Azelastine Hydrochloride Nasal Spray and Its Preparation Method

Abstract

The present invention provides a azelastine hydrochloride nasal spray and a preparation method thereof, belonging to the technical field of nasal sprays. The azelastine hydrochloride nasal spray is composed of the following components by mass percentage: 0.1% of azelastine hydrochloride, 0.3 - 0.4% of a composite water extraction fermentation product of chamomile, houttuynia cordata, and peony flower, 0.005 - 0.01% of a stabilizer, 0.002 - 0.01% of a preservative, 0.95 - 1.05% of a thickening agent, 0.7 - 0.8% of a pH regulator, 0.45 - 0.48% of sodium chloride, and the balance of purified water; the composite water extraction fermentation product of chamomile, houttuynia cordata, and peony flower is prepared by first subjecting a mixture of chamomile, houttuynia cordata, and peony flower to water extraction to obtain a water extract and then subjecting it to composite enzyme fermentation. The composite enzyme includes cellulase, pectate lyase, and laccase. The present invention can effectively reduce the irritation to the eyes during use and ensure safer and more reassuring use.

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;

[0007] The chamomile-houttuynia cordata-peony composite water extract fermentation product is prepared by first subjecting a mixture of chamomile, houttuynia cordata, and peony to water extraction to obtain a water extract, and then subjecting the water extract to composite enzyme fermentation. The mass ratio of chamomile, houttuynia cordata, 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 cordata, 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);

[0008] 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.

[0009] Furthermore, the preparation method of the chamomile-houttuynia cordata-peony composite water extract fermentation product is as follows:

[0010] A1. Mix chamomile, houttuynia cordata, and peony to obtain a mixture, add water 3 - 4 times the mass of the mixture, heat up to 80 ± 5°C, soak for 1 - 1.5 h, then add water 5 - 7 times the mass of the mixture, perform distillation and reflux water extraction for 5 - 7 h, and concentrate to 2 - 3 times the mass of the mixture to obtain a water extract;

[0011] A2. Add the composite enzyme to the water extract obtained in A1, continuously stir, ferment, inactivate, and filter to obtain the chamomile-houttuynia cordata-peony composite water extract fermentation product.

[0012] Furthermore, in A1, a water-soluble antioxidant is also added, and the mass of the water-soluble antioxidant is 2 - 3% of the mass of the mixture.

[0013] Furthermore, the water-soluble antioxidant includes vitamin C and / or tea polyphenols.

[0014] Furthermore, in A2, the continuous stirring speed is 80 - 100 r / min.

[0015] Furthermore, in A2, the fermentation temperature is 48 - 58°C, and the fermentation time is 56 - 64 h.

[0016] Furthermore, in A2, the inactivation temperature is 98 ± 2°C, and the inactivation time is 20 - 30 min.

[0017] Furthermore, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hypromellose; the pH regulator is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid and disodium hydrogen phosphate is 1:(5 - 6).

[0018] In a second aspect, the present invention provides a method for preparing the above-mentioned azelastine hydrochloride nasal spray, which 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 °C, stirring and dissolving; then adding a thickening agent, maintaining the temperature at 80-90 °C, and stirring at high speed with an emulsifier for 15-20 min 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 the chamomile-houttuynia cordata-peony flower composite water extract fermentation product, stirring at high speed for 10 min, adding the remaining 1 / 7 of the total amount of purified water, and continuing to stir for 5 min to obtain the product.

[0019] The present application has the following beneficial effects:

[0020] 1. On the one hand, components such as azelastine hydrochloride in the raw materials of the present invention are inherently somewhat irritating to the eyes. In the viscosity range of 1.1 mPa·s to 2.8 mPa·s, as the viscosity increases, the residence time of the pharmaceutical components in the eyes will be prolonged, which will further lead to an increase in the irritation to the eyes.

[0021] On the other hand, the chamomile-houttuynia cordata-peony flower composite water extract fermentation product in the raw materials of the present invention is prepared by the combined water extraction fermentation of chamomile, houttuynia cordata and peony flower, taking into account the improvement of the drug efficacy and the drug efficacy release / action speed, so as to more quickly relieve / eliminate eye irritation; at the same time, the viscosity of the pharmaceutical agent will also affect the drug efficacy release speed and action speed;

[0022] When the viscosity is low (about 1.1 mPa·s to 2.0 mPa·s), the residence time of the pharmaceutical agent in the eyes is too short, and the drug efficacy of the chamomile-houttuynia cordata-peony flower composite water extract fermentation product is not fully exerted. Therefore, as the viscosity increases, the residence time of the pharmaceutical agent will be prolonged, and the drug efficacy of the chamomile-houttuynia cordata-peony flower composite water extract fermentation product will be exerted more thoroughly, thereby improving the effect of relieving / eliminating eye irritation;

[0023] When the viscosity is high (about 2.0 mPa·s to 2.8 mPa·s), the residence time of the pharmaceutical agent in the eyes is long enough for the drug efficacy of the chamomile-houttuynia cordata-peony flower composite water extract fermentation product to be fully exerted. However, the high viscosity will lead to low fluidity of the pharmaceutical agent, affecting the drug efficacy release / action speed of the chamomile-houttuynia cordata-peony flower composite water extract fermentation product. Therefore, as the viscosity increases, the drug efficacy release / action speed of the chamomile-houttuynia cordata-peony flower composite water extract fermentation product decreases, resulting in a decrease in the effect of relieving / eliminating eye irritation.

[0024] When the above two aspects work together and the dosage of the thickener is 0.95 - 1.05%, the azelastine hydrochloride nasal spray prepared by adding the chamomile - houttuynia cordata - peony flower composite water extract fermentation product of the present invention has less irritation to the eyes and is safer and more reassuring to use.

[0025] 2. In the preparation of the chamomile - houttuynia cordata - peony flower composite water extract fermentation product of the present invention, the composite enzyme prepared from cellulase, pectate lyase and laccase is used to ferment the mixed water extract of chamomile, houttuynia cordata and peony flower. It can not only produce secondary metabolites and mutually enhance with the pharmacodynamic components, thereby improving the drug efficacy, but also convert macromolecular substances into small molecules to make them more easily absorbed, thereby improving the release / action speed of the drug efficacy; ultimately, while enhancing the effect of relieving / eliminating eye irritation, the therapeutic effect on allergic rhinitis is enhanced. Brief Description of the Drawings

[0026] Figure 1 The comparison trend chart of the test data of the azelastine hydrochloride nasal sprays prepared in Examples 1 - 5 and Comparative Examples 1 - 5 in Test Example 1 of the present invention for eye irritation score;

[0027] Figure 2 The comparison trend chart of the test data of the azelastine hydrochloride nasal sprays prepared in Example 1 and Comparative Example 2 in Test Example 2 of the present invention for the treatment effect of rhinitis. Detailed Description of the Invention

[0028] The following further elaborates on the present application in conjunction with the examples.

[0029] The raw materials of the examples and comparative examples of the present application are all commercially available as ordinary products unless otherwise specified.

[0030] Example 1: (1) Preparation of the chamomile - houttuynia cordata - peony flower composite water extract fermentation product, and its preparation method is as follows:

[0031] A1. Mix chamomile, houttuynia cordata and peony flower according to a mass ratio of 5:1.5:4 to obtain a mixture; add water - soluble antioxidant vitamin C, and the mass of vitamin C is 2.5% of the mass of the mixture. Add 3.5 times the mass of the mixture of water, heat up to 80°C, soak for 1.2 h, then add 6 times the mass of the mixture of water, and perform distillation and reflux water extraction for 6 h, and then concentrate to 2.5 times the mass of the mixture to obtain a water extract.

[0032] A2. Add a complex enzyme to the aqueous extract obtained in A1. The complex enzyme includes cellulase, pectate lyase, and laccase, and the mass ratio of the three is 2:0.8:1.3. The mass of the complex enzyme is 0.25% of the mass of the mixture of chamomile, houttuynia cordata, and peony flowers. Continuously stir and ferment at a stirring speed of 90 r / min. The fermentation temperature is about 52 °C, and the fermentation time is 60 h. Then inactivate at an inactivation temperature of 98 °C and an inactivation time of 25 min. Then filter, and the obtained filtrate is the chamomile-houttuynia cordata-peony flower composite aqueous extract fermentate.

[0033] Among them, cellulase (YT2466) is purchased from Beijing Yita Biotechnology Co., Ltd. Pectate lyase (MGZ-E-PCLYAN) is purchased from Shanghai Yubo Biotechnology Co., Ltd. Laccase (YT1218) is purchased from Beijing Yita Biotechnology Co., Ltd.

[0034] (2) Prepare azelastine hydrochloride nasal spray, and its preparation method is as follows:

[0035] Weigh the following components by mass percentage: azelastine hydrochloride 0.1%, chamomile-houttuynia cordata-peony flower composite aqueous extract fermentate 0.35%, stabilizer 0.008%, preservative 0.005%, thickener 1.0%, pH regulator 0.75%, sodium chloride 0.46%, and purified water for the balance.

[0036] Among them, azelastine hydrochloride (R341445) is purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. The stabilizer is disodium edetate, which is purchased from Nanjing Chemical Reagent Co., Ltd. The preservative is benzalkonium bromide, which is purchased from Shandong Taiyu Chemical Co., Ltd. The thickener is hypromellose, which is purchased from Guangdong Jian'er Pharmaceutical Co., Ltd. The pH regulator is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (i.e., citric acid 0.115%, disodium hydrogen phosphate 0.63%); both citric acid and disodium hydrogen phosphate are purchased from Hunan Erkang Pharmaceutical Co., Ltd.

[0037] Put the preservative, stabilizer, pH regulator, and sodium chloride in a beaker, add 2 / 7 of the total amount of purified water at 85 °C, and stir evenly at a stirring speed of 240 r / min for 30 min to dissolve. Then add the thickener, keep the temperature at 85 °C, stir at high speed (3000 r / min) with an emulsifier for 15 min to fully swell, cool to room temperature, add 4 / 7 of the total amount of purified water, stir at high speed with an emulsifier, add azelastine hydrochloride and chamomile-houttuynia cordata-peony flower composite aqueous extract fermentate, stir at high speed for 10 min, add the remaining 1 / 7 of the total amount of purified water, and continue to stir for 5 min to obtain azelastine hydrochloride nasal spray.

[0038] The viscosity of azelastine hydrochloride nasal spray is 1.99 mPa·s; the pH value of azelastine hydrochloride nasal spray is 6.83.

[0039] Example 2: The difference between this example and Example 1 is as follows: (1) The preparation method of chamomile - houttuynia cordata - peony composite water - extraction fermentate is as follows:

[0040] 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, and the mass of vitamin C is 2% of the mass of the mixture. Add water with a mass 3 times that of the mixture, heat up to 75 °C, soak for 1.5 h, then add water with a mass 5 times that of the mixture, perform distillation and reflux water - extraction for 7 h, and concentrate to 2 times the mass of the mixture to obtain a water - extract.

[0041] 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 cordata and peony; continuously stir and ferment at a stirring speed of 80 r / min, the fermentation temperature is about 52 °C, and the fermentation time is 56 h. Then inactivate at an inactivation temperature of 96 °C and an inactivation time of 30 min. Then filter, and the obtained filtrate is the chamomile - houttuynia cordata - peony composite water - extraction fermentate.

[0042] Example 3: The difference between this example and Example 1 is as follows: (1) The preparation method of chamomile - houttuynia cordata - peony composite water - extraction fermentate is as follows:

[0043] 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, and the mass of vitamin C is 3% of the mass of the mixture. Add water with a mass 4 times that of the mixture, heat up to 85 °C, soak for 1 h, then add water with a mass 7 times that of the mixture, perform distillation and reflux water - extraction for 5 h, and concentrate to 3 times the mass of the mixture to obtain a water - extract.

[0044] 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 2:1:1.5; the mass of the composite enzyme is 0.2% of the mass of the mixture of chamomile, houttuynia cordata and peony; continuously stir and ferment at a stirring speed of 100 r / min, the fermentation temperature is about 52 °C, and the fermentation time is 64 h. Then inactivate at an inactivation temperature of 98 °C and an inactivation time of 20 min. Then filter, and the obtained filtrate is the chamomile - houttuynia cordata - peony composite water - extraction fermentate.

[0045] Example 4: The difference between this example and Example 1 is: (2) Prepare azelastine hydrochloride nasal spray, and its preparation method is as follows:

[0046] Weigh the following components by mass percentage: azelastine hydrochloride 0.1%, chamomile-houttuynia cordata-peony composite water extract ferment 0.3%, stabilizer 0.005%, preservative 0.002%, thickener 0.95%, pH regulator 0.75%, sodium chloride 0.45% and purified water as the balance. Among them, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hypromellose; the pH regulator is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (that is, citric acid 0.115%, disodium hydrogen phosphate 0.63%).

[0047] Put the preservative, stabilizer, pH regulator and sodium chloride into a beaker, add 2 / 7 of the total amount of purified water at 85°C, and stir evenly at a stirring speed of 240 r / min for 30 min to dissolve. Then add the thickener, keep the temperature at 85°C, stir at high speed (3000 r / min) with an emulsifier for 15 min to fully swell, cool to room temperature, add 4 / 7 of the total amount of purified water, stir at high speed with an emulsifier, add azelastine hydrochloride and chamomile-houttuynia cordata-peony composite water extract ferment, stir at high speed for 10 min, add the remaining 1 / 7 of the total amount of purified water, and continue to stir for 5 min to obtain azelastine hydrochloride nasal spray.

[0048] 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.

[0049] Example 5: The difference between this example and Example 1 is: (2) Prepare azelastine hydrochloride nasal spray, and its preparation method is as follows:

[0050] Weigh the following components by mass percentage: azelastine hydrochloride 0.1%, chamomile-houttuynia cordata-peony composite water extract ferment 0.4%, stabilizer 0.01%, preservative 0.01%, thickener 1.05%, pH regulator 0.75%, sodium chloride 0.48% and purified water as the balance. Among them, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hypromellose; the pH regulator is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (that is, citric acid 0.115%, disodium hydrogen phosphate 0.63%).

[0051] Put the preservative, stabilizer, pH regulator and sodium chloride in a beaker, add 2 / 7 of the total amount of purified water at 85°C, and stir evenly at a stirring speed of 240 r / min for 30 min to dissolve. Then add the thickening agent, keep the temperature at 85°C, and stir at high speed (3000 r / min) with an emulsifier for 15 min to fully swell. Cool to room temperature, add 4 / 7 of the total amount of purified water, stir at high speed with an emulsifier, add azelastine hydrochloride and the complex aqueous extract fermentation product of chamomile, houttuynia cordata and peony flower, stir at high speed for 10 min, add the remaining 1 / 7 of the total amount of purified water, and continue to stir for 5 min to obtain azelastine hydrochloride nasal spray.

[0052] 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.

[0053] Comparative Example 1: The difference between this comparative example and Example 1 is that in the preparation of azelastine hydrochloride nasal spray, the complex aqueous extract fermentation product of chamomile, houttuynia cordata and peony flower is deleted, and the dosage of the thickening agent is 0.6%.

[0054] Specifically, for the preparation of azelastine hydrochloride nasal spray, the preparation method is as follows:

[0055] Weigh the following components by mass percentage: 0.1% azelastine hydrochloride, 0.008% stabilizer, 0.005% preservative, 0.6% thickening agent, 0.75% pH regulator, 0.46% sodium chloride and the balance of purified water. Among them, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickening agent is hypromellose; the pH regulator is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (that is, 0.115% citric acid and 0.63% disodium hydrogen phosphate).

[0056] Put the preservative, stabilizer, pH regulator and sodium chloride in a beaker, add 2 / 7 of the total amount of purified water at 85°C, and stir evenly at a stirring speed of 240 r / min for 30 min to dissolve. Then add the thickening agent, keep the temperature at 85°C, and stir at high speed (3000 r / min) with an emulsifier for 15 min to fully swell. Cool to room temperature, add 4 / 7 of the total amount of purified water, stir at high speed with an emulsifier, add azelastine hydrochloride, stir at high speed for 10 min, add the remaining 1 / 7 of the total amount of purified water, and continue to stir for 5 min to obtain azelastine hydrochloride nasal spray.

[0057] The viscosity of the azelastine hydrochloride nasal spray is 1.11 mPa·s.

[0058] Comparative Example 2: The difference between this comparative example and Example 1 lies in that in the preparation of azelastine hydrochloride nasal spray, the chamomile-houttuynia cordata-peony composite water extract fermented product is deleted (the dosage of the thickener remains unchanged at 1.0%).

[0059] Specifically, to prepare azelastine hydrochloride nasal spray, the preparation method is as follows:

[0060] Weigh the following components by mass percentage: 0.1% azelastine hydrochloride, 0.008% stabilizer, 0.005% preservative, 1.0% thickener, 0.75% pH regulator, 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 hypromellose; the pH regulator 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).

[0061] Put the preservative, stabilizer, pH regulator, and sodium chloride into a beaker, add 2 / 7 of the total amount of purified water at 85°C, and stir evenly at a stirring speed of 240 r / min for 30 min to dissolve. Then add the thickener, keep the temperature at 85°C, stir at high speed (3000 r / min) with an emulsifier for 15 min to fully swell, cool to room temperature, add 4 / 7 of the total amount of purified water, stir at high speed with an emulsifier, add azelastine hydrochloride, stir at high speed for 10 min, add the remaining 1 / 7 of the total amount of purified water, and continue to stir for 5 min to obtain azelastine hydrochloride nasal spray.

[0062] The viscosity of the azelastine hydrochloride nasal spray is 2.0 mPa·s.

[0063] Comparative Example 3: The difference between this comparative example and Example 1 lies in that in the preparation of azelastine hydrochloride nasal spray, the chamomile-houttuynia cordata-peony composite water extract fermented product is deleted, and the dosage of the thickener is 1.4%.

[0064] Specifically, to prepare azelastine hydrochloride nasal spray, the preparation method is as follows:

[0065] Weigh the following components by mass percentage: 0.1% azelastine hydrochloride, 0.008% stabilizer, 0.005% preservative, 1.4% thickener, 0.75% pH regulator, 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 hypromellose; the pH regulator 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).

[0066] Place the preservative, stabilizer, pH regulator, and sodium chloride in a beaker, add purified water at 85°C accounting for 2 / 7 of the total amount, and stir at a speed of 240 r / min uniformly for 30 min to dissolve. Then add the thickener, keep the temperature at 85°C, and stir with a high-speed emulsifier (3000 r / min) for 15 min to fully swell. Cool to room temperature, add purified water accounting for 4 / 7 of the total amount, stir with a high-speed emulsifier, add azelastine hydrochloride, stir at high speed for 10 min, add the remaining purified water accounting for 1 / 7 of the total amount, and continue to stir for 5 min to obtain azelastine hydrochloride nasal spray.

[0067] The viscosity of azelastine hydrochloride nasal spray is 2.83 mPa·s.

[0068] Comparative Example 4: The difference between this comparative example and Example 1 is that in the preparation of azelastine hydrochloride nasal spray, the dosage of the thickener is 0.6%.

[0069] Specifically, to prepare azelastine hydrochloride nasal spray, the preparation method is as follows:

[0070] Weigh the following components by mass percentage: azelastine hydrochloride 0.1%, chamomile-houttuynia cordata-peony composite water extract ferment 0.35%, stabilizer 0.008%, preservative 0.005%, thickener 0.6%, pH regulator 0.75%, sodium chloride 0.46%, and the balance is purified water. Among them, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickener is hypromellose; the pH regulator is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (i.e., citric acid 0.115%, disodium hydrogen phosphate 0.63%).

[0071] Place the preservative, stabilizer, pH regulator, and sodium chloride in a beaker, add purified water at 85°C accounting for 2 / 7 of the total amount, and stir at a speed of 240 r / min uniformly for 30 min to dissolve. Then add the thickener, keep the temperature at 85°C, and stir with a high-speed emulsifier (3000 r / min) for 15 min to fully swell. Cool to room temperature, add purified water accounting for 4 / 7 of the total amount, stir with a high-speed emulsifier, add azelastine hydrochloride and chamomile-houttuynia cordata-peony composite water extract ferment, stir at high speed for 10 min, add the remaining purified water accounting for 1 / 7 of the total amount, and continue to stir for 5 min to obtain azelastine hydrochloride nasal spray.

[0072] The viscosity of azelastine hydrochloride nasal spray is 1.08 mPa·s.

[0073] Comparative Example 5: The difference between this comparative example and Example 1 is that in the preparation of azelastine hydrochloride nasal spray, the dosage of the thickener is 1.4%.

[0074] Specifically, to prepare azelastine hydrochloride nasal spray, the preparation method is as follows:

[0075] Weigh the following components by mass percentage: azelastine hydrochloride 0.1%, chamomile-houttuynia cordata-peony composite water extract ferment 0.35%, stabilizer 0.008%, preservative 0.005%, thickening agent 1.4%, pH regulator 0.75%, sodium chloride 0.46%, and the balance is purified water. Among them, the stabilizer is disodium edetate; the preservative is benzalkonium bromide; the thickening agent is hypromellose; the pH regulator is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid to disodium hydrogen phosphate is 1:5.5 (i.e., citric acid 0.115% and disodium hydrogen phosphate 0.63%).

[0076] Put the preservative, stabilizer, pH regulator and sodium chloride into a beaker, add 2 / 7 of the total amount of purified water at 85°C, and stir evenly at a stirring speed of 240 r / min for 30 min to dissolve. Then add the thickening agent, keep the temperature at 85°C, stir at high speed (3000 r / min) with an emulsifier for 15 min to fully swell, cool to room temperature, add 4 / 7 of the total amount of purified water, stir at high speed with an emulsifier, add azelastine hydrochloride and chamomile-houttuynia cordata-peony composite water extract ferment, stir at high speed for 10 min, add the remaining 1 / 7 of the total amount of purified water, and continue to stir for 5 min to obtain azelastine hydrochloride nasal spray.

[0077] The viscosity of azelastine hydrochloride nasal spray is 2.81 mPa·s.

[0078] Test Example 1: Test item: Eye irritation test.

[0079] Test subjects: Azelastine hydrochloride nasal sprays prepared in Examples 1-5 and Comparative Examples 1-5.

[0080] Test content: Take 50 white rats, and conduct a routine examination on the two eyes of all white rats to ensure no irritation symptoms; randomly divide them into 10 groups corresponding to 10 test subjects, with 5 white rats in each group, labeled I, II, III, IV, VI. During the test, drop 0.1 ml of the test sample into the conjunctival sac, and use the other eye as a control. Passively close the eyes for 5 s after dropping the medicine. The observation time is 24 h. If local reaction symptoms appear within 24 h, record the corresponding highest score; if no local reaction symptoms appear within 24 h, record 0 points. The scoring basis for local reaction symptoms is shown in Table 1.

[0081] Table 1. Scoring basis for local reaction symptoms of eye irritation

[0082]

[0083] Test results: See Table 2.

[0084] Table 2. Test data of eye irritation test in Test Example 1

[0085]

[0086] Result analysis: Analyze Examples 1 - 5 and combine with the data in Table 2 and Figure 1 It can be seen that the azelastine hydrochloride nasal spray prepared by the present invention (Examples 1 - 5) has a low eye irritation symptom score of less than 0.2 points, and is safe and reassuring to use.

[0087] From 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, when the raw material components do not contain the composite water extraction ferment of chamomile - houttuynia cordata - peony flower, with the increase of the viscosity of the finally prepared azelastine hydrochloride nasal spray, the irritation to the eyes will increase.

[0088] Combined with Comparative Example 4 (viscosity 1.08 mPa·s), Example 1 (viscosity 1.99 mPa·s) and Comparative Example 5 (viscosity 2.81 mPa·s) for comparison, it can be known that adding the composite water extraction ferment of chamomile - houttuynia cordata - peony flower to the raw material components can significantly reduce the irritation of the finally prepared azelastine hydrochloride nasal spray to the eyes. And this reduction effect will first increase with the increase of the viscosity of the prepared azelastine hydrochloride nasal spray, and then weaken with the continuous increase of the viscosity of the prepared azelastine hydrochloride nasal spray.

[0089] In summary, when the dosage of the thickening agent in the present invention is 0.95 - 1.05%, the azelastine hydrochloride nasal spray prepared by adding the composite water extraction ferment of chamomile - houttuynia cordata - peony flower has the least irritation to the eyes and is safer and more reassuring to use.

[0090] Test Example 2: Test item: Rhinitis treatment test.

[0091] Test subjects: Azelastine hydrochloride nasal sprays prepared in Example 1 and Comparative Example 2.

[0092] Test content: All 50 patients presented with continuous sneezing, nasal congestion, nasal itching, and excessive clear nasal discharge. They were randomly divided into two groups, Group A and Group 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 nasal cavity with the azelastine hydrochloride nasal spray three times a day, once in the morning, once at noon, and once in the evening, with one spray in each nostril each time. After continuous medication for 1 week, the spraying dose began to decrease. In the second week, it was sprayed twice a day, once in the morning and once in the evening, with one spray in each nostril each time. In the third week, it was sprayed once a day, with an interval of more than 20 hours each time, and one spray in each nostril each time. In the fourth week, it was sprayed three times a week (on Monday, Thursday, and Sunday), with one spray in each nostril each time. After 1 month, it was sprayed once a week, with one spray in each nostril each time. After continuous medication for 2 months, according to Table 3 and Table 4, the reduction in scores after treatment was statistically analyzed, and the curative effects were recorded (there was no overlapping phenomenon in the cases of special effects, marked effects, and effective conditions).

[0093] Table 3. Basis for scoring rhinitis attack symptoms

[0094]

[0095] Table 4. Criteria for judging curative effects

[0096]

[0097] Test results: See Table 5.

[0098] Table 5. Test data for rhinitis treatment in Test Example 2

[0099]

[0100] 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 the composite water extract fermentation product of chamomile - houttuynia cordata - peony flower in the present invention (Example 1) has an increased special efficiency for rhinitis treatment and a significant treatment effect.

[0101] In addition, it should be noted that for each of the specific technical features described in the above specific embodiments, without conflict, they can be combined in any suitable way. To avoid unnecessary repetition, the present invention will not separately describe various possible combination methods.

[0102] In addition, any combination can be made between various different embodiments of the present invention, as long as it does not violate the idea of the present invention, it should also be regarded as the content disclosed by the present invention.

Claims

1. A azelastine hydrochloride nasal spray, characterized in that, By mass percentage, it consists of the following components: azelastine hydrochloride 0.1%, chamomile-houttuynia cordata-peony composite water extract ferment 0.3 - 0.4%, stabilizer 0.005 - 0.01%, preservative 0.002 - 0.01%, thickener 0.95 - 1.05%, pH regulator 0.7 - 0.8%, sodium chloride 0.45 - 0.48% and the balance of purified water; The chamomile-houttuynia cordata-peony composite water extract ferment is prepared by first subjecting the mixture of chamomile, houttuynia cordata and peony to water extraction to obtain a water extract, and then subjecting it to composite enzyme fermentation. The mass ratio of chamomile, houttuynia cordata 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 cordata and peony; The composite enzyme consists of 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; The preparation method of the chamomile-houttuynia cordata-peony composite water extract ferment is as follows: A1. Mix chamomile, houttuynia cordata and peony to obtain a mixture, add water 3 - 4 times the mass of the mixture, heat up to 80 ± 5 °C, soak for 1 - 1.5 h, then add water 5 - 7 times the mass of the mixture, perform distillation and reflux water extraction for 5 - 7 h, and concentrate to 2 - 3 times the mass of the mixture to obtain a water extract; A2. Add the composite enzyme to the water extract obtained in A1, continuously stir, ferment, inactivate, and filter to obtain the chamomile-houttuynia cordata-peony composite water extract ferment; In A1, water-soluble antioxidant vitamin C is also added, and its mass is 2 - 3% of the mass of the mixture.

2. The azelastine hydrochloride nasal spray according to claim 1, characterized in that, In A2, the continuous stirring speed is 80 - 100 r / min.

3. The azelastine hydrochloride nasal spray according to claim 1, wherein In A2, the fermentation temperature is 48 - 58 °C, and the fermentation time is 56 - 64 h.

4. The azelastine hydrochloride nasal spray according to claim 1, characterized in that, In A2, the inactivation temperature is 98 ± 2 °C, and the inactivation time is 20 - 30 min.

5. 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 hypromellose; The pH regulator is citric acid and disodium hydrogen phosphate, and the mass ratio of citric acid and disodium hydrogen phosphate is 1:(5 - 6).

6. A preparation method of azelastine hydrochloride nasal spray according to any one of claims 1-5, characterized in that, It includes the following steps: Place the preservative, stabilizer, pH regulator and sodium chloride in a beaker, add purified water at 80 - 90 °C accounting for 2 / 7 of the total amount, stir and dissolve; Then add the thickener, keep the temperature at 80 - 90 °C, stir to fully swell, cool to room temperature, add purified water accounting for 4 / 7 of the total amount, stir, then add azelastine hydrochloride and chamomile-houttuynia cordata-peony composite water extract ferment, stir, add the remaining purified water accounting for 1 / 7 of the total amount, and continue to stir to obtain.

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