A compound preparation composition containing olopatadine and brimonidine for use in the nasal cavity and its preparation method.

Abstract

This application relates to the field of pharmaceutical preparations, and discloses a compound preparation composition containing olopatadine and brimonidine for nasal use, and its preparation method. The compound preparation composition for nasal use comprises 0.01-0.5% olopatadine and 0.01-0.5% brimonidine by weight percentage. The compound preparation composition of this invention, with olopatadine and brimonidine used in combination, significantly improves efficacy compared to monotherapy, showing a good synergistic effect, and achieves multiple pharmacological effects with a single dose, greatly improving the convenience of medication and long-term treatment compliance.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparations, and more specifically, to a compound preparation composition containing olopatadine and brimonidine for use in the nasal cavity and a method for preparing the same. Background Technology

[0002] Allergic rhinitis and other nasal allergic diseases are IgE-mediated inflammatory reactions of the nasal mucosa. Typical symptoms include nasal itching, sneezing, nasal congestion, and runny nose. The pathological mechanism involves a cascade reaction of massive histamine release, vasodilation, and inflammatory factors (such as TNF-α and IL-6). Currently, first-line clinical treatment mainly uses second-generation antihistamines (such as olopatadine), which effectively inhibit histamine activity by antagonizing H1 receptors, but cannot specifically relieve congestion and edema caused by nasal mucosal vasodilation. While α2 receptor agonists (such as brimonidine) can constrict blood vessels and inhibit some inflammatory mediators, they do not directly intervene in the core pathways of allergic reactions.

[0003] Both types of drugs have limited efficacy when used alone, often requiring patients to use multiple formulations in combination. This leads to increased dosing frequency, a higher risk of local irritation, poor adherence, and underutilization of the drug synergistic effect. Currently, nasal combination formulations mostly focus on combinations of antihistamines and glucocorticoids, and there are no reports on simultaneously targeting multiple aspects of the allergic reaction through the synergistic mechanism of olopatadine and brimonidine.

[0004] Therefore, developing a compound nasal preparation that integrates the advantages of two drugs to achieve multiple pharmacological effects through a single administration has significant clinical demand and market value. Summary of the Invention

[0005] The purpose of this invention is to explore the synergistic effect of olopatadine and brimonidine, and to develop a compound nasal preparation that integrates the advantages of the two drugs to achieve multiple pharmacological effects through a single administration.

[0006] To achieve the above-mentioned objectives, this application adopts the following technical solution:

[0007] In a first aspect, the present invention provides a compound preparation composition, wherein the compound preparation composition comprises, by weight percentage, 0.01-0.5% olopatadine and 0.01-0.5% brimonidine.

[0008] Furthermore, the compound preparation composition, by weight percentage, includes 0.03-0.1% olopatadine and 0.01-0.05% brimonidine.

[0009] Furthermore, the compound formulation composition also includes an isotonic regulator, a pH buffer, a thickener, and a preservative.

[0010] Further, the compound formulation composition, by weight percentage, comprises:

[0011] Olopatadine 0.01–0.5%;

[0012] Brimonidine 0.01–0.5%;

[0013] Isotonic conditioner 0.6–1.0%;

[0014] Thickener 0.1-0.3%;

[0015] Preservative 0.01-0.03%;

[0016] Adjust the pH to 6.5 with a pH buffer and then replenish with purified water.

[0017] Furthermore, the isotonic regulator is sodium chloride; the pH buffer is phosphate or borate; the thickener is hydroxypropyl methylcellulose; and the preservative is benzalkonium chloride.

[0018] Further, the compound formulation composition, by weight percentage, comprises:

[0019] Oletastatin 0.05%;

[0020] Brimonidine 0.03%;

[0021] Sodium chloride 0.9%;

[0022] Hydroxypropyl methylcellulose 0.2%;

[0023] Benzalkonium chloride 0.01%;

[0024] Adjust the pH to 6.5 with citrate buffer and add purified water to make up the difference.

[0025] In a second aspect, the present invention provides a method for preparing the compound preparation composition described in the first aspect, comprising the following steps: dissolving olopatadine and brimonidine in citrate buffer, adding preservatives, isotonic adjusters and thickeners, homogenizing and adjusting the pH to 6.5 to obtain the compound preparation composition.

[0026] Thirdly, the present invention provides a nasal spray comprising the compound formulation composition described in the first aspect.

[0027] Fourthly, the present invention provides a method for preparing the nasal spray described in the third aspect, comprising the following steps:

[0028] Step 1: Dissolve olopatadine and brimonidine in citrate buffer, add preservatives, isotonicity adjusters and thickeners, homogenize and adjust pH to 6.5 to obtain the compound preparation composition, and then add water for injection or purified water to the prescribed amount.

[0029] Step 2: Fill the metering spray device.

[0030] Fifthly, the present invention provides a method of using the nasal spray described in the third aspect, wherein 50 μL is administered to each nasal cavity twice daily.

[0031] In summary, compared with the prior art, this application has the following beneficial effects:

[0032] 1. Olopatadine can effectively inhibit histamine release and relieve typical allergy symptoms such as nasal itching and sneezing; brimonidine can rapidly reduce congestion and edema by constricting nasal mucosal blood vessels and inhibit pro-inflammatory factors such as TNF-α and IL-6; the combination of the two forms a triple synergistic mechanism of "antihistamine + anticongestion + anti-inflammation", which significantly improves the efficacy compared with monotherapy and shows a good synergistic effect.

[0033] 2. The compound preparation composition of the present invention can achieve multiple pharmacological effects with a single administration, and can control symptoms with 1-2 administrations per day, greatly improving the convenience of medication and long-term treatment compliance.

[0034] 3. Brimonidine alone may cause mucosal dryness or rebound congestion due to excessive vasoconstriction, while olopatadine can reduce its dosage (e.g., brimonidine concentration can be reduced to 0.05% to achieve good efficacy), reducing side effects while maintaining efficacy; compound preparations, through optimized formulation, avoid local irritation from high concentrations of brimonidine and improve safety. Detailed Implementation

[0035] The technical solutions and effects of this application will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely for explaining the invention and are not intended to limit the invention.

[0036] Example 1

[0037] This embodiment discloses a compound preparation composition, and the raw materials used in its preparation are as follows (prescription 100g):

[0038] Olopatadine 0.05g;

[0039] Brimonidine 0.03g;

[0040] Sodium chloride 0.9g;

[0041] Hydroxypropyl methylcellulose 0.2g;

[0042] Benzalkonium chloride 0.01g;

[0043] Adjust the pH to 6.5 with citrate buffer and bring purified water to the prescribed volume.

[0044] Preparation method:

[0045] Olopatadine and brimonidine were dissolved in citrate buffer, and benzalkonium chloride, sodium chloride and hydroxypropyl methylcellulose were added. After homogenization, citrate buffer was added to adjust the pH to 6.5 to obtain the compound preparation composition. Then, water for injection or purified water was added to the prescribed amount.

[0046] Example 2

[0047] This embodiment discloses a compound preparation composition, and the raw materials used in its preparation are as follows (prescription 100g):

[0048] Olopatadine 0.03g;

[0049] Brimonidine 0.01g;

[0050] Sodium chloride 0.7g;

[0051] Hydroxypropyl methylcellulose 0.2g;

[0052] Benzalkonium chloride 0.01g;

[0053] Adjust the pH to 6.5 with citrate buffer and bring purified water to the prescribed volume.

[0054] Preparation method:

[0055] Olopatadine and brimonidine were dissolved in citrate buffer, and benzalkonium chloride, sodium chloride and hydroxypropyl methylcellulose were added. After homogenization, citrate buffer was added to adjust the pH to 6.5 to obtain the compound preparation composition. Then, water for injection or purified water was added to the prescribed amount.

[0056] Example 3

[0057] This embodiment discloses a compound preparation composition, and the raw materials used in its preparation are as follows (prescription 100g):

[0058] Olopatadine 0.1g;

[0059] Brimonidine 0.05g;

[0060] 1g of sodium chloride;

[0061] Hydroxypropyl methylcellulose 0.2g;

[0062] Benzalkonium chloride 0.01g;

[0063] Adjust the pH to 6.5 with citrate buffer and bring purified water to the prescribed volume.

[0064] Preparation method:

[0065] Olopatadine and brimonidine were dissolved in citrate buffer, and benzalkonium chloride, sodium chloride and hydroxypropyl methylcellulose were added. After homogenization, citrate buffer was added to adjust the pH to 6.5 to obtain the compound preparation composition. Then, water for injection or purified water was added to the prescribed amount.

[0066] Comparative Example 1

[0067] This embodiment discloses a formulation, the raw materials used in its preparation are as follows (prescription 100g):

[0068] Olopatadine 0.5g;

[0069] Sodium chloride 0.9g;

[0070] Hydroxypropyl methylcellulose 0.2g;

[0071] Benzalkonium chloride 0.01g;

[0072] Adjust the pH to 6.5 with citrate buffer and bring purified water to the prescribed volume.

[0073] Preparation method:

[0074] Olopatadine was dissolved in citrate buffer, and benzalkonium chloride, sodium chloride and hydroxypropyl methylcellulose were added. After homogenization, citrate buffer was added to adjust the pH to 6.5 to obtain the compound preparation composition. Then, water for injection or purified water was added to the prescribed amount.

[0075] Comparative Example 2

[0076] This embodiment discloses a formulation, the raw materials used in its preparation are as follows (prescription 100g):

[0077] Olopatadine 0.05g;

[0078] Sodium chloride 0.9g;

[0079] Hydroxypropyl methylcellulose 0.2g;

[0080] Benzalkonium chloride 0.01g;

[0081] Adjust the pH to 6.5 with citrate buffer and bring purified water to the prescribed volume.

[0082] Preparation method:

[0083] Olopatadine was dissolved in citrate buffer, and benzalkonium chloride, sodium chloride and hydroxypropyl methylcellulose were added. After homogenization, citrate buffer was added to adjust the pH to 6.5 to obtain the compound preparation composition. Then, water for injection or purified water was added to the prescribed amount.

[0084] Comparative Example 3

[0085] This embodiment discloses a compound preparation composition, and the raw materials used in its preparation are as follows (prescription 100g):

[0086] Brimonidine 0.03g;

[0087] Sodium chloride 0.9g;

[0088] Hydroxypropyl methylcellulose 0.2g;

[0089] Benzalkonium chloride 0.01g;

[0090] Adjust the pH to 6.5 with citrate buffer and bring purified water to the prescribed volume.

[0091] Preparation method:

[0092] Brimonidine was dissolved in citrate buffer, and benzalkonium chloride, sodium chloride and hydroxypropyl methylcellulose were added. After homogenization, citrate buffer was added to adjust the pH to 6.5 to obtain the compound preparation composition. Then, water for injection or purified water was added to the prescribed amount.

[0093] Comparative Example 4

[0094] This embodiment discloses a compound preparation composition, and the raw materials used in its preparation are as follows (prescription 100g):

[0095] Brimonidine 0.5g;

[0096] Sodium chloride 0.9g;

[0097] Hydroxypropyl methylcellulose 0.2g;

[0098] Benzalkonium chloride 0.01g;

[0099] Adjust the pH to 6.5 with citrate buffer and bring purified water to the prescribed volume.

[0100] Preparation method:

[0101] Brimonidine was dissolved in citrate buffer, and benzalkonium chloride, sodium chloride and hydroxypropyl methylcellulose were added. After homogenization, citrate buffer was added to adjust the pH to 6.5 to obtain the compound preparation composition. Then, water for injection or purified water was added to the prescribed amount.

[0102] Performance testing

[0103] Test 1: Stability test (40℃ / 75%RH, 6 months, taking Example 1 as an example):

[0104] index initial value 6 months later Brimonidine content 0.03g(100％) 0.0285g(95％) Olopatadine content 0.05g(100％) 0.048g(96％) Appearance colorless clear solution colorless clear solution Microbial limits Meets pharmacopoeia standards Meets pharmacopoeia standards

[0105] Test 2: Treatment efficacy trial (rhinitis)

[0106] (1) Model building

[0107] SPF-grade male SD rats, weighing 180-220g, were selected and acclimatized for one week, excluding those with underlying nasal diseases. From days 1 to 7, OVA suspension (100μg OVA + 20mg Al(OH)3 adjuvant dissolved in 1mL physiological saline) was injected intraperitoneally every other day for a total of 3 times. From days 8 to 14, 5% OVA solution (20μL / nasal cavity) was instilled bilaterally once daily, while the control group received an equal volume of physiological saline. Successful model establishment was indicated by ≥20 sneezes per rat within 30 minutes of challenge, an OVA-specific IgE level more than 5-fold higher than the control group, and eosinophil infiltration of the nasal mucosa (≥30 cells / HP).

[0108] (2) Experimental grouping and treatment

[0109] Group deal with Blank control group Healthy mice, nasal spray with physiological saline Model group Rhinitis rat model, saline nasal spray Positive control group Rhinitis rat model, 0.1% mometasone furoate nasal spray Experimental group 1 Rhinitis rat model, Example 1: Compound preparation nasal spray Experimental group 2 Rhinitis rat model, Example 2: Compound preparation nasal spray Experimental group 3 Rhinitis rat model, Example 3: Compound preparation nasal spray Control group 1 Rhinitis rat model, Comparative Example 1: Nasal spray formulation Control group 2 Rhinitis rat model, comparative example 2 formulation nasal spray Control group 3 Rhinitis rat model, comparative example 3 formulation nasal spray Control group 4 Rhinitis rat model, comparative example 4 formulation nasal spray

[0110] (3) Dosing regimen

[0111] Administer 50 μL into each nostril once daily for 7 days.

[0112] (4) Behavioral experiments

[0113] Test method:

[0114] ① Number of sneezes: Counted within 30 minutes after OVA stimulation;

[0115] ②Number of nose scratches: Video recording of the number of times the front paws scratched the nose within 1 hour;

[0116] Experimental results:

[0117]

[0118]

[0119] The data above show that the sneezing and nasal scratching suppression rates in experimental groups 1-3 were significantly higher than those in the single-drug control groups 1-4 (p<0.01). High-concentration olopatadine monotherapy (control groups 1-2) had limited effect on improving nasal scratching; brimonidine monotherapy (control groups 3-4) was ineffective in controlling sneezing. Therefore, the combined use of olopatadine and brimonidine shows a good synergistic effect.

[0120] (5) Detection of inflammatory factor levels

[0121] Test method:

[0122] ①Histamine: The nasal lavage fluid of experimental mice was detected by LC-MS / MS;

[0123] ②TNF-α / IL-6: The nasal mucosa homogenate of experimental mice was detected using an ELISA kit;

[0124] Experimental results:

[0125]

[0126]

[0127] Note: Data are mean ± SD, *p<0.05, **p<0.01 (vs. model group).

[0128] The data above show that the histamine inhibition rate in experimental groups 1 and 3 was significantly better than that in the single-drug group, confirming that olopatadine directly inhibits mast cell degranulation by blocking H1 receptors. Brimonidine monotherapy (control group 3) can inhibit TNF-α / IL-6, but cannot reduce histamine levels; experimental groups 1 and 3, through the synergistic effect of olopatadine and brimonidine, achieved TNF-α and IL-6 levels close to those of the hormone-positive control group (p>0.05).

[0129] Therefore, the formulation composition of this invention, in which olopatadine and brimonidine are used in combination, forms a triple synergistic mechanism of "antihistamine + anticongestion + anti-inflammation," significantly improving efficacy compared to monotherapy and demonstrating a good synergistic effect. Furthermore, the compound formulation composition of this invention achieves multiple pharmacological effects with a single dose, and symptom control is achieved with 1-2 doses daily, greatly improving the convenience of medication and long-term treatment adherence. In addition, brimonidine monotherapy may cause mucosal dryness or rebound congestion due to excessive vasoconstriction, while olopatadine can reduce its dosage (e.g., brimonidine concentration reduced to 0.05% can still achieve good efficacy), maintaining efficacy while reducing side effects; the compound formulation, through optimized ratio, avoids local irritation from high concentrations of brimonidine, improving safety.

[0130] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A composition for nasal cavity, characterized by comprising, The compound preparation composition comprises, by weight percentage: Olopatadine 0.03~0.1%; Brimonidine 0.01~0.05%; Isotonicity regulator 0.6~1.0%; Thickening agent 0.1~0.3%; Preservative 0.01~0.03%; pH buffer to adjust pH to 6.5, purified water to supplement; The isotonicity regulator is sodium chloride; the pH buffer is phosphate or borate; the thickening agent is hypromellose; the preservative is benzalkonium chloride.

2. The complex preparation composition according to claim 1, characterized by, The compound preparation composition comprises, by weight percentage: Olopatadine 0.05%; Brimonidine 0.03%; Sodium chloride 0.9%; Hypromellose 0.2%; Benzalkonium chloride 0.01%; Citric acid buffer to adjust pH to 6.5, purified water to supplement.

3. The method of producing the complex preparation composition according to claims 1-2, characterized in that, The method comprises the following steps: Dissolving olopatadine and brimonidine in citric acid buffer, adding preservative, isotonicity regulator and thickening agent, homogenizing, adjusting pH to 6.5, to obtain the compound preparation composition.

4. A nasal spray characterized in that, The compound preparation composition of claims 1-2.

5. The method of preparing a nasal spray of claim 4, characterized in that, The method comprises the following steps: Step 1, dissolving olopatadine and brimonidine in citric acid buffer, adding preservative, isotonicity regulator and thickening agent, homogenizing, adjusting pH to 6.5, to obtain the compound preparation composition, then adding water for injection or purified water to the prescription amount; Step 2, filling to the quantitative spray device.

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