Olopatadine and brimonidine-containing compound preparation composition for eyes and preparation method thereof

Abstract

The invention relates to the field of medical preparations, and discloses a compound preparation composition containing olopatadine and brimonidine for eyes and a preparation method of the compound preparation composition. The compound preparation composition comprises the following components in percentage by weight: 0.01 to 1.5 percent of olopatadine and 0.01 to 0.8 percent of brimonidine. The compound preparation composition can be used for treating allergic conjunctivitis, glaucoma and ocular surface inflammation at the same time, is especially suitable for patients with coexistence of multiple diseases, and achieves multiple pharmacological effects through one-time administration. Through compound compatibility, the single dosage is reduced, and irritation or systemic side effects are reduced.

Description

Technical Field

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

[0002] Eye diseases (such as dry eye, conjunctivitis, glaucoma, cataracts, etc.) are common health problems that seriously affect patients' quality of life. At present, most commonly used eye treatments are eye drops or ophthalmic preparations with a single active ingredient. However, a single ingredient is often insufficient to fully address the complex pathological mechanisms of the eye, such as conditions involving multiple factors such as inflammation, oxidative stress, and corneal damage.

[0003] While existing compound ophthalmic preparations combine multiple ingredients, they still have drawbacks. For example, physical or chemical interactions may occur between different active ingredients, leading to poor formulation stability, such as precipitation, degradation, or reduced potency, affecting efficacy and safety; the cornea and blood-eye barrier limit ocular absorption of drugs, especially water-soluble or large molecule drugs, making it difficult to achieve effective therapeutic concentrations; traditional eye drops have a short retention time, requiring frequent administration, resulting in poor patient compliance.

[0004] Therefore, there is an urgent need to develop a novel ocular compound formulation that optimizes the compatibility of active ingredients to achieve synergistic drug delivery, thereby overcoming the shortcomings of existing technologies and realizing efficient, safe, and stable ocular drug delivery. Summary of the Invention

[0005] The purpose of this invention is to develop a compound ophthalmic formulation that integrates the advantages of multiple drugs, achieving multiple pharmacological effects through a single administration, so as to achieve efficient, safe and stable ophthalmic drug delivery.

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

[0007] This application provides a compound preparation composition for use in the eye, wherein the compound preparation composition comprises, by weight percentage, 0.01-1.5% olopatadine and 0.01-0.8% brimonidine.

[0008] Furthermore, the compound formulation composition also includes a pH adjuster, a thickener, a preservative, and a solvent.

[0009] Furthermore, the pH buffer is a phosphate or a borate.

[0010] Furthermore, the compound preparation composition further includes 0.01 to 0.1% ketotifen.

[0011] Furthermore, the dosage form of the compound preparation composition is eye drops.

[0012] Further, the eye drops, by weight percentage, comprise:

[0013] Olopatadine 0.1%;

[0014] Brimonidine 0.05%;

[0015] Hydroxypropyl methylcellulose 0.3%;

[0016] Benzalkonium chloride 0.01%;

[0017] Adjust the pH to 6.5 with phosphate buffer and add purified water to make up the difference.

[0018] Further, the preparation method of the eye drops is as follows: olopatadine and brimonidine are dissolved in phosphate buffer and stirred until completely dissolved; benzalkonium chloride is added and stirred until completely dissolved; hydroxypropyl methylcellulose is added, homogenized, and the pH is adjusted to 6.5; purified water is added to the prescribed amount; the solution is filtered through a 0.22μm filter membrane for sterilization and dispensed into sterile eye drop bottles.

[0019] Further, the eye drops, by weight percentage, comprise:

[0020] Olopatadine 0.1%;

[0021] Brimonidine 0.05%;

[0022] Ketotifen 0.01%;

[0023] Hydroxypropyl methylcellulose 0.3%;

[0024] Benzalkonium chloride 0.01%;

[0025] Adjust the pH to 6.5 with phosphate buffer and add purified water to make up the difference.

[0026] Further, the preparation method of the eye drops is as follows: olopatadine, brimonidine, and ketotifen are dissolved in phosphate buffer and stirred until completely dissolved; benzalkonium chloride is added and stirred until completely dissolved; hydroxypropyl methylcellulose is added, homogenized, and the pH is adjusted to 6.5; purified water is added to the prescribed amount; the solution is filtered through a 0.22 μm filter membrane for sterilization and dispensed into sterile eye drop bottles.

[0027] In summary, this application has the following beneficial effects:

[0028] The compound formulation of this application achieves multiple effects of anti-allergy, intraocular pressure reduction and ocular surface protection for the first time through the synergistic combination of olopatadine, brimonidine and ketotifen. Moreover, the formulation has significantly better stability, safety and patient compliance than existing single-agent drugs.

[0029] The compound formulation of this invention can simultaneously treat allergic conjunctivitis, glaucoma, and ocular surface inflammation, and is especially suitable for patients with multiple coexisting conditions, achieving multiple pharmacological effects with a single dose. The compound formulation reduces the dosage of single drugs, thereby minimizing irritation or systemic side effects. Detailed Implementation

[0030] 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.

[0031] Example 1

[0032] This embodiment discloses a compound preparation composition containing olopatadine and brimonidine for ocular use. The raw materials used in its preparation are as follows (prescription 100g):

[0033] Olopatadine 0.1g;

[0034] Brimonidine 0.05g;

[0035] Hydroxypropyl methylcellulose 0.3g;

[0036] Benzalkonium chloride 0.01g;

[0037] Adjust the pH to 6.5 with phosphate buffer and bring the purified water to a total of 100g.

[0038] Preparation method: Dissolve olopatadine and brimonidine in phosphate buffer and stir until completely dissolved; add benzalkonium chloride and stir until completely dissolved; add hydroxypropyl methylcellulose, homogenize and adjust pH to 6.5; add purified water to the prescribed volume; filter through a 0.22μm filter membrane for sterilization and dispense into sterile eye drop bottles.

[0039] Example 2

[0040] This embodiment discloses a compound preparation composition containing olopatadine and brimonidine for ocular use. The raw materials used in its preparation are as follows (prescription 100g):

[0041] Olopatadine 0.05g;

[0042] Brimonidine 0.05g;

[0043] Hydroxypropyl methylcellulose 0.3g;

[0044] Benzalkonium chloride 0.01g;

[0045] Adjust the pH to 6.5 with phosphate buffer and bring the purified water to a total of 100g.

[0046] Preparation method: Dissolve olopatadine and brimonidine in phosphate buffer and stir until completely dissolved; add benzalkonium chloride and stir until completely dissolved; add hydroxypropyl methylcellulose, homogenize and adjust pH to 6.5; add purified water to the prescribed volume; filter through a 0.22μm filter membrane for sterilization and dispense into sterile eye drop bottles.

[0047] Example 3

[0048] This embodiment discloses a compound preparation composition containing olopatadine and brimonidine for ocular use. The raw materials used in its preparation are as follows (prescription 100g):

[0049] Olopatadine 0.2g;

[0050] Brimonidine 0.03g;

[0051] Hydroxypropyl methylcellulose 0.3g;

[0052] Benzalkonium chloride 0.01g;

[0053] Adjust the pH to 6.5 with phosphate buffer and bring the purified water to a total of 100g.

[0054] Preparation method: Dissolve olopatadine and brimonidine in phosphate buffer and stir until completely dissolved; add benzalkonium chloride and stir until completely dissolved; add hydroxypropyl methylcellulose, homogenize and adjust pH to 6.5; add purified water to the prescribed volume; filter through a 0.22μm filter membrane for sterilization and dispense into sterile eye drop bottles.

[0055] Example 4

[0056] This embodiment discloses a compound preparation composition containing olopatadine and brimonidine for ocular use. The raw materials used in its preparation are as follows (prescription 100g):

[0057] Olopatadine 0.1g;

[0058] Brimonidine 0.05g;

[0059] Ketotifen 0.01g;

[0060] Hydroxypropyl methylcellulose 0.3g;

[0061] Benzalkonium chloride 0.01g;

[0062] Adjust the pH to 6.5 with phosphate buffer and add purified water to make up the difference.

[0063] Preparation method: Dissolve olopatadine, bromonidin, and ketotifen in phosphate buffer and stir until completely dissolved; add benzalkonium chloride and stir until completely dissolved; add hydroxypropyl methylcellulose, homogenize and adjust pH to 6.5; add purified water to the prescribed volume; filter through a 0.22μm filter membrane for sterilization and dispense into sterile eye drop bottles.

[0064] Comparative Example 1

[0065] This embodiment discloses a formulation composition for use in the eye, and the raw materials used in its preparation are as follows (prescription 100g):

[0066] Olopatadine 0.15g;

[0067] Hydroxypropyl methylcellulose 0.3g;

[0068] Benzalkonium chloride 0.01g;

[0069] Adjust the pH to 6.5 with phosphate buffer and bring the purified water to a total of 100g.

[0070] Preparation method: Dissolve olopatadine in phosphate buffer and stir until completely dissolved; add benzalkonium chloride and stir until completely dissolved; add hydroxypropyl methylcellulose, homogenize and adjust pH to 6.5; add purified water to the prescribed volume; filter through a 0.22μm filter membrane for sterilization and dispense into sterile eye drop bottles.

[0071] Comparative Example 2

[0072] This embodiment discloses a formulation composition for use in the eye, and the raw materials used in its preparation are as follows (prescription 100g):

[0073] Brimonidine 0.15g;

[0074] Hydroxypropyl methylcellulose 0.3g;

[0075] Benzalkonium chloride 0.01g;

[0076] Adjust the pH to 6.5 with phosphate buffer and bring the purified water to a total of 100g.

[0077] Preparation method: Dissolve brimonidine in phosphate buffer and stir until completely dissolved; add benzalkonium chloride and stir until completely dissolved; add hydroxypropyl methylcellulose, homogenize and adjust pH to 6.5; add purified water to the prescribed volume; filter through a 0.22μm filter membrane for sterilization and dispense into sterile eye drop bottles.

[0078] Performance testing

[0079] Test 1: Stability test (40℃ / 75%RH, 6 months, using Examples 1 and 4 as examples):

[0080]

[0081]

[0082] Test 2: Treatment efficacy trial (glaucoma, allergic conjunctivitis, dry eye syndrome)

[0083] (1) Mouse model construction

[0084] Glaucoma model: C57BL / 6 mice were used, and changes in the angle structure of the anterior chamber were induced by laser photocoagulation to establish a chronic high intraocular pressure model. Intraocular pressure was monitored using a non-contact tonometer (measured 3 times a week for 4 weeks; a stable intraocular pressure >21 mmHg was considered a successful model).

[0085] Allergic conjunctivitis model: Induced by ovalbumin (OVA) sensitization. Sensitization was achieved by intraperitoneal injection of a mixture of OVA (100 μg) and aluminum hydroxide adjuvant. Seven days later, an allergic reaction was induced by intraocular instillation of 1% OVA solution (once daily for 7 consecutive days). The appearance of conjunctival hyperemia, edema, and scratching behavior was considered a success.

[0086] Dry eye model: The benzalkonium chloride (BAC) induction method was used. 0.2% BAC solution was instilled into the eyes (twice daily for 14 consecutive days), and the model was validated by tear secretion test (Schirmer test <5mm / 5min) and corneal fluorescein staining score (≥4 points).

[0087] (2) Experimental grouping and treatment

[0088]

[0089]

[0090] (3) Dosing regimen

[0091] Take 1 drop twice daily.

[0092] (4) Evaluation indicators

[0093] ① Glaucoma model

[0094] Group Changes in intraocular pressure (mmHg, mean ± SD) RGC survival rate (%) Model Group 1 25.3±1.2 42.5±5.1 Experimental group 1 18.7±1.1* 68.4±6.3* Experimental group 2 16.5±0.9** 75.2±7.0** Control group 1 24.1±1.0 45.2±4.8 Control group 2 17.8±1.2* 70.1±6.5*

[0095] The data above show that the compound preparation prepared in Example 4 has the best intraocular pressure lowering effect (16.5 mmHg), which is significantly better than brimonidine or olopatadine alone (*p<0.05).

[0096] ② Allergic conjunctivitis model

[0097] Group <![CDATA[Mast cell count (cells / mm 2 )]]> Number of times of eye itching (per 30 minutes) Model Group 2 35.2±4.1 12.5±2.1 Experimental group 3 16.4±2.3* 4.3±1.0* Experimental group 4 10.1±1.5** 3.1±0.8** Control group 3 20.5±2.6* 6.2±1.2* Control group 4 19.3±1.8** 5.8±0.9**

[0098] The data above show that the compound preparation prepared in Example 4 has the best anti-allergic effect, with significantly lower mast cell count and number of eye itching episodes compared to olopatadine alone (*p<0.05).

[0099] ③ Dry eye model

[0100] Group Schirmer value (mm / 5min) Tear film breakup time (s) Model Group 3 3.2±0.5 4.1±0.8 Experimental group 5 6.8±0.7* 8.5±1.1* Experimental group 6 8.1±0.9** 10.3±1.3** Control group 5 5.1±0.6* 6.2±0.9* Control group 6 5.5±0.8** 6.8±1.2**

[0101] The data above show that Example 4 significantly improved dry eye symptoms, and the Schirmer value (8.1 mm) was close to the normal level (>10 mm), indicating that the compound has the function of repairing the ocular surface.

[0102] 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 compound preparation composition for use in the eye, characterized in that, The compound preparation composition, by weight percentage, includes 0.01-1.5% olopatadine and 0.01-0.8% brimonidine.

2. The compound preparation composition for ocular use according to claim 1, characterized in that, The compound preparation composition further includes a pH adjuster, a thickener, a preservative, and a solvent.

3. The compound preparation composition for ocular use according to claim 2, characterized in that, The pH buffer is a phosphate or a borate.

4. The compound preparation composition for ocular use according to claim 1, characterized in that, The compound preparation composition further includes 0.01-0.1% ketotifen.

5. The compound preparation composition for ocular use according to claim 1, characterized in that, The dosage form of the compound preparation composition is eye drops.

6. The compound preparation composition for ocular use according to claim 5, characterized in that, The eye drops, by weight percentage, comprise: Olopatadine 0.1%; Brimonidine 0.05%; Hydroxypropyl methylcellulose 0.3%; Benzalkonium chloride 0.01%; Adjust the pH to 6.5 with phosphate buffer and add purified water to make up the difference.

7. The compound preparation composition for ocular use according to claim 6, characterized in that, The preparation method of the eye drops is as follows: dissolve olopatadine and brimonidine in phosphate buffer and stir until completely dissolved; add benzalkonium chloride and stir until completely dissolved; add hydroxypropyl methylcellulose, homogenize and adjust the pH to 6.5; add purified water to the prescribed amount; filter through a 0.22μm filter membrane for sterilization and dispense into sterile eye drop bottles.

8. The compound formulation composition for ocular use according to claim 4, characterized in that, The eye drops, by weight percentage, comprise: Olopatadine 0.1%; Brimonidine 0.05%; Ketotifen 0.01%; Hydroxypropyl methylcellulose 0.3%; Benzalkonium chloride 0.01%; Adjust the pH to 6.5 with phosphate buffer and add purified water to make up the difference.

9. The compound preparation composition for ocular use according to claim 8, characterized in that, The preparation method of the eye drops is as follows: dissolve olopatadine, bromonidin, and ketotifen in phosphate buffer and stir until completely dissolved; add benzalkonium chloride and stir until completely dissolved; add hydroxypropyl methylcellulose, homogenize and adjust the pH to 6.5; add purified water to the prescribed amount; filter through a 0.22μm filter membrane for sterilization and dispense into sterile eye drop bottles.

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