine hydrochloride nasal spray is 2.0mPa.s.

[0047] Comparative Example 3: The difference between this comparative example and Example 1 is that in the preparation of azelastine hydrochloride nasal spray, the chamomile-houttuynia-peony flower composite water extraction fermentation product is deleted, and the amount of thickener used is 1.4%.

[0048] Specifically, azelastine hydrochloride nasal spray is prepared, and its preparation method is as follows: The following components were weighed in percentage by mass: 0.1% azelastine hydrochloride, 0.008% stabilizer, 0.005% preservative, 1.4% thickener, 0.75% pH adjuster, 0.46% sodium chloride and the balance of purified water. Among them, the stabilizer was edetate disodium; the preservative was benzalkonium bromide; the thickener was hydroxypropyl methylcellulose; the pH adjuster was citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate was 1:5.5 (i.e. 0.115% citric acid and 0.63% disodium hydrogen phosphate).

[0049] Preservatives, stabilizers, pH adjusters and sodium chloride are placed in a beaker, and 2 / 7 of the total amount of purified water at 85°C is added, and stirred at a stirring speed of 240r / min for 30 minutes to dissolve. Then, a thickener is added, the temperature is maintained at 85°C, and an emulsifier is used to stir at high speed (3000r / min) for 15 minutes to fully swell, and the mixture is cooled to room temperature, and 4 / 7 of the total amount of purified water is added, and the mixture is stirred at high speed with an emulsifier, and azelastine hydrochloride is added, and the mixture is stirred at high speed for 10 minutes, and the remaining 1 / 7 of the total amount of purified water is added, and the mixture is stirred for 5 minutes to obtain azelastine hydrochloride nasal spray.

[0050] The viscosity of azelastine hydrochloride nasal spray is 2.83mPa.s.

[0051] Comparative Example 4: The difference between this comparative example and Example 1 is that in the preparation of azelastine hydrochloride nasal spray, the amount of thickener used is 0.6%.

[0052] Specifically, azelastine hydrochloride nasal spray is prepared, and its preparation method is as follows: The following components were weighed by mass percentage: 0.1% azelastine hydrochloride, 0.35% chamomile-houttuynia-peony flower composite water extraction fermentation product, 0.008% stabilizer, 0.005% preservative, 0.6% thickener, 0.75% pH adjuster, 0.46% sodium chloride and the balance of purified water. Among them, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hydroxypropyl methylcellulose; the pH adjuster is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (i.e. 0.115% citric acid and 0.63% disodium hydrogen phosphate).

[0053] Preservatives, stabilizers, pH adjusters and sodium chloride are placed in a beaker, 2 / 7 of the total amount of purified water at 85°C is added, and the mixture is stirred at a constant speed of 240 r / min for 30 minutes to dissolve. Then, a thickener is added, the temperature is maintained at 85°C, and the mixture is stirred at high speed (3000 r / min) with an emulsifier for 15 minutes to fully swell, and the mixture is cooled to room temperature, 4 / 7 of the total amount of purified water is added, and the mixture is stirred at high speed with an emulsifier, and azelastine hydrochloride and chamomile-houttuynia-peony flower composite water extraction fermentation product are added, and the mixture is stirred at high speed for 10 minutes, and the remaining 1 / 7 of the total amount of purified water is added, and the mixture is stirred for 5 minutes to obtain azelastine hydrochloride nasal spray.

[0054] The viscosity of azelastine hydrochloride nasal spray is 1.08mPa.s.

[0055] Comparative Example 5: The difference between this comparative example and Example 1 is that in the preparation of azelastine hydrochloride nasal spray, the amount of thickener used is 1.4%.

[0056] Specifically, azelastine hydrochloride nasal spray is prepared, and its preparation method is as follows: The following components were weighed by mass percentage: 0.1% azelastine hydrochloride, 0.35% chamomile-houttuynia-peony flower composite water extraction fermentation product, 0.008% stabilizer, 0.005% preservative, 1.4% thickener, 0.75% pH adjuster, 0.46% sodium chloride and the balance of purified water. Among them, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hydroxypropyl methylcellulose; the pH adjuster is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (i.e. 0.115% citric acid and 0.63% disodium hydrogen phosphate).

[0057] Preservatives, stabilizers, pH adjusters and sodium chloride are placed in a beaker, 2 / 7 of the total amount of purified water at 85°C is added, and the mixture is stirred at a constant speed of 240 r / min for 30 minutes to dissolve. Then, a thickener is added, the temperature is maintained at 85°C, and the mixture is stirred at high speed (3000 r / min) with an emulsifier for 15 minutes to fully swell, and the mixture is cooled to room temperature, 4 / 7 of the total amount of purified water is added, and the mixture is stirred at high speed with an emulsifier, and azelastine hydrochloride and chamomile-houttuynia-peony flower composite water extraction fermentation product are added, and the mixture is stirred at high speed for 10 minutes, and the remaining 1 / 7 of the total amount of purified water is added, and the mixture is stirred for 5 minutes to obtain azelastine hydrochloride nasal spray.

[0058] The viscosity of azelastine hydrochloride nasal spray is 2.81mPa.s.

[0059] Test example 1: Test item: eye irritation test.

[0060] Test subjects: Azelastine hydrochloride nasal spray was prepared according to Example 1 to Example 5 and Comparative Example 1 to Comparative Example 5.

[0061] Test content: Take 50 rats and perform routine examinations on both eyes of all rats to ensure that there are no irritation symptoms; randomly divide them into 10 groups, corresponding to 10 groups of test subjects, with 5 rats in each group, marked I, II, III, IV, VI. During the test, 0.1 ml of the test sample was dripped into the conjunctival sac, and the other eye was used as a control. After dripping the medicine, the eye was passively closed for 5 seconds. The observation time is 24 hours. If local reaction symptoms appear within 24 hours, the corresponding highest score will be recorded; if no local reaction symptoms appear within 24 hours, 0 points will be recorded. The basis for scoring local reaction symptoms is shown in Table 1.

[0062] Table 1. Scoring basis for local reaction symptoms of eye irritation

[0063] Test results: See Table 2.

[0064] Table 2. Test Example 1 Eye Irritation Test Data

[0065] Result analysis: Analyze Example 1-Example 5 and combine the data in Table 2 and Figure 1 It can be seen that the eye irritation symptom score of the azelastine hydrochloride nasal spray prepared in the present invention (Example 1 to Example 5) is as low as 0.2 points or less, and it is safe and reliable to use.

[0066] Comparative Example 1 (viscosity 1.11 mPa.s), Comparative Example 2 (viscosity 2.0 mPa.s) and Comparative Example 3 (viscosity 2.83 mPa.s) combined with the data in Table 2 and Figure 1 By comparison, it can be seen that when the raw material components do not contain the chamomile-houttuynia-peony flower composite water extraction and fermentation product, as the viscosity of the final azelastine hydrochloride nasal spray increases, it will lead to increased irritation to the eyes.

[0067] By comparing Comparative Example 4 (viscosity 1.08 mPa.s), Example 1 (viscosity 1.99 mPa.s) and Comparative Example 5 (viscosity 2.81 mPa.s), it can be seen that the addition of chamomile-houttuynia-peony flower composite water extraction fermentation product to the raw material components can significantly reduce the irritation of the final azelastine hydrochloride nasal spray to the eyes. Moreover, this reduction effect will first increase with the increase of the viscosity of the azelastine hydrochloride nasal spray, and then weaken with the continued increase of the viscosity of the azelastine hydrochloride nasal spray.

[0068] In summary, when the dosage of the thickener of the present invention is 0.95-1.05%, the azelastine hydrochloride nasal spray prepared by adding the chamomile-houttuynia-peony flower composite water extraction fermentation product has the least irritation to the eyes and is safer and more reliable to use.

[0069] Test example 2: Test item: Rhinitis treatment test.

[0070] Test subjects: Azelastine hydrochloride nasal spray was prepared in Example 1 and Comparative Example 2.

[0071] Test content: 50 patients all showed continuous sneezing, nasal congestion, nasal itching, and clear watery nasal discharge, and were randomly divided into two groups, A and B, with 25 patients in each group. Patients in group A used the azelastine hydrochloride nasal spray prepared in Example 1, and patients in group B used the azelastine hydrochloride nasal spray prepared in Comparative Example 2. Each patient sprayed the nose with azelastine hydrochloride nasal spray three times a day, once in the morning, noon and evening, and 1 spray in each nostril each time; after 1 week of continuous medication, the amount of spray began to decrease, in the second week, twice a day, once in the morning and evening, 1 spray in each nostril each time; in the third week, once a day, each time with an interval of more than 20h, 1 spray in each nostril each time; in the fourth week, 3 times a week (Monday, Thursday and Sunday), 1 spray in each nostril each time; after 1 month, once a week, 1 spray in each nostril each time; after 2 months of continuous medication, according to Table 3 and Table 4, the reduction in scores after treatment was statistically analyzed, and the efficacy was recorded (no overlap was found in the special effect, significant effect, and effective situation).

[0072] Table 3. Rhinitis attack symptom scoring basis

[0073] Table 4. Criteria for determining efficacy

[0074] Test results: See Table 5.

[0075] Table 5. Test data of rhinitis treatment in Experimental Example 2

[0076] Result analysis: Analyze Example 1 and Comparative Example 2 and combine the data in Table 5 and Figure 2 It can be seen that the azelastine hydrochloride nasal spray prepared by adding chamomile-houttuynia cordata-peony flower composite water extraction fermentation product in the present invention (Example 1) has improved specific efficiency in treating rhinitis and has significant therapeutic effect.

[0077] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0078] In addition, various embodiments of the present invention may be arbitrarily combined, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A azelastine hydrochloride nasal spray, characterized in that: The invention is composed of the following components by mass percentage: 0.1% of azelastine hydrochloride, 0.3-0.4% of chamomile-houttuynia-peony flower composite water extraction fermentation product, 0.005-0.01% of stabilizer, 0.002-0.01% of preservative, 0.95-1.05% of thickener, 0.7-0.8% of pH regulator, 0.45-0.48% of sodium chloride and the balance of purified water; The chamomile-houttuynia-peony composite water extraction fermentation product is prepared by first extracting a mixture of chamomile, houttuynia and peony with water to obtain a water extract and then fermenting it with a composite enzyme. The mass ratio of chamomile, houttuynia and peony is 5:(1-2):(3-5), and the mass of the composite enzyme is 0.2-0.3% of the mass of the mixture of chamomile, houttuynia and peony. The composite enzyme includes cellulase, pectate lyase and laccase, and the mass ratio of the three is 2:(0.7-1):(1.2-1.5). The viscosity of the azelastine hydrochloride nasal spray is 1.91-2.07 mPa.s; the pH value of the azelastine hydrochloride nasal spray is 6.75-6.

90.

2. The azelastine hydrochloride nasal spray according to claim 1, characterized in that The preparation method of the chamomile-houttuynia-peony flower composite water extraction fermentation product is as follows: A1. Mix chamomile, houttuynia and peony to obtain a mixture, add water 3-4 times the mass of the mixture, heat to 80±5°C, soak for 1-1.5h, then add water 5-7 times the mass of the mixture, distill and reflux water for 5-7h, and concentrate to 2-3 times the mass of the mixture to obtain an aqueous extract; A2, adding complex enzyme to the water extract obtained in A1, continuously stirring, fermenting, inactivating, filtering, and obtaining chamomile-houttuynia-peony flower complex water extract fermentation product.

3. The azelastine hydrochloride nasal spray according to claim 2, characterized in that A water-soluble antioxidant is also added to A1, and the mass of the water-soluble antioxidant is 2-3% of the mass of the mixture.

4. The azelastine hydrochloride nasal spray according to claim 3, characterized in that The water-soluble antioxidant includes vitamin C and / or tea polyphenols.

5. The azelastine hydrochloride nasal spray according to claim 2, characterized in that: In A2, the continuous stirring speed is 80-100r / min.

6. The azelastine hydrochloride nasal spray according to claim 2, characterized in that In A2, the fermentation temperature is 48-58°C and the fermentation time is 56-64h.

7. The azelastine hydrochloride nasal spray according to claim 2, characterized in that: In A2, the inactivation temperature is 98±2°C and the inactivation time is 20-30min.

8. The azelastine hydrochloride nasal spray according to claim 1, characterized in that The stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hydroxypropyl methylcellulose; the pH adjuster is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:(5-6).

9. A method for preparing the azelastine hydrochloride nasal spray according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: placing a preservative, a stabilizer, a pH regulator and sodium chloride in a beaker, adding 2 / 7 of the total amount of purified water at 80-90 DEG C, stirring and dissolving; then adding a thickener, maintaining the temperature at 80-90 DEG C, stirring to fully swell, cooling to room temperature, adding 4 / 7 of the total amount of purified water, stirring, then adding azelastine hydrochloride and chamomile-houttuynia-peony flower composite water extraction fermentation product, stirring, adding the remaining 1 / 7 of the total amount of purified water, continuing to stir, and obtaining the product.

Images