Olopatadine and budesonide composition nasal spray and preparation method thereof

Abstract

The invention discloses an olopatadine and budesonide composition nasal spray and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, and the olopatadine and budesonide composition nasal spray comprises 0.03% (w / v)-0.3% (w / v) of budesonide, 0.05% (w / v)-5% (w / v) of olopatadine, 0.05% (w / v)-4% (w / v) of a suspending aid, 0.001% (w / v)-0.05% (w / v) of a metal ion chelating agent, 0.05% (w / v)-10% (w / v) of an osmotic pressure regulator, 0.01% (w / v)-1% (w / v) of an absorption promoting penetrating agent, 0.008% (w / v)-0.128% (w / v) of a surfactant the solvent is water. According to the olopatadine and budesonide composition nasal spray, the treatment effect on rhinitis is improved, meanwhile, the spray composition is also very warm in the storage period, and the liquidity and atomization performance of liquid medicine are also very good.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a nasal spray containing a combination of olopatadine and budesonide and its preparation method. Background Technology

[0002] Olopatadine is a second-generation antihistamine, belonging to the class of selective histamine H1 receptor antagonists, primarily used to relieve symptoms of allergic diseases. Its core functions include reducing discomfort such as itching, redness, swelling, sneezing, and runny nose caused by allergic rhinitis, urticaria, etc., and it also has anti-inflammatory effects. Currently, oral formulations of olopatadine (tablets, capsules, granules) and olopatadine eye drops are available on the market.

[0003] Olopatadine oral preparations are primarily used to treat allergic rhinitis, urticaria, and pruritic skin diseases (eczema, dermatitis, prurigo, pruritus, psoriasis vulgaris, and erythema multiforme). Olopatadine eye drops are primarily used to treat the signs and symptoms of allergic conjunctivitis.

[0004] When olopatadine is used to treat rhinitis, if administered orally, the dosage is relatively high (5 mg / dose), leading to a higher incidence of side effects due to the drug's systemic effects. These side effects include drowsiness (affecting driving or operating dangerous machinery), liver damage, or changes in other biochemical indicators, and there have been reports of myocardial infarction. However, when administered topically as a nasal spray, it has a local effect, requires a relatively low dosage, and avoids side effects caused by systemic effects.

[0005] Budesonide is a glucocorticoid with highly effective local anti-inflammatory properties. Its affinity for glucocorticoid receptors is approximately 15 times higher than that of prednisolone, resulting in potent anti-inflammatory effects. It can inhibit the release of inflammatory mediators and suppress cytokine-mediated immune responses. It is primarily used to treat seasonal and perennial allergic rhinitis, perennial non-allergic rhinitis, prevent the recurrence of nasal polyps after polyp removal, and provide symptomatic treatment for nasal polyps.

[0006] However, the therapeutic effects of using olopatadine alone or budesonide alone for the treatment of rhinitis are limited. Summary of the Invention

[0007] Given the current problem of poor therapeutic effects when directly using olopatadine and budesonide to treat rhinitis, the purpose of this invention is to provide a nasal spray composed of olopatadine and budesonide and its preparation method, which not only improves the therapeutic effect of rhinitis, but also ensures that the spray composition is stable during storage and has good fluidity and atomization performance.

[0008] This invention is achieved through the following technical solution:

[0009] In a first aspect, this application provides a nasal spray consisting of olopatadine and budesonide, comprising, by weight-volume percentage, 0.03% (w / v) to 0.3% (w / v) budesonide, 0.05% (w / v) to 5% (w / v) olopatadine, 0.05% (w / v) to 4% (w / v) suspending agent, 0.001% (w / v) to 0.05% (w / v) metal ion chelating agent, 0.05% (w / v) to 10% (w / v) osmotic pressure regulator, 0.01% (w / v) to 1% (w / v) absorption-enhancing penetration agent, 0.008% (w / v) to 0.128% (w / v) surfactant, and 0.002% (w / v) to 0.2% (w / v) antibacterial agent, with water as the solvent.

[0010] Olopatadine, a selective histamine H1 receptor antagonist, can block allergic reactions such as vasodilation and increased permeability caused by histamine. It also stabilizes mast cell membranes, preventing the degranulation and release of histamine and other inflammatory mediators, thereby relieving symptoms such as nasal itching, sneezing, and runny nose. Budesonide, a glucocorticoid with highly effective local anti-inflammatory effects, can inhibit the release of inflammatory mediators and suppress cytokine-mediated immune responses. Both have a synergistic effect in treating allergic rhinitis, enhancing drug efficacy. The added suspending agent increases drug viscosity and provides thixotropy, thus prolonging the drug's residence time at the administration site and enhancing efficacy. The added metal ion chelating agent inhibits drug degradation in aqueous environments, ensuring the physicochemical stability of the drug formulation during storage. The added absorption and penetration enhancer promotes drug absorption, and together with the suspending agent, enhances drug retention at the administration site. These two synergistic effects enhance overall efficacy.

[0011] In one specific embodiment, the suspending agent includes any one or more combinations of pectin, sodium carboxymethyl cellulose microcrystalline fiber, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and povidone.

[0012] In one specific embodiment, the metal ion chelating agent includes ethylenediaminetetraacetic acid compounds, including disodium edetate.

[0013] In one specific embodiment, the osmotic pressure regulator includes any one or more combinations of mannitol, glucose, glycerol, and sodium chloride. Specifically, if sodium chloride is used as the osmotic pressure regulator, its dosage is 0.05% (w / v) to 2% (w / v); if propylene glycol, glycerol, or glucose is used as the osmotic pressure regulator, its dosage is 0.5% (w / v) to 10% (w / v).

[0014] In one specific embodiment, the absorption-enhancing penetrant includes any one or more combinations of dodecyl β-D-maltodextrin, tetradecyl maltodextrin, and dodecyl phosphocholine.

[0015] In one specific embodiment, a pH adjuster is also added to adjust the pH of the spray composition to 4.0-7.0.

[0016] In one specific embodiment, the pH adjuster includes any one or more combinations of citric acid, sodium citrate, acetic acid, sodium acetate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid, and sulfuric acid.

[0017] Secondly, this application provides a method for preparing a nasal spray consisting of a combination of olopatadine and budesonide, comprising the following steps:

[0018] Preparation of suspending agent: Add purified water to the mixing tank, slowly add the suspending agent under stirring and / or high shear conditions, disperse evenly, continue to stir and disperse at 80℃~100℃ for 1~4 hours, then perform cooling treatment and cyclic shear for 5~20 minutes;

[0019] Preparation of budesonide suspension: Prepare a solution of metal ion chelating agent and surfactant, add budesonide, stir to wet, and then transfer to a dispensing tank for dispersion.

[0020] Preparation of solution-type materials: Add purified water to the mixing tank, add pH buffer salt, antibacterial agent, osmotic pressure regulator and absorption osmotic agent, stir to dissolve, continue to add olopatadine, stir to dissolve, and obtain the drug solution;

[0021] Add the drug solution and budesonide suspension to the suspending agent and stir well. Adjust the pH to 4.0-7.0 using a pH adjuster, add water to the total volume, and stir well to obtain the nasal spray.

[0022] In one specific embodiment, when preparing the suspending agent, the temperature after stirring and dispersing is reduced to no more than 40°C.

[0023] In one specific embodiment, the dispersion treatment method for preparing budesonide suspension includes ultrasonic dispersion or wetting dispersion of budesonide under high-speed shear conditions.

[0024] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0025] (1) By limiting the amount of metal ion chelating agent and combining it with a suitable pH buffer system to limit the pH value to 4.0~7.0, the present invention inhibits the degradation of the drug in an aqueous environment and ensures the physicochemical stability of the drug preparation during storage.

[0026] (2) This invention limits the amount of suspending agent and uses a specific process to thermally disperse the thickener, followed by high-speed shear homogenization or high-pressure homogenization, to give it good fluidity and easy dispersion, thus giving the liquid a good spray performance. Its characteristic lies in the droplet distribution D 50 With droplets ranging from 20 to 80 μm and less than 5% smaller than 10 μm, and a spray angle of 22° to 50°, the drug can be effectively delivered to the absorption site, reducing the risk of inhalation into the lungs. Furthermore, the selected thickener increases drug viscosity and provides thixotropy, thus prolonging the drug's residence time at the administration site and enhancing its therapeutic effect.

[0027] (3) The absorption-promoting permeation agent added in this invention can promote the absorption of the drug, and the suspending agent can help the drug stay at the administration site. The two work together to enhance the therapeutic effect.

[0028] (4) In the treatment of allergic rhinitis, the nasal spray of the present invention uses olopatadine as a selective histamine H1 receptor antagonist to block allergic reactions such as vasodilation and increased permeability caused by histamine. In addition, it can stabilize mast cell membranes and prevent them from degranulating and releasing inflammatory mediators such as histamine, thereby relieving symptoms such as nasal itching, sneezing and runny nose. Budesonide is a glucocorticoid with highly effective local anti-inflammatory effects. It can inhibit the release of inflammatory mediators and inhibit cytokine-mediated immune responses. The two can play a synergistic role in the treatment of allergic rhinitis and enhance the efficacy of the drug. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of this invention are only used to explain this invention and are not intended to limit this invention.

[0030] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that these specific details are not necessary to practice the invention. In other embodiments, well-known materials or methods have not been specifically described in order to avoid obscuring the invention.

[0031] Throughout this specification, references to "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in connection with that embodiment or example is included in at least one embodiment of the invention. Therefore, the phrases "an embodiment," "an example," "an example," or "an example" appearing in various places throughout the specification do not necessarily refer to the same embodiment or example. Furthermore, specific features, structures, or characteristics can be combined in one or more embodiments or examples in any suitable combination and / or sub-combination. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described herein, as well as the features of those different embodiments or examples.

[0032] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for a specific parameter, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this application, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0033] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the method may also include step (c), indicating that step (c) may be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0034] The sources of the active pharmaceutical ingredients in the following examples and comparative examples are as follows:

[0035] Budesonide: Hubei Gedian Renfu Pharmaceutical Co., Ltd.; Olopatadine: Xinxiang Haibin Pharmaceutical Co., Ltd.; Sodium carboxymethyl cellulose: Nutrition & Biosciences USA 1, LLC; Disodium edetate: Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.; Polysorbate 80: Hunan Ercon Pharmaceutical Co., Ltd.; Benzalkonium chloride: Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.; Dodecyl-β-D maltodextrin: Jiangsu Huafu Biomedical Co., Ltd.; Glucose: Weifang Shengtai Pharmaceutical Co., Ltd.

[0036] Example 1

[0037] This embodiment provides a method for preparing a nasal spray composed of olopatadine and budesonide, the formulation of which is as follows: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0038] The specific preparation method is as follows:

[0039] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0040] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0041] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride and 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0042] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to 500ml, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0043] Example 2

[0044] This embodiment provides a method for preparing a nasal spray containing a combination of olopatadine and budesonide. The difference from Example 1 is that the amount of budesonide added in this embodiment is 0.15g, and the amount of olopatadine added is 0.25g. Everything else is the same as in Example 1.

[0045] Its formulation consists of: 0.15g budesonide, 0.25g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0046] The specific preparation method is as follows:

[0047] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0048] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.15g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0049] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 0.25g olopatadine and stir to dissolve.

[0050] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0051] Example 3

[0052] This embodiment provides a method for preparing a nasal spray containing a combination of olopatadine and budesonide. The difference from Example 1 is that the amount of budesonide added in this embodiment is 0.015g, and the amount of olopatadine added is 0.025g. Everything else is the same as in Example 1.

[0053] Its formulation consists of: 0.015g budesonide, 0.025g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0054] The specific preparation method is as follows:

[0055] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0056] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.015g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0057] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 0.025g olopatadine and stir to dissolve.

[0058] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0059] Example 4

[0060] This embodiment provides a method for preparing a nasal spray of olopatadine and budesonide composition. The difference from Example 1 is that the amount of disodium edetate used in this embodiment is 0.005g, while the rest is the same as in Example 1.

[0061] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.005g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0062] The specific preparation method is as follows:

[0063] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0064] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.005g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0065] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0066] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0067] Example 5

[0068] This embodiment provides a method for preparing a nasal spray of olopatadine and budesonide composition. The difference from Example 1 is that the amount of disodium edetate used in this embodiment is 0.25g, while the rest is the same as in Example 1.

[0069] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.25g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0070] The specific preparation method is as follows:

[0071] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0072] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.25g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0073] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0074] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0075] Example 6

[0076] This embodiment provides a method for preparing a nasal spray consisting of olopatadine and budesonide. The difference from Example 1 is that the amount of sodium carboxymethyl cellulose (MCC) used in this embodiment is 0.25 g. Everything else is the same as in Example 1.

[0077] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 0.25g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0078] The specific preparation method is as follows:

[0079] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 0.25g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0080] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0081] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0082] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0083] Example 7

[0084] This embodiment provides a method for preparing a nasal spray consisting of olopatadine and budesonide. The difference from Example 1 is that the amount of sodium carboxymethyl cellulose (MCC) used in this embodiment is 2g. Everything else is the same as in Example 1.

[0085] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 2g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0086] The specific preparation method is as follows:

[0087] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 2g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0088] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0089] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0090] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0091] Example 8

[0092] This embodiment provides a method for preparing a nasal spray of olopatadine and budesonide composition. The difference from Example 1 is that in step S4 of this embodiment, the pH value is adjusted to 4.0. Everything else is the same as in Example 1.

[0093] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0094] The specific preparation method is as follows:

[0095] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0096] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0097] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0098] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.0 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0099] Example 9

[0100] This embodiment provides a method for preparing a nasal spray of olopatadine and budesonide composition. The difference from Example 1 is that in step S4 of this embodiment, the pH value is adjusted to 7.0. Everything else is the same as in Example 1.

[0101] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0102] The specific preparation method is as follows:

[0103] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0104] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0105] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0106] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 7.0 with 1M hydrochloric acid, add water to the total volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0107] Example 10

[0108] This embodiment provides a method for preparing a nasal spray consisting of olopatadine and budesonide. The difference from Example 1 is that the dispersion temperature in step S1 of this embodiment is 80°C. Everything else is the same as in Example 1.

[0109] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0110] The specific preparation method is as follows:

[0111] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 80℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0112] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0113] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0114] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0115] Example 11

[0116] This embodiment provides a method for preparing a nasal spray consisting of olopatadine and budesonide. The difference from Example 1 is that the dispersion temperature in step S1 of this embodiment is 100°C. Everything else is the same as in Example 1.

[0117] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0118] The specific preparation method is as follows:

[0119] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 100℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0120] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0121] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0122] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0123] Comparative Example 1

[0124] This comparative example provides a method for preparing a nasal spray of olopatadine and budesonide, which differs from Example 1 in that disodium edetate is not added. Everything else is the same as in Example 1.

[0125] The formulation consists of: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0126] The specific preparation method is as follows:

[0127] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0128] S2. Preparation of budesonide suspension: Prepare a solution of 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B, and sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0129] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0130] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0131] Comparative Example 2

[0132] This comparative example provides a method for preparing a budesonide nasal spray, which differs from Example 1 in that it does not contain olopatadine. Everything else is the same as in Example 1.

[0133] Its formulation consists of: 0.64g budesonide, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0134] The specific preparation method is as follows:

[0135] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0136] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0137] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, and 22.5g glucose and stir to dissolve.

[0138] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain budesonide nasal spray.

[0139] Comparative Example 3

[0140] This comparative example provides a method for preparing an olopatadine nasal spray, which differs from Example 1 in that it does not contain budesonide, disodium edetate, or polysorbate 80. Everything else is the same as in Example 1.

[0141] Its prescription consists of: 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0142] The specific preparation method is as follows:

[0143] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0144] S2. Preparation of solution-type materials: Add purified water to the mixing tank B, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0145] S3. Slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain olopatadine nasal spray.

[0146] Comparative Example 4

[0147] This comparative example provides a method for preparing a nasal spray of olopatadine and budesonide composition. The difference from Example 1 is that the dispersion temperature in step S1 of this example is 25°C. Everything else is the same as in Example 1.

[0148] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, 22.5g glucose, and water as the solvent.

[0149] The specific preparation method is as follows:

[0150] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue stirring and dispersing at 25℃ for 4 hours, then cool down to no more than 40℃ and circulate shear for 20 minutes.

[0151] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0152] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, 0.25g dodecyl-β-D maltodextrin, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0153] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0154] Comparative Example 5

[0155] This comparative example provides a method for preparing a nasal spray of olopatadine and budesonide, which differs from Example 1 in that it does not contain dodecyl-β-D-maltodextrin. Everything else is the same as in Example 1.

[0156] Its formulation consists of: 0.64g budesonide, 4g olopatadine, 10g sodium carboxymethyl cellulose microcrystalline cellulose, 0.05g disodium edetate, 0.16g polysorbate 80, 0.1g benzalkonium chloride, 22.5g glucose, and water as the solvent.

[0157] The specific preparation method is as follows:

[0158] S1. Preparation of suspending agent: Add purified water to the mixing tank A, and slowly add 10g of sodium carboxymethyl cellulose microcrystalline cellulose while stirring. After dispersing evenly, continue to stir and disperse at 90℃ for 4 hours, cool down to no more than 40℃, and circulate and shear for 20 minutes.

[0159] S2. Preparation of budesonide suspension: Prepare a solution by mixing 0.05g disodium edetate and 0.16g polysorbate 80, add 0.64g budesonide, stir magnetically for 10min, and after stirring and wetting, transfer to solution tank B. Sonicate for 30min to ensure uniform wetting and dispersion of budesonide.

[0160] S3. Preparation of solution-type materials: Add purified water to the mixing tank C, add 0.1g benzalkonium chloride, add 22.5g glucose and stir to dissolve, then add 4g olopatadine and stir to dissolve.

[0161] S4. Slowly pump the drug solution from mixing tank C into mixing tank A, then slowly pump the drug solution from mixing tank B into mixing tank A, stir evenly, adjust the pH of the drug solution to 4.5 with 1M hydrochloric acid, add water to the full volume, stir evenly, and obtain the nasal spray of olopatadine and budesonide combination.

[0162] The nasal sprays prepared in Examples 1-11 and Comparative Examples 1-5 were placed at 50°C for 1 month, and then their properties, pH value, and related substances were tested. The test results are shown in Table 1.

[0163] Table 1

[0164]

[0165] The results of Examples 1-3 show that the budesonide solution is relatively stable when the concentration is in the range of 0.03% to 0.3% and the olopatadine solution is in the range of 0.05% to 5%.

[0166] The comparison results of Example 1 and Comparative Examples 2 and 3 show that there is no physicochemical interaction between budesonide and olopatadine, and the two components have good compatibility.

[0167] The comparative results of Examples 1, 4, 5, and Comparative Example 1 show that a concentration of disodium edetate within the range of 0.001% to 0.05% can maintain the stability of the drug solution, while the impurity level increases significantly without the addition of disodium edetate. The results of Examples 1, 6, and 7 show that the amount of sodium carboxymethyl cellulose in microcrystalline cellulose has no significant effect on the stability of the drug solution.

[0168] The results of Examples 1, 8 and 9 show that the solution can remain stable within the pH range of 4.0 to 7.0.

[0169] The comparison results of Examples 1, 10, 11 and Comparative Example 4 show that the dispersion temperature of sodium carboxymethyl cellulose microcrystalline cellulose has no significant effect on the stability of the drug solution.

[0170] The viscosity and spray particle size of the nasal sprays prepared in Examples 1-11 and Comparative Examples 1-5 were tested, and the test results are shown in Table 2.

[0171] Table 2

[0172]

[0173] The results of Examples 1-10 show that the main factor affecting the viscosity and droplet size distribution of this product is the amount of sodium carboxymethyl cellulose microcrystalline cellulose.

[0174] The results of Examples 1, 6 and 7 show that as the amount of sodium carboxymethyl cellulose in microcrystalline cellulose increases, the viscosity increases and the droplet size also increases. When the amount of sodium carboxymethyl cellulose in microcrystalline cellulose is in the range of 0.05% to 4%, its viscosity and droplet size distribution are suitable for nasal spray administration.

[0175] The comparison results of Examples 1, 10, and 11 with Comparative Example 4 show that when the dispersion temperature is below 80 degrees Celsius, the viscosity and droplet size increase significantly, the fluidity deteriorates, and it is not suitable for nasal spray administration.

[0176] The nasal sprays prepared in Example 1 and Comparative Example 5 were subjected to pharmacokinetic tests. Beagle dogs were randomly divided into two groups of six dogs each. After administration of the drug through the nasal cavity with two sprays per nostril, samples were taken at different time points to determine the contents of budesonide and olopatadine. The pharmacokinetic parameters were calculated, and the test results are shown in Table 3.

[0177] Table 3

[0178]

[0179] As demonstrated in Example 1 and Comparative Example 5, the addition of dodecyl-β-D-maltodextrin to this product can promote the absorption of budesonide and olopatadine, shorten Tmax, and reduce AUC. 0-t The increase in bioavailability shortens the onset time of the drug, increases its bioavailability, and can achieve the goal of rapid onset of action and improved efficacy.

[0180] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be covered within the scope of the claims and specification of the present invention.

Claims

1. A nasal spray containing a combination of olopatadine and budesonide, characterized in that, Based on mass-volume percentage concentration, it includes 0.03% (w / v) to 0.3% (w / v) budesonide, 0.05% (w / v) to 5% (w / v) olopatadine, 0.05% (w / v) to 4% (w / v) suspending agent, 0.001% (w / v) to 0.05% (w / v) metal ion chelating agent, 0.05% (w / v) to 10% (w / v) osmotic pressure regulator, 0.01% (w / v) to 1% (w / v) absorption-enhancing permeabilizer, 0.008% (w / v) to 0.128% (w / v) surfactant, and 0.002% (w / v) to 0.2% (w / v) antibacterial agent, with water as the solvent.

2. The nasal spray containing olopatadine and budesonide according to claim 1, characterized in that, The suspending agent includes any one or more combinations of pectin, sodium carboxymethyl cellulose microcrystalline fiber, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and povidone.

3. A nasal spray containing a combination of olopatadine and budesonide according to claim 1, characterized in that, The metal ion chelating agent includes ethylenediaminetetraacetic acid (EDTA) compounds.

4. A nasal spray containing olopatadine and budesonide according to claim 1, characterized in that, The osmotic pressure regulator includes any one or more combinations of mannitol, glucose, glycerol, and sodium chloride.

5. A nasal spray containing a combination of olopatadine and budesonide according to claim 1, characterized in that, The absorption-enhancing penetrant includes any one or more combinations of dodecyl β-D-maltodextrin, tetradecyl maltodextrin, and dodecyl phosphocholine.

6. A nasal spray containing a combination of olopatadine and budesonide according to claim 1, characterized in that, A pH adjuster is also added to adjust the pH of the spray composition to 4.0-7.

0.

7. A nasal spray containing a combination of olopatadine and budesonide according to claim 6, characterized in that, The pH adjuster includes any one or more combinations of citric acid, sodium citrate, acetic acid, sodium acetate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid, and sulfuric acid.

8. A method for preparing a nasal spray consisting of olopatadine and budesonide, characterized in that, Includes the following steps: Preparation of suspending agent: Add purified water to the mixing tank, slowly add the suspending agent under stirring and / or high shear conditions, disperse evenly, continue to stir and disperse at 80℃~100℃ for 1~6 hours, then perform cooling treatment and cyclic shear for 5~20 minutes; Preparation of budesonide suspension: Prepare a solution of metal ion chelating agent and surfactant, add budesonide, stir to wet, and then transfer to a dispensing tank for dispersion. Preparation of solution-type materials: Add purified water to the mixing tank, add pH buffer salt, antibacterial agent, osmotic pressure regulator and absorption osmotic agent, stir to dissolve, continue to add olopatadine, stir to dissolve, and obtain the drug solution; Add the drug solution and budesonide suspension to the suspending agent and stir well. Adjust the pH to 4.0-7.0 using a pH adjuster, add water to the total volume, and stir well to obtain the nasal spray.

9. A method for preparing a nasal spray of olopatadine and budesonide composition according to claim 8, characterized in that, When preparing suspending agents, the temperature after stirring and dispersing should be reduced to no more than 40°C.

10. A method for preparing a nasal spray of olopatadine and budesonide composition according to claim 8, characterized in that, Dispersion methods for preparing budesonide suspensions include ultrasonic dispersion or wetting dispersion of budesonide under high-speed shear conditions.

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