Mometasone Furoate Nasal Spray and Its Preparation Method

Abstract

The present invention belongs to the field of pharmaceutical technology, and particularly relates to a mometasone furoate nasal spray and a preparation method thereof. The preparation method of the mometasone furoate nasal spray includes purified water treatment, preparation of a suspension base liquid, preparation of a main drug suspension, preparation of a buffer solution, total mixing and shearing, and nitrogen filling and canning. The present invention improves the stability of the drug active ingredient mometasone furoate through the interaction of various components, and at the same time combines frequency conversion ultrasonic treatment, repeated shearing, and homogenization treatment in the production process to obtain a mometasone furoate nasal spray with good dispersion performance, high stability, and excellent spraying effect.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a mometasone furoate nasal spray and a preparation method thereof. Background Art

[0002] Mometasone furoate (CAS: 83919-23-7) is a new topical potent glucocorticoid preparation developed and produced by Schering-Plough Corporation of the United States, and was first marketed in the United States in 1987.

[0003] Mometasone furoate is a topical glucocorticoid with obvious local anti-allergic effect without causing obvious systemic effects. It enhances the stability of endothelial cells, smooth muscle cells and lysosomal membranes, inhibits the release of mediators, promotes their metabolism, inhibits immune responses and reduces antibody synthesis; inhibits capillary exudation and reduces sticky cells, thus rapidly relieving symptoms. Allergic rhinitis is not a systemic reaction, and the nasal mucosa is the only effector organ, and the pathophysiological processes of its onset are concentrated here. The mometasone furoate nasal spray acts directly on the nasal mucosa, only exerting local hormonal effects, with low bioavailability, can be used for a long time, and will not cause systemic side effects at therapeutic doses, and is one of the effective drugs for treating allergic rhinitis at present.

[0004] The addition amount of the main drug mometasone furoate in the mometasone furoate nasal spray is very low, so it is particularly important to fully mix the main drug and improve the drug stability. Summary of the Invention

[0005] The purpose of the present invention is to provide a mometasone furoate nasal spray and a preparation method thereof, which improve the stability of the drug active ingredient mometasone furoate through the interaction of various components, and at the same time combine frequency conversion ultrasonic treatment, repeated shearing and homogenization treatment in the production process to obtain a mometasone furoate nasal spray with good dispersion performance, high stability and excellent spraying effect.

[0006] In order to achieve the above purpose, the present application adopts the following technical solutions:

[0007] On the one hand, the present invention provides a preparation method of a mometasone furoate nasal spray, comprising the following steps:

[0008] S1. Purified water treatment: After the purified water is heated and boiled for 20 ± 2 min, it is cooled to below 40 °C for standby;

[0009] The purified water is treated by heating and boiling, which can effectively remove the dissolved oxygen in the purified water and has a bactericidal effect, which is beneficial to the stability of the drug preparation.

[0010] S2. Preparation of suspension base solution: Add 1%-3% of the total prescription amount of purified water and microcrystalline cellulose-sodium carboxymethylcellulose to the batching tank. After ultrasonic mixing, perform pre-shearing to obtain the suspension base solution;

[0011] In the present invention, microcrystalline cellulose-sodium carboxymethylcellulose is used as a suspending agent. The inventor found during the production process that after pre-shearing and dispersing microcrystalline cellulose-sodium carboxymethylcellulose, it is beneficial to the stability of the product. If it is directly added without pre-dispersion and mixed with other components, the solution is prone to layering during storage.

[0012] S3. Preparation of the main drug suspension: Add 1%-3% of the total prescription amount of purified water to a clean container, heat it to 70-80 °C, then add benzalkonium chloride, and after ultrasonic dissolution, cool it to 40-50 °C; then add polysorbate 80, and after ultrasonic dissolution, cool it to below 30 °C. Finally, add mometasone furoate monohydrate, and after variable-frequency ultrasonic dispersion, homogenize to obtain the main drug suspension;

[0013] It should be noted that when preparing the main drug suspension, benzalkonium chloride must be added first, then polysorbate 80, and finally mometasone furoate monohydrate. Benzalkonium chloride is a cationic surfactant and a non-oxidizing bactericide. Choosing to add the bactericide at the beginning provides a sterile environment, avoids the influence of miscellaneous bacteria on the preparation, and effectively improves the stability of the preparation during later storage; Polysorbate-80 is an oil / water type emulsifier and can also be used as a wetting agent. By reducing the surface tension or interfacial tension, water can spread or penetrate into the surface of mometasone furoate, making the main drug mometasone furoate evenly dispersed and uniform in content in water.

[0014] The addition amount of the main drug mometasone furoate is very low. To fully mix the main drug, during the dispersion of the main drug, the process combines variable-frequency ultrasonic and homogenization treatments. The mechanical vibration and cavitation effect of ultrasonic waves can accelerate the vibration and diffusion of molecules, making the main drug evenly dispersed. The variable-frequency ultrasonic treatment will not damage the structure of the main drug components. The homogenization treatment can disperse the mixture into a suspension with a certain particle size, improving the dispersion of the main drug mometasone furoate.

[0015] S4. Preparation of buffer solution: Add 1%-2% of the total prescription amount of purified water to a clean container, add citric acid and sodium citrate and stir to dissolve to obtain the buffer solution;

[0016] Adding the buffer solution can keep the pH value of the preparation stable at 4.4-4.8.

[0017] S5, Total mixing and shearing: Under stirring, glycerol, the main drug suspension, and the buffer solution are sequentially added to the suspension base solution obtained in S1. The containers for the main drug suspension and the buffer solution are rinsed with the remaining purified water respectively, and the rinsing solutions are combined into the batching tank. It is ultrasonically treated at an ultrasonic frequency of 35 - 45 KHz for 10 - 15 min, the pH is detected, and total mixing and shearing are carried out to obtain the total mixing solution;

[0018] S6, Nitrogen filling and canning: Under stirring, the total mixing solution is canned while vacuum is pumped and nitrogen is filled, and then the lid is pressed to obtain the product.

[0019] Furthermore, in S2, the ultrasonic frequency for ultrasonic mixing is 20 - 30 KHz, and the ultrasonic time is 5 - 10 min.

[0020] Furthermore, in S2, the pre - shearing is: reciprocating shearing is carried out 6 - 8 times at a shearing frequency of 90.0 Hz.

[0021] Furthermore, in S3, the ultrasonic frequency for ultrasonic dissolution is 30 - 40 KHz, and the ultrasonic time is 5 - 10 min.

[0022] Furthermore, in S3, the variable - frequency ultrasonic dispersion is: with a low - frequency ultrasonic frequency of 25 - 35 KHz and a high - frequency ultrasonic frequency of 50 - 60 KHz, low - frequency and high - frequency ultrasonic alternating treatments are carried out, each ultrasonic segment is treated for 5 - 6 min, and the total treatment duration is 30 - 40 min.

[0023] Furthermore, in S3, the rotation speed for homogenization is 4500 - 5500 rpm, and the time is 3 - 5 min.

[0024] Furthermore, in S5, the pH is 4.4 - 4.8;

[0025] The total mixing and shearing is: reciprocating shearing is carried out 4 - 6 times at a shearing frequency of 90 Hz.

[0026] Another aspect of the present invention is to provide mometasone furoate nasal spray obtained by the above - mentioned preparation method.

[0027] Furthermore, by weight percentage, it is made of 0.02% - 0.08% of mometasone furoate monohydrate, 1% - 3% of microcrystalline cellulose - sodium carboxymethylcellulose, 1% - 4% of glycerol, 0.005% - 0.03% of polysorbate 80, 0.1% - 0.3% of citric acid, 0.1% - 0.4% of sodium citrate, 0.01% - 0.03% of benzalkonium chloride, and the balance of purified water.

[0028] Microcrystalline cellulose - sodium carboxymethylcellulose has a unique network structure, which can adsorb mometasone furoate, slow down the sedimentation rate of the drug in the aqueous medium, increase the degree of uniform dispersion of the drug, and enhance the stability during storage; glycerol can be used as an osmotic pressure regulator to adjust the osmotic pressure of the liquid medicine and promote the stability of the drug; benzalkonium chloride is an antibacterial agent, which makes the drug quality stable; polysorbate 80 is a wetting agent, which makes the main drug mometasone furoate disperse uniformly in water with uniform content; citric acid and sodium citrate are used as pH regulators to make the pH value of the preparation stable at 4.4 - 4.8.

[0029] Advantages over the prior art:

[0030] 1. When preparing the main drug suspension in the present invention, it is necessary to first add benzalkonium chloride, then add polysorbate 80, and finally add mometasone furoate monohydrate. Benzalkonium chloride is a cationic surfactant and a non - oxidizing bactericide. Choosing to add the bactericide at the beginning provides a sterile environment to avoid the influence of miscellaneous bacteria on the preparation and effectively improves the stability of the preparation during later storage; polysorbate - 80 is an oil / water type emulsifier and can also be used as a wetting agent. By reducing the surface tension or interfacial tension, water can spread or penetrate into the surface of mometasone furoate, making the main drug mometasone furoate disperse uniformly in water with uniform content.

[0031] The addition amount of the main drug mometasone furoate is very low. To fully mix the main drug, during the dispersion of the main drug, the process combines variable - frequency ultrasonic and homogenization treatments. The mechanical vibration and cavitation effect of ultrasonic waves can accelerate the vibration and diffusion of molecules, making the main drug disperse uniformly. The variable - frequency ultrasonic treatment will not damage the structure of the main drug components, and the homogenization treatment can disperse the mixture into a suspension with a certain particle size, improving the dispersion of the main drug mometasone furoate.

[0032] 2. By combining variable - frequency ultrasonic treatment, repeated shearing, and homogenization treatment, a mometasone furoate nasal spray with good dispersion performance, high stability, and excellent spraying effect is obtained.

[0033] 3. The preparation method of the present invention is simple, has a short production cycle, low energy consumption, and is suitable for large - scale production. Detailed implementation mode

[0034] All the above - mentioned technical features of the present invention and the technical features specifically described below (such as in the implementation cases) can be combined with each other to form new or preferred technical solutions. However, the present invention is not limited to these embodiments, and these embodiments do not limit the present invention in any way.

[0035] The experimental methods in the following embodiments are all conventional methods unless otherwise specified. The preparations involved in the following embodiments are all ordinary commercially available products and can be obtained through the market unless otherwise specified.

[0036] In the following embodiments, mometasone furoate nasal spray is prepared from 0.05% of mometasone furoate monohydrate, 2% of microcrystalline cellulose - sodium carboxymethylcellulose, 2.1% of glycerol, 0.01% of polysorbate 80, 0.2% of citric acid, 0.28% of sodium citrate, 0.02% of benzalkonium chloride and the balance of purified water by weight percentage.

[0037] The present invention will be further described in detail below in conjunction with the embodiments:

[0038] Example 1: Preparation of mometasone furoate nasal spray

[0039] S1. Purified water treatment: The purified water is heated to boiling for 20 min and then cooled to below 40 °C for standby.

[0040] S2. Preparation of suspension base: 3% of the total amount of purified water in the prescription and microcrystalline cellulose - sodium carboxymethylcellulose are added to the batching tank, ultrasonicated at an ultrasonic frequency of 25 KHz for 8 min, and after ultrasonic mixing, the shear frequency is set to 90.0 Hz and reciprocally sheared 7 times to obtain the suspension base.

[0041] S3. Preparation of main drug suspension: 2% of the total amount of purified water in the prescription is added to a clean container, heated to 80 °C, then benzalkonium chloride is added, ultrasonicated at an ultrasonic frequency of 35 KHz for 8 min, and cooled to 45 °C; then polysorbate 80 is added, ultrasonicated at an ultrasonic frequency of 35 KHz for 8 min, and cooled to below 30 °C. Finally, mometasone furoate monohydrate is added, and alternately ultrasonicated at a low - frequency ultrasonic frequency of 25 KHz and a high - frequency ultrasonic frequency of 50 KHz, with each ultrasonic section treated for 5 min and a total treatment duration of 30 min. After ultrasonic dispersion, it is homogenized at a rotational speed of 5000 rpm for 4 min to obtain a non - aggregated and uniform main drug suspension.

[0042] S4. Preparation of buffer solution: 2% of the total amount of purified water in the prescription is added to a clean container, and citric acid and sodium citrate are added and stirred until dissolved to obtain the buffer solution.

[0043] S5. Total mixing and shearing: Under stirring at a stirring speed of 50 rpm, glycerol, the main drug suspension, and the buffer solution are sequentially added to the suspension base obtained in S1, and the containers containing the main drug suspension and the buffer solution are rinsed with the remaining purified water, and the rinsing solutions are combined into the batching tank. Ultrasonicated at an ultrasonic frequency of 40 KHz for 10 min, the pH is detected to be 4.5, the shear frequency is set to 90 Hz, and reciprocally sheared 5 times for total mixing to obtain the total mixing solution.

[0044] S6. Nitrogen - filling and canning: Under stirring, the total mixing solution is canned, while vacuum - pumping and nitrogen - filling are carried out, and then capping is performed to obtain the product.

[0045] Example 2: Preparation of mometasone furoate nasal spray

[0046] S1. Purified water treatment: After heating the purified water to boiling for 22 min, cool it to below 40 °C for standby;

[0047] S2. Preparation of suspension base: Add 2% of the total amount of purified water in the prescription and microcrystalline cellulose - sodium carboxymethylcellulose to the batching tank, ultrasonically treat for 6 min at an ultrasonic frequency of 30 KHz. After ultrasonic mixing, set the shear frequency to 90.0 Hz and perform 6 reciprocating shears to obtain the suspension base;

[0048] S3. Preparation of main drug suspension: Add 3% of the total amount of purified water in the prescription to a clean container, heat it to 75 °C, then add benzalkonium chloride, ultrasonically treat for 6 min at an ultrasonic frequency of 40 KHz, and cool it to 50 °C; then add polysorbate 80, ultrasonically treat for 6 min at an ultrasonic frequency of 40 KHz, and cool it to below 30 °C. Finally, add mometasone furoate monohydrate, and perform low - frequency and high - frequency ultrasonic alternating treatment at a low - frequency ultrasonic frequency of 30 KHz and a high - frequency ultrasonic frequency of 55 KHz. Each ultrasonic section is treated for 6 min, and the total treatment duration is 36 min. After ultrasonic dispersion, homogenize at a rotational speed of 4500 rpm for 5 min to obtain a non - aggregated and uniform main drug suspension;

[0049] S4. Preparation of buffer solution: Add 2% of the total amount of purified water in the prescription to a clean container, add citric acid and sodium citrate and stir to dissolve to obtain the buffer solution;

[0050] S5. Total mixing and shearing: Under stirring conditions with a stirring speed of 50 rpm, add glycerol, the main drug suspension, and the buffer solution to the suspension base obtained in S1 in sequence, and use the remaining purified water to rinse the containers containing the main drug suspension and the buffer solution respectively, and combine the rinsing solutions into the batching tank. Ultrasonically treat for 15 min at an ultrasonic frequency of 35 KHz, detect the pH to be 4.7, set the shear frequency to 90 Hz, and perform 4 reciprocating total mixing shears to obtain the total mixing solution;

[0051] S6. Nitrogen filling and canning: Under stirring conditions, can the total mixing solution, while performing vacuum pumping and nitrogen filling, and capping to obtain the product.

[0052] Example 3: Preparation of mometasone furoate nasal spray

[0053] S1. Purified water treatment: After heating the purified water to boiling for 18 min, cool it to below 40 °C for standby;

[0054] S2. Preparation of suspension base liquid: Add 2% of the total prescription amount of purified water and microcrystalline cellulose - sodium carboxymethylcellulose into the batching tank, perform ultrasonic treatment at an ultrasonic frequency of 20 KHz for 10 min. After ultrasonic mixing, set the shear frequency to 90.0 Hz and perform 8 reciprocating shears to obtain the suspension base liquid;

[0055] S3. Preparation of main drug suspension: Add 2% of the total prescription amount of purified water into a clean container, heat it to 70 °C, then add benzalkonium chloride, perform ultrasonic treatment at an ultrasonic frequency of 30 KHz for 10 min, and cool it to 40 °C; then add polysorbate 80, perform ultrasonic treatment at an ultrasonic frequency of 30 KHz for 10 min, and cool it to below 30 °C. Finally, add mometasone furoate monohydrate, and perform low - frequency and high - frequency ultrasonic alternating treatment according to a low - frequency ultrasonic frequency of 35 KHz and a high - frequency ultrasonic frequency of 60 KHz. Each ultrasonic segment is treated for 5.5 min, and the total treatment duration is 33 min. After ultrasonic dispersion, homogenize at a rotation speed of 5500 rpm for 3 min to obtain a non - aggregated and uniform main drug suspension;

[0056] S4. Preparation of buffer solution: Add 2% of the total prescription amount of purified water into a clean container, add citric acid and sodium citrate and stir to dissolve to obtain the buffer solution;

[0057] S5. Total mixing and shearing: Under the stirring state, with a stirring speed of 50 rpm, add glycerol, the main drug suspension, and the buffer solution into the suspension base liquid obtained in S1 in sequence, and use the remaining purified water to rinse the containers containing the main drug suspension and the buffer solution respectively, and merge the rinsing solutions into the batching tank. Perform ultrasonic treatment at an ultrasonic frequency of 35 KHz for 12 min, detect the pH to be 4.6, set the shear frequency to 90 Hz, and perform 6 reciprocating total mixing shears to obtain the total mixing solution;

[0058] S6. Nitrogen filling and canning: Under the stirring state, can the total mixing solution, while performing vacuum pumping and nitrogen filling, and capping to obtain the product.

[0059] Comparative Example 1

[0060] S1. Purified water treatment: Heat the purified water to boiling for 20 min, and then cool it to below 40 °C for standby;

[0061] S2. Preparation of suspension base liquid: Add 3% of the total prescription amount of purified water and microcrystalline cellulose - sodium carboxymethylcellulose into the batching tank, perform ultrasonic treatment at an ultrasonic frequency of 25 KHz for 8 min. After ultrasonic mixing, set the shear frequency to 90.0 Hz and perform 7 reciprocating shears to obtain the suspension base liquid;

[0062] S3. Preparation of the main drug suspension: Add 2% of the total prescription amount of purified water into a clean container, heat it to 80°C, then add polysorbate 80, and ultrasonically treat it for 8 minutes at an ultrasonic frequency of 35 KHz, and cool it to 45°C; then add benzalkonium chloride, ultrasonically treat it for 8 minutes at an ultrasonic frequency of 35 KHz, and cool it to below 30°C. Finally, add mometasone furoate monohydrate, and perform low-frequency and high-frequency ultrasonic alternating treatment according to a low-frequency ultrasonic frequency of 25 KHz and a high-frequency ultrasonic frequency of 50 KHz. Each ultrasonic section is treated for 5 minutes, and the total treatment duration is 30 minutes. After ultrasonic dispersion, homogenize it at a stable rotation speed of 5000 rpm for 4 minutes to obtain a non-aggregated and uniform main drug suspension;

[0063] S4. Preparation of the buffer solution: Add 2% of the total prescription amount of purified water into a clean container, add citric acid and sodium citrate, and stir to dissolve to obtain a buffer solution;

[0064] S5. Total mixing and shearing: Under the stirring state, with a stirring speed of 50 rpm, add glycerol, the main drug suspension, and the buffer solution to the suspension base liquid obtained in S1 in sequence, and use the remaining purified water to rinse the containers containing the main drug suspension and the buffer solution respectively, and merge the rinsing solutions into the batching tank. Ultrasonically treat it for 10 minutes at an ultrasonic frequency of 40 KHz, detect the pH to be 4.4, set the shearing frequency to 90 Hz, and perform 5 reciprocating total mixing and shearing operations to obtain a total mixing solution;

[0065] S6. Nitrogen filling and canning: Under the stirring state, can the total mixing solution, and at the same time perform vacuum pumping and nitrogen filling, and then crimp the lid to obtain the product.

[0066] Comparative Example 2

[0067] S1. Purified water treatment: Heat the purified water to boiling for 20 minutes, and then cool it to below 40°C for standby;

[0068] S2. Preparation of the suspension base liquid: Add 3% of the total prescription amount of purified water and microcrystalline cellulose - sodium carboxymethylcellulose to the batching tank, ultrasonically treat it for 8 minutes at an ultrasonic frequency of 25 KHz, and after ultrasonic mixing, set the shearing frequency to 90.0 Hz and perform 7 reciprocating shearing operations to obtain a suspension base liquid;

[0069] S3. Preparation of the main drug suspension: Add 2% of the total prescription amount of purified water into a clean container, heat it to 80°C, then add benzalkonium chloride, ultrasonically treat it for 8 minutes at an ultrasonic frequency of 35 KHz, and cool it to 45°C; then add polysorbate 80, ultrasonically treat it for 8 minutes at an ultrasonic frequency of 35 KHz, and cool it to below 30°C. Finally, add mometasone furoate monohydrate, ultrasonically treat it for 30 minutes at an ultrasonic frequency of 25 KHz, and after ultrasonic dispersion, homogenize it at a stable rotation speed of 5000 rpm for 4 minutes to obtain a non-aggregated and uniform main drug suspension;

[0070] S4, Preparation of buffer solution: Add 2% of the total prescription amount of purified water into a clean container, add citric acid and sodium citrate, stir and dissolve to obtain the buffer solution;

[0071] S5, Total mixing and shearing: Under stirring condition, with the stirring speed of 50 rpm, add glycerol, the main drug suspension, and the buffer solution into the suspension base liquid obtained in S1 in sequence. Use the remaining purified water to rinse the containers for the main drug suspension and the buffer solution respectively, and combine the rinsing solutions into the batching tank. Perform ultrasonic treatment at an ultrasonic frequency of 40 KHz for 10 min, detect the pH to be 4.6, set the shearing frequency to 90 Hz, and perform 5 reciprocating total mixing and shearing operations to obtain the total mixing solution;

[0072] S6, Nitrogen filling and canning: Under stirring condition, can the total mixing solution, while performing vacuum pumping and nitrogen filling, and then crimp the lid to obtain the product.

[0073] Comparative Example 3

[0074] S1, Purified water treatment: Heat the purified water to boiling for 20 min, and then cool it to below 40 °C for standby;

[0075] S2, Preparation of suspension base liquid: Add 3% of the total prescription amount of purified water and microcrystalline cellulose - sodium carboxymethylcellulose into the batching tank, perform ultrasonic treatment at an ultrasonic frequency of 25 KHz for 8 min. After ultrasonic mixing, set the shearing frequency to 90.0 Hz and perform 7 reciprocating shearing operations to obtain the suspension base liquid;

[0076] S3, Preparation of main drug suspension: Add 2% of the total prescription amount of purified water into a clean container, heat it to 80 °C, then add benzalkonium chloride, perform ultrasonic treatment at an ultrasonic frequency of 35 KHz for 8 min, and cool it to 45 °C; then add polysorbate 80, perform ultrasonic treatment at an ultrasonic frequency of 35 KHz for 8 min, and cool it to below 30 °C. Finally, add mometasone furoate monohydrate, perform ultrasonic treatment at an ultrasonic frequency of 50 KHz for 30 min. After ultrasonic dispersion, homogenize at a rotation speed of 5000 rpm for 4 min to obtain a main drug suspension without aggregation and with uniform distribution;

[0077] S4, Preparation of buffer solution: Add 2% of the total prescription amount of purified water into a clean container, add citric acid and sodium citrate, stir and dissolve to obtain the buffer solution;

[0078] S5, Total mixing and shearing: Under stirring condition, with the stirring speed of 50 rpm, add glycerol, the main drug suspension, and the buffer solution into the suspension base liquid obtained in S1 in sequence. Use the remaining purified water to rinse the containers for the main drug suspension and the buffer solution respectively, and combine the rinsing solutions into the batching tank. Perform ultrasonic treatment at an ultrasonic frequency of 40 KHz for 10 min, detect the pH to be 4.5, set the shearing frequency to 90 Hz, and perform 5 reciprocating total mixing and shearing operations to obtain the total mixing solution;

[0079] S6, Nitrogen-filled canning: Under stirring, can the total mixed solution while performing vacuum pumping and nitrogen filling, and then crimp the lid to obtain the product.

[0080] Comparative Example 4

[0081] S1, Purified water treatment: Heat the purified water to boiling for 20 min, and then cool it to below 40 °C for standby.

[0082] S2, Preparation of suspension base: Add 3% of the total amount of the prescription of purified water and microcrystalline cellulose - sodium carboxymethylcellulose to the batching tank, perform ultrasonic treatment at an ultrasonic frequency of 25 KHz for 8 min. After ultrasonic mixing, set the shear frequency to 90.0 Hz and perform 3 reciprocating shears to obtain the suspension base.

[0083] S3, Preparation of main drug suspension: Add 2% of the total amount of the prescription of purified water to a clean container, heat it to 80 °C, then add benzalkonium chloride, perform ultrasonic treatment at an ultrasonic frequency of 35 KHz for 8 min, and cool it to 45 °C; then add polysorbate 80, perform ultrasonic treatment at an ultrasonic frequency of 35 KHz for 8 min, and cool it to below 30 °C. Finally, add mometasone furoate monohydrate, and perform low-frequency and high-frequency ultrasonic alternating treatment according to a low-frequency ultrasonic frequency of 25 KHz and a high-frequency ultrasonic frequency of 50 KHz. Each ultrasonic section is treated for 5 min, and the total treatment duration is 30 min. After ultrasonic dispersion, homogenize at a rotation speed of 5000 rpm for 4 min to obtain a non-aggregated and uniform main drug suspension.

[0084] S4, Preparation of buffer solution: Add 2% of the total amount of the prescription of purified water to a clean container, add citric acid and sodium citrate and stir to dissolve to obtain the buffer solution.

[0085] S5, Total mixing and shearing: Under stirring with a stirring speed of 50 rpm, add glycerol, the main drug suspension, and the buffer solution to the suspension base obtained in S1 in sequence, and use the remaining purified water to rinse the containers containing the main drug suspension and the buffer solution respectively, and combine the rinsing solutions into the batching tank. Perform ultrasonic treatment at an ultrasonic frequency of 40 KHz for 10 min, detect the pH to be 4.5, set the shear frequency to 90 Hz, and perform 3 reciprocating total mixing and shearing to obtain the total mixed solution.

[0086] S6, Nitrogen-filled canning: Under stirring, can the total mixed solution while performing vacuum pumping and nitrogen filling, and then crimp the lid to obtain the product.

[0087] Comparative Example 5

[0088] S1, Purified water treatment: Heat the purified water to boiling for 20 min, and then cool it to below 40 °C for standby.

[0089] S2. Preparation of suspension base: Add 3% of the total prescription amount of purified water and microcrystalline cellulose - sodium carboxymethylcellulose to the batching tank, ultrasonically treat for 8 min at an ultrasonic frequency of 25 KHz. After ultrasonic mixing, set the shear frequency to 90.0 Hz and perform 10 reciprocating shears to obtain the suspension base;

[0090] S3. Preparation of main drug suspension: Add 2% of the total prescription amount of purified water to a clean container, heat to 80 °C, then add benzalkonium chloride, ultrasonically treat for 8 min at an ultrasonic frequency of 35 KHz, and cool to 45 °C; then add polysorbate 80, ultrasonically treat for 8 min at an ultrasonic frequency of 35 KHz, and cool to below 30 °C. Finally, add mometasone furoate monohydrate, and perform low - frequency and high - frequency ultrasonic alternating treatment according to a low - frequency ultrasonic frequency of 25 KHz and a high - frequency ultrasonic frequency of 50 KHz. Each ultrasonic section is treated for 5 min, and the total treatment duration is 30 min. After ultrasonic dispersion, homogenize at a rotation speed of 5000 rpm for 4 min to obtain a non - aggregated and uniform main drug suspension;

[0091] S4. Preparation of buffer solution: Add 2% of the total prescription amount of purified water to a clean container, add citric acid and sodium citrate and stir to dissolve to obtain the buffer solution;

[0092] S5. Total mixing and shearing: Under stirring conditions with a stirring speed of 50 rpm, add glycerol, the main drug suspension, and the buffer solution to the suspension base obtained in S1 in sequence, and use the remaining purified water to rinse the containers containing the main drug suspension and the buffer solution respectively, and merge the rinsing solutions into the batching tank. Ultrasonically treat for 10 min at an ultrasonic frequency of 40 KHz, detect the pH to be 4.5, set the shear frequency to 90 Hz, and perform 10 reciprocating total mixing shears to obtain the total mixing solution;

[0093] S6. Nitrogen - filling and canning: Under stirring conditions, can the total mixing solution, and at the same time perform vacuum pumping and nitrogen filling, and then crimp the cap to obtain the product.

[0094] Test Example 1

[0095] Perform accelerated stability tests on the mometasone furoate nasal sprays prepared in Examples 1 - 3 and Comparative Examples 1 - 6. Test method: Refer to the "Guidelines for Stability Testing of Raw Materials and Preparations" in the "Chinese Pharmacopoeia (2020 Edition)", and conduct 6 - month accelerated stability tests under the conditions of a temperature of 40 ± 2 °C and a relative humidity of 75% ± 5%. Inspect the appearance, viscosity, total impurity content, droplet distribution, and microbial limit indicators on the 0th day and the 6th month respectively. The operating methods for relevant inspection items refer to the "Chinese Pharmacopoeia (2020 Edition)", and the results are shown in Table 1.

[0096] Table 1 Results of Stability Tests

[0097]

[0098] As can be seen from the results in Table 1, the mometasone furoate nasal spray obtained by the preparation method of the present invention has relatively stable properties, small and delicate droplet particle size, uniform dispersion, and good stability.

[0099] In Comparative Example 1, after the addition order of benzalkonium chloride and polysorbate 80 was reversed, serious delamination occurred after standing for 6 months, and the microbial indicators did not meet the requirements.

[0100] In Comparative Examples 2 and 3, when preparing the main drug suspension, after not using variable-frequency ultrasonic treatment, the droplet particle size was not as delicate as that in Example 1, and delamination and slight delamination occurred after standing for 6 months, with poor stability.

[0101] In Comparative Examples 4 and 5, when the pre-shearing and total mixing shearing times were 3 times and 10 times respectively, the droplet particle size of the obtained nasal spray did not meet the requirements, and serious delamination and slight delamination occurred after standing for 6 months, with poor stability.

[0102] In summary, the drug particle size and droplet particle size of the nasal spray obtained by the formula and preparation method of the present invention are small and delicate, uniformly dispersed, have good stability, are more conducive to absorption, will not cause waste, and have no side effects.

[0103] Finally, it should be emphasized that the above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation method of mometasone furoate nasal spray, characterized in that, It includes the following steps: S1. Purified water treatment: The purified water is heated and boiled for 20 ± 2 min, and then cooled to below 40 °C for standby. S2. Preparation of suspension base liquid: 1%-3% of the total amount of the prescription of purified water and microcrystalline cellulose - sodium carboxymethylcellulose are added to the batching tank. After ultrasonic mixing, pre - shearing is carried out to obtain the suspension base liquid. S3. Preparation of main drug suspension: 1%-3% of the total amount of the prescription of purified water is added to a clean container, heated to 70 - 80 °C, and then benzalkonium chloride is added. After ultrasonic dissolution, it is cooled to 40 - 50 °C; then polysorbate 80 is added. After ultrasonic dissolution, it is cooled to below 30 °C. Finally, mometasone furoate monohydrate is added. After variable - frequency ultrasonic dispersion and homogenization, the main drug suspension is obtained; the variable - frequency ultrasonic dispersion is: with a low - frequency ultrasonic frequency of 25 - 35 KHz and a high - frequency ultrasonic frequency of 50 - 60 KHz, low - frequency and high - frequency ultrasonic alternating treatment is carried out, each ultrasonic segment is treated for 5 - 6 min, and the total treatment duration is 30 - 40 min. S4. Preparation of buffer solution: 1%-2% of the total amount of the prescription of purified water is added to a clean container, and citric acid and sodium citrate are added and stirred to dissolve to obtain the buffer solution. S5. Total mixing and shearing: Under stirring, glycerol, the main drug suspension, and the buffer solution are sequentially added to the suspension base liquid obtained in S2. The containers for loading the main drug suspension and the buffer solution are rinsed with the remaining purified water respectively, and the washing liquid is combined into the batching tank. Ultrasonic treatment is carried out at an ultrasonic frequency of 35 - 45 KHz for 10 - 15 min, the pH is detected, and total mixing and shearing are carried out to obtain the total mixing solution; the total mixing and shearing is: reciprocating shearing is carried out 4 - 6 times at a shearing frequency of 90 Hz. S6. Nitrogen - filling and canning: Under stirring, the total mixing solution is canned, and at the same time, vacuum pumping and nitrogen filling are carried out, and then capping is carried out to obtain the product.

2. The preparation method according to claim 1, wherein In S2, the ultrasonic frequency for ultrasonic mixing is 20 - 30 KHz, and the ultrasonic time is 5 - 10 min.

3. The preparation method according to claim 1, characterized in that, In S2, the pre - shearing is: reciprocating shearing is carried out 6 - 8 times at a shearing frequency of 90.0 Hz.

4. The preparation method according to claim 1, characterized in that, In S3, the ultrasonic frequency for ultrasonic dissolution is 30 - 40 KHz, and the ultrasonic time is 5 - 10 min.

5. The preparation method according to claim 1, characterized in that, In S3, the rotation speed for homogenization is 4500 - 5500 rpm, and the time is 3 - 5 min.

6. The preparation method according to claim 1, characterized in that, In S5, the pH is 4.4 - 4.

8.

7. A mometasone furoate nasal spray obtained by the preparation method according to any one of claims 1 - 6.

8. The mometasone furoate nasal spray according to claim 7, wherein By weight percentage, it is made of 0.02%-0.08% of mometasone furoate monohydrate, 1%-3% of microcrystalline cellulose - sodium carboxymethylcellulose, 1%-4% of glycerol, 0.005%-0.03% of polysorbate 80, 0.1%-0.3% of citric acid, 0.1%-0.4% of sodium citrate, 0.01%-0.03% of benzalkonium chloride and the balance of purified water.

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