Olopatadine and brimonidine-containing compound preparation composition for nasal cavity and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and discloses a compound preparation composition containing olopatadine and brimonidine for a nasal cavity and a preparation method of the compound preparation composition. The compound preparation composition for the nasal cavity is prepared from the following components in percentage by weight: 0.01 to 0.5 percent of olopatadine and 0.01 to 0.5 percent of brimonidine. According to the compound preparation composition, olopatadine and brimonidine are combined for use, the curative effect is remarkably improved compared with single-drug treatment, a good synergistic interaction effect is shown, multiple pharmacological effects are achieved through one-time drug administration, and drug use convenience and long-term treatment compliance are greatly improved.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparations, and more specifically, it relates to a compound preparation composition containing olopatadine and brimonidine for nasal cavity and its preparation method. Background Art

[0002] Nasal allergic diseases such as allergic rhinitis are IgE-mediated nasal mucosal inflammatory reactions. Typical symptoms include nasal itching, sneezing, nasal congestion, and rhinorrhea. Its pathological mechanism involves a large release of histamine, vasodilation, and a cascade reaction of inflammatory factors (such as TNF-α, IL-6). Currently, the first-line clinical treatment drugs are mainly second-generation antihistamines (such as olopatadine), which effectively inhibit histamine activity by antagonizing the H1 receptor, but cannot specifically relieve the congestion and edema caused by nasal mucosal vasodilation; while α2 receptor agonists (such as brimonidine) can constrict blood vessels and inhibit some inflammatory mediators, but have no direct intervention on the core pathway of allergic reactions.

[0003] When the two types of drugs are used alone, there are limitations in efficacy. Patients often need to use multiple preparations in combination, resulting in an increased dosing frequency, an increased risk of local irritation, poor compliance, and the lack of full utilization of the drug synergistic effect. Currently, most nasal compound preparations focus on the combination of antihistamines and glucocorticoids, and there is no relevant report on simultaneously targeting multiple links of allergic reactions through the synergistic mechanism of olopatadine and brimonidine.

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

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

[0006] To achieve the above invention object, this application adopts the following technical solutions:

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

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

[0009] Further, the compound preparation composition further includes an isotonicity regulator, a pH buffer, a thickening agent, and a preservative.

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

[0011] Olopatadine 0.01 - 0.5%;

[0012] Brimonidine 0.01 - 0.5%;

[0013] Isotonic regulator 0.6 - 1.0%;

[0014] Thickening agent 0.1 - 0.3%;

[0015] Preservative 0.01 - 0.03%;

[0016] pH buffer adjusts the pH to 6.5, and purified water is added to make up the volume.

[0017] Further, the isotonic regulator is sodium chloride; the pH buffer is phosphate or borate; the thickening agent is hydroxypropyl methylcellulose; the preservative is benzalkonium chloride.

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

[0019] Olopatadine 0.05%;

[0020] Brimonidine 0.03%;

[0021] Sodium chloride 0.9%;

[0022] Hydroxypropyl methylcellulose 0.2%;

[0023] Benzalkonium chloride 0.01%;

[0024] Citric acid buffer adjusts the pH to 6.5, and purified water is added to make up the volume.

[0025] In the second aspect, the present invention provides a preparation method of the compound preparation composition described in the first aspect, comprising the following steps: dissolving olopatadine and brimonidine in citric acid buffer, adding a preservative, an isotonic regulator and a thickening agent, homogenizing and then adjusting the pH to 6.5 to obtain the compound preparation composition.

[0026] In the third aspect, the present invention provides a nasal spray comprising the compound preparation composition described in the first aspect.

[0027] In the fourth aspect, the present invention provides a preparation method of the nasal spray described in the third aspect, comprising the following steps:

[0028] Step 1, dissolving olopatadine and brimonidine in citric acid buffer, adding a preservative, an isotonic regulator and a thickening agent, homogenizing and then adjusting the pH to 6.5 to obtain the compound preparation composition, and then adding injection water or purified water to the prescription amount;

[0029] Step 2: Fill into a metered-dose spray device.

[0030] In a fifth aspect, the present invention provides a method for using the nasal spray described in the third aspect, wherein 50 μL of the drug is administered to each nasal cavity of the patient twice a day.

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

[0032] 1. Olopatadine can efficiently inhibit histamine release and relieve typical allergic symptoms such as nasal itching and sneezing; Brimonidine can rapidly reduce congestion, edema by constricting nasal mucosa 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 "anti-histamine + anti-congestion + anti-inflammatory", significantly improving the therapeutic effect compared with single-drug treatment, showing a good synergistic effect.

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

[0034] 3. Monotherapy with Brimonidine may cause mucosal dryness or rebound congestion due to excessive blood vessel constriction, while Olopatadine can reduce its dosage (for example, a good therapeutic effect can also be achieved when the concentration of Brimonidine is reduced to 0.05%); The compound preparation optimizes the ratio to avoid local irritation of high-concentration Brimonidine and improves safety. Detailed implementation manners

[0035] The technical solutions and effects of the present application will be further described in detail below in conjunction with examples. It can be understood that the specific examples described herein are only used to explain the present invention, rather than limiting the present invention.

[0036] Example 1

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

[0038] Olopatadine 0.05 g;

[0039] Brimonidine 0.03 g;

[0040] Sodium chloride 0.9 g;

[0041] Hydroxypropyl methylcellulose 0.2 g;

[0042] Benzalkonium chloride 0.01 g;

[0043] Adjust the pH to 6.5 with citrate buffer solution, and add purified water to the prescription amount.

[0044] Preparation method:

[0045] Olopatadine and brimonidine are dissolved in a citric acid buffer solution, benzalkonium chloride, sodium chloride, and hypromellose are added, and after homogenization, the citric acid buffer solution is added to adjust the pH to 6.5 to obtain a compound preparation composition, and then water for injection or purified water is added to the prescription amount.

[0046] Example 2

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

[0048] Olopatadine 0.03 g;

[0049] Brimonidine 0.01 g;

[0050] Sodium chloride 0.7 g;

[0051] Hypromellose 0.2 g;

[0052] Benzalkonium chloride 0.01 g;

[0053] Adjust the pH to 6.5 with a citric acid buffer solution, and add purified water to the prescription amount.

[0054] Preparation method:

[0055] Olopatadine and brimonidine are dissolved in a citric acid buffer solution, benzalkonium chloride, sodium chloride, and hypromellose are added, and after homogenization, the citric acid buffer solution is added to adjust the pH to 6.5 to obtain a compound preparation composition, and then water for injection or purified water is added to the prescription amount.

[0056] Example 3

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

[0058] Olopatadine 0.1 g;

[0059] Brimonidine 0.05 g;

[0060] Sodium chloride 1 g;

[0061] Hypromellose 0.2 g;

[0062] Benzalkonium chloride 0.01 g;

[0063] Adjust the pH to 6.5 with a citric acid buffer solution, and add purified water to the prescription amount.

[0064] Preparation method:

[0065] Olopatadine and brimonidine are dissolved in citric acid buffer solution, benzalkonium chloride, sodium chloride and hypromellose are added, and after homogenization, citric acid buffer solution is added to adjust the pH to 6.5 to obtain a compound preparation composition, and then water for injection or purified water is added to the prescribed amount.

[0066] Comparative Example 1

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

[0068] Olopatadine 0.5 g;

[0069] Sodium chloride 0.9 g;

[0070] Hypromellose 0.2 g;

[0071] Benzalkonium chloride 0.01 g;

[0072] Adjust the pH to 6.5 with citric acid buffer solution, and add purified water to the prescribed amount.

[0073] Preparation method:

[0074] Dissolve olopatadine in citric acid buffer solution, add benzalkonium chloride, sodium chloride and hypromellose, after homogenization, add citric acid buffer solution to adjust the pH to 6.5 to obtain a compound preparation composition, and then add water for injection or purified water to the prescribed amount.

[0075] Comparative Example 2

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

[0077] Olopatadine 0.05 g;

[0078] Sodium chloride 0.9 g;

[0079] Hypromellose 0.2 g;

[0080] Benzalkonium chloride 0.01 g;

[0081] Adjust the pH to 6.5 with citric acid buffer solution, and add purified water to the prescribed amount.

[0082] Preparation method:

[0083] Dissolve olopatadine in citric acid buffer solution, add benzalkonium chloride, sodium chloride and hypromellose, after homogenization, add citric acid buffer solution to adjust the pH to 6.5 to obtain a compound preparation composition, and then add water for injection or purified water to the prescribed amount.

[0084] Comparative Example 3

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

[0086] Brimonidine 0.03 g;

[0087] Sodium chloride 0.9 g;

[0088] Hypromellose 0.2 g;

[0089] Benzalkonium chloride 0.01 g;

[0090] Adjust the pH to 6.5 with citric acid buffer solution, and add purified water to the prescribed amount.

[0091] Preparation method:

[0092] Dissolve brimonidine in citric acid buffer solution, add benzalkonium chloride, sodium chloride and hypromellose, homogenize, then adjust the pH to 6.5 with citric acid buffer solution to obtain the compound preparation composition, and then add injection water or purified water to the prescribed amount.

[0093] Comparative Example 4

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

[0095] Brimonidine 0.5 g;

[0096] Sodium chloride 0.9 g;

[0097] Hypromellose 0.2 g;

[0098] Benzalkonium chloride 0.01 g;

[0099] Adjust the pH to 6.5 with citric acid buffer solution, and add purified water to the prescribed amount.

[0100] Preparation method:

[0101] Dissolve brimonidine in citric acid buffer solution, add benzalkonium chloride, sodium chloride and hypromellose, homogenize, then adjust the pH to 6.5 with citric acid buffer solution to obtain the compound preparation composition, and then add injection water or purified water to the prescribed amount.

[0102] Performance detection

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

[0104] Index Initial value After 6 months Brimonidine content 0.03g(100％) 0.0285g(95％) Olopatadine content 0.05g(100％) 0.048g(96％) Appearance Colorless clear solution Colorless clear solution Microbial limit Complies with pharmacopoeia standards Complies with pharmacopoeia standards

[0105] Detection 2: Efficacy test (rhinitis)

[0106] (1) Model construction

[0107] SPF-grade SD rats, male, weighing 180-220 g, were adaptively fed for 1 week to exclude basic nasal diseases. On days 1-7, an OVA suspension (100 μg OVA + 20 mg Al(OH)3 adjuvant, dissolved in 1 mL of normal saline) was intraperitoneally injected once every other day for a total of 3 times; on days 8-14, a 5% OVA solution (20 μL / side) was instilled into both nasal cavities once a day, and the control group was instilled with an equal amount of normal saline. If the number of sneezes was ≥20 times / rat within 30 min after challenge, the level of OVA-specific IgE was increased by more than 5 times compared with the blank group, and eosinophil infiltration in the nasal mucosa (≥30 cells / HP), the model was successfully constructed.

[0108] (2) Experimental grouping and treatment

[0109] Group Treatment Blank control group Healthy mice, nasal spray with normal saline Model group Rhinitis rat model, nasal spray with normal saline Positive control group Rhinitis rat model, nasal spray with 0.1% mometasone furoate Experimental group 1 Rhinitis rat model, nasal spray with the compound preparation composition of Example 1 Experimental group 2 Rhinitis rat model, nasal spray with the compound preparation composition of Example 2 Experimental group 3 Rhinitis rat model, nasal spray with the compound preparation composition of Example 3 Control group 1 Rhinitis rat model, nasal spray with the preparation of Comparative Example 1 Control group 2 Rhinitis rat model, nasal spray with the preparation of Comparative Example 2 Control group 3 Rhinitis rat model, nasal spray with the preparation of Comparative Example 3 Control group 4 Rhinitis rat model, nasal spray with the preparation of Comparative Example 4

[0110] (3) Drug administration regimen

[0111] Administer 50 μL of the drug to each nasal cavity once a day for 7 days.

[0112] (4) Behavioral experiments

[0113] Experimental method:

[0114] ① Number of sneezes: Counted within 30 min after OVA challenge;

[0115] ② Number of nose scratches: The number of times the front paw scratched the nose was recorded by video within 1 h;

[0116] Experimental results:

[0117]

[0118]

[0119] From the above data, it can be seen that the inhibition rates of sneezing and nose scratching in experimental groups 1-3 were significantly higher than those in single-drug control groups 1-4 (p < 0.01). Olopatadine at high concentration alone (control groups 1-2) had limited improvement in nose scratching; brompheniramine alone (control groups 3-4) could not effectively control sneezing. It can be seen that the combination of olopatadine and brompheniramine showed a good synergistic effect.

[0120] (5) Detection of inflammatory factor levels

[0121] Experimental method:

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

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

[0124] Test results:

[0125]

[0126]

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

[0128] From the above data, it can be seen that the histamine inhibition rates of experimental groups 1 and 3 are significantly better than those of the single-drug group, confirming that olopatadine directly inhibits mast cell degranulation by blocking the H1 receptor. Brimonidine alone (control group 3) can inhibit TNF-α / IL-6, but cannot reduce histamine; experimental groups 1 and 3 through the synergistic effect of olopatadine and brimonidine, make the levels of TNF-α and IL-6 close to those of the hormone-positive control group (p > 0.05).

[0129] Thus, in the pharmaceutical composition of the present invention, the combination of olopatadine and brimonidine forms a triple synergistic mechanism of "antihistamine + decongestant + anti-inflammatory", significantly improving the efficacy compared with single-drug treatment, showing a good synergistic effect. Moreover, the compound pharmaceutical composition of the present invention achieves multiple pharmacological effects with a single administration, and the symptoms can be controlled with 1-2 administrations per day, greatly improving the medication convenience and long-term treatment compliance. In addition, brimonidine alone may cause mucosal dryness or rebound congestion due to excessive vasoconstriction, while olopatadine can reduce its dosage (for example, a good therapeutic effect can also be achieved when the brimonidine concentration is reduced to 0.05%), reducing side effects while maintaining the efficacy; the compound preparation improves safety by optimizing the ratio and avoiding local irritation of high-concentration brimonidine.

[0130] This specific embodiment is only an interpretation of the present application, and it does not limit the present application. Those skilled in the art can make modifications without creative contributions to this embodiment after reading this specification, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A compound preparation composition for the nasal cavity, characterized in that, The compound preparation composition, calculated by weight percentage, comprises olopatadine 0.01 - 0.5% and brimonidine 0.01 - 0.5%.

2. The compound preparation composition according to claim 1, wherein The compound preparation composition, calculated by weight percentage, comprises olopatadine 0.03 - 0.1% and brimonidine 0.01 - 0.05%.

3. The compound preparation composition according to claim 1, characterized in that The compound preparation composition further comprises an isotonicity regulator, a pH buffer, a thickening agent and a preservative.

4. The compound preparation composition according to claim 3, wherein The compound preparation composition, calculated by weight percentage, comprises: olopatadine 0.01 - 0.5%; brimonidine 0.01 - 0.5%; isotonicity regulator 0.6 - 1.0%; thickening agent 0.1 - 0.3%; preservative 0.01 - 0.03%; pH buffer adjusts the pH to 6.5, and purified water is added to make up the volume.

5. The compound preparation composition according to claim 4, wherein The isotonicity regulator is sodium chloride; the pH buffer is phosphate or borate; the thickening agent is hypromellose; the preservative is benzalkonium chloride.

6. The compound preparation composition according to claim 5, wherein The compound preparation composition, calculated by weight percentage, comprises: olopatadine 0.05%; brimonidine 0.03%; sodium chloride 0.9%; hypromellose 0.2%; benzalkonium chloride 0.01%; citric acid buffer adjusts the pH to 6.5, and purified water is added to make up the volume.

7. A method for preparing the compound preparation composition according to claims 1-6, characterized in that, Comprises the following steps: Dissolve olopatadine and brimonidine in citric acid buffer, add the preservative, isotonicity regulator and thickening agent, homogenize and then adjust the pH to 6.5 to obtain the compound preparation composition.

8. A nasal spray, characterized in that, Comprises the compound preparation composition described in claims 1 - 6.

9. The preparation method of the nasal spray according to claim 8, characterized in that, Comprises the following steps: Step 1, dissolve olopatadine and brimonidine in citric acid buffer, add the preservative, isotonicity regulator and thickening agent, homogenize and then adjust the pH to 6.5 to obtain the compound preparation composition, and then add injection water or purified water to the prescribed amount; Step 2, fill into a metered spray device.

10. The method of using the nasal spray according to claim 8, characterized in that, The patient administers 50 μL to each nasal cavity, twice a day.

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