Two-component combination pharmaceutical composition for treating glaucoma and use thereof

Abstract

Provided are a two-component combination pharmaceutical composition and use thereof, which belong to the field of pharmaceuticals. The pharmaceutical composition comprises: carteolol or timolol, netarsudil, a buffer, a tonicity agent, a pH regulator, a tackifier, and water for injection. By adding the pH regulator to a solution of netarsudil free base and carteolol free base or timolol free base, the problem that netarsudil is immiscible with carteolol or timolol is successfully solved. The preparation process is simple, the intraocular pressure is reduced by means of different mechanisms of action, and the therapeutic effect is significant and precise. The ophthalmic pharmaceutical composition provides the possibility for clinically safe and effective reduction of intraocular pressure and treatment of glaucoma.

Description

A dual-combination drug composition for the treatment of glaucoma and its uses Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a dual-combination drug composition and its uses. Background Technology

[0002] Glaucoma is a group of multifactorial optic nerve diseases, accompanied by characteristic optic nerve damage and corresponding visual field defects. Severe glaucoma can even lead to blindness. Therefore, glaucoma has become the leading cause of blindness in humans.

[0003] Elevated intraocular pressure is one of its primary risk factors. Statistics show that in 2020, the number of glaucoma patients worldwide was approximately 7.6-79.6 million, with a prevalence of about 3.54% in the global population aged 40-80. Glaucoma has several types, such as primary glaucoma, secondary glaucoma, and congenital glaucoma, many of which are closely related to age. Therefore, against the backdrop of a global aging population, the number of glaucoma patients is constantly increasing, and by 2040, the number may exceed 111.8 million.

[0004] To date, the only globally recognized method for controlling the progression of glaucoma is lowering intraocular pressure. Medications, as the earliest treatment for glaucoma, have always played a crucial role in its management.

[0005] Currently, commonly used single-agent preparations include the following categories: (1) Rho kinase inhibitors: Intraocular pressure-lowering drugs that act directly on the trabecular meshwork. They mainly affect the cytoskeleton, altering the morphology, cell movement, cytokinesis, and smooth muscle contraction of trabecular meshwork cells, thereby increasing aqueous humor outflow, protecting the optic nerve, and reducing bleb scarring. The commonly used drug in clinical practice is netardil dimethylsulfonate. (2) Adrenaline β-receptor blockers: By blocking β-receptors, they reduce aqueous humor production and promote aqueous humor drainage, exhibiting a strong and sustained intraocular pressure-lowering effect and effectively controlling intraocular pressure. The commonly used drugs in clinical practice are timolol maleate, carteolol hydrochloride, betalol hydrochloride, levobunolol hydrochloride, etc.; (3) α 2 Adrenergic receptor agonists: They reduce intraocular pressure by decreasing the production of aqueous humor and the outflow through the sclera, and are first-line drugs for the treatment of primary open-angle glaucoma. The commonly used drug in clinical practice is brimonidine tartrate; (4) Prostaglandin analogs: They reduce intraocular pressure by relaxing the ciliary muscle, increasing the intermuscular space, and increasing the outflow and drainage of aqueous humor through the uveal-scleral pathway. They have a strong effect on reducing intraocular pressure at night, especially for patients who cannot tolerate or do not respond well to other intraocular pressure-lowering drugs. The commonly used drugs in clinical practice are latanoprost, bimatoprost, travoprost, tafluprost, etc.

[0006] Glaucoma is a chronic eye disease requiring long-term medication. However, single-agent formulations are often insufficient to effectively control intraocular pressure, necessitating the use of two medications in combination. For the combined use of two single-agent formulations or currently marketed dual-combination formulations (such as...), (etc.) Due to the increased frequency of administration, the exposure to preservatives will also increase significantly, leading to problems such as poor safety, many side effects, and poor patient compliance.

[0007] Thickeners can prolong the residence time of drugs on the ocular surface through physical thickening, membrane affinity, and drug binding, thus confining the drug within the eye and reducing its absorption into the mouth and nasal cavity. This improves the bioavailability of the drug in the eye. Commercially available eye drops containing thickeners are mostly artificial tears used to treat dry eye, such as sodium hyaluronate eye drops, sodium carboxymethyl cellulose eye drops, polyvinyl alcohol eye drops, and polyethylene glycol eye drops. Other eye drops with added thickeners include Mikelan eye drops for treating glaucoma. Sodium alginate was added as a thickener to increase its viscosity. Although eye drops with a certain viscosity can increase the time the drug stays on the ocular surface, improve comfort, and reduce the frequency of use, they can also easily cause blurred vision and cause inconvenience to patients.

[0008] Furthermore, the immiscibility of the salt forms of netardil dimethylsulfonate and carteolol hydrochloride limits the development of compound eye drops. Therefore, developing a dual-combination drug composition for the treatment of eye diseases that is simple to prepare, has excellent stability, high safety, and good patient compliance is a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0009] To overcome the shortcomings of existing technologies, the present invention aims to provide a dual-combination drug composition and its uses. This ophthalmic dual-combination drug composition solution, comprising neltadil free base and carteolol free base, is simple to prepare, exhibits excellent stability, high safety, and good patient compliance. It can be used to treat glaucoma, high intraocular pressure, and / or related symptoms, with a once-daily dose, effectively and rapidly lowering intraocular pressure with minimal side effects and high patient compliance.

[0010] To solve the above problems, the present invention adopts the following technical solution: a dual-combination drug composition, the drug composition comprising: carteolol or timolol, neltaldil, buffer, tension agent, pH adjuster, thickener, and water for injection.

[0011] Among them, 5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydro-2(1H)-quinolone (captilolol), and 4-[(1S)-1-(aminomethyl)-2-(6-isoquinolinyl)-2-oxoethyl]phenyl]methyl 2,4-dimethylbenzoate (netadil)

[0012] The preferred ophthalmic pharmaceutical composition comprises:

[0013] (1) 0.02% w / v to 4.0% w / v of adrenaline β-receptor blockers, such as carteolol or timolol;

[0014] (2) Nettadil free base at 0.005% w / v to 0.1% w / v;

[0015] (3) Tensioning agents ranging from 0.01% w / v to 10.0% w / v;

[0016] (4) 0.01% w / v to 1.0% w / v buffer;

[0017] (5) Tackifiers ranging from 0.1% w / v to 1.0% w / v;

[0018] (6) Adjust the pH to 4.5 to 5.4 using a pH adjuster;

[0019] (7) The osmotic pressure is 280 to 320 mOsmol / kg.

[0020] Furthermore, the ophthalmic pharmaceutical composition comprises

[0021] (1) 0.02% w / v to 2.0% w / v of free carteolol base or free timolol base;

[0022] (2) Nettadil free base from 0.005% w / v to 0.02% w / v;

[0023] (3) Tensioning agents ranging from 0.01% w / v to 10.0% w / v;

[0024] (4) 0.01% w / v to 1.0% w / v buffer;

[0025] (5) Thickener of 0.1% w / v to 1.0% w / v; v is the volume of the composition system after the addition of water for injection;

[0026] (6) Adjust the pH to 4.5 to 5.4 using a pH adjuster;

[0027] (7) The osmotic pressure is 280 to 320 mOsmol / kg.

[0028] Preferably, the composition solution wherein the tensile agent comprises, but is not limited to, glycerol, sorbitol, mannitol, propylene glycol, erythritol, arabinitol, xylitol, ribitol, galactitol, polyethylene glycol, lactotol, mannitol, dextran and other sugar alcohols, sodium chloride, potassium chloride, and calcium chloride, or any combination thereof.

[0029] Preferably, the composition solution wherein the buffer comprises, but is not limited to, boric acid or a salt thereof, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous sodium phosphate, citric acid or a salt thereof, carbonic acid, gluconic acid or a salt thereof, acetic acid or a salt thereof, phosphate or a salt thereof, various amino acids such as glutamic acid and ε-aminocaproic acid and trimethylolpropane buffer, or any combination thereof.

[0030] Preferably, the composition solution contains a thickener comprising, but not limited to, one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium hydroxyethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, sodium alginate, chitosan, and polyvinylpyrrolidone.

[0031] Preferably, the composition solution wherein examples of pH adjusters include, but are not limited to, methanesulfonic acid, hydrobromic acid, phosphoric acid, hydrochloric acid, citric acid, tartaric acid, malic acid, lactic acid, succinic acid, hydroiodic acid, formic acid, acetic acid, benzoic acid, ethanesulfonic acid, oxalic acid, sodium oxychloride, and tromethamine.

[0032] Preferably, the composition solution comprises 0.02% w / v to 4.0% w / v of the adrenaline β-receptor blocker carteolol free base; more preferably 0.3% w / v to 2.0% w / v, most preferably 2.0% w / v. Alternatively, it comprises 0.02% w / v to 4.0% w / v of the adrenaline β-receptor blocker timolol free base; more preferably 0.1% w / v to 2.0% w / v, most preferably 0.5% w / v.

[0033] Preferably, the composition solution comprises 0.005% w / v to 0.1% w / v of natedil free base; more preferably 0.02% w / v to 0.04% w / v, and most preferably 0.02% w / v.

[0034] Preferably, the composition solution contains 1.0% w / v to 10.0% w / v mannitol.

[0035] Preferably, the composition solution contains 0.05% w / v boric acid.

[0036] Preferably, the composition solution contains 0.5%-1.0% w / v hydroxypropyl methylcellulose; more preferably 0.5% w / v hydroxypropyl methylcellulose.

[0037] Preferably, the composition solution has an osmotic pressure of 280-320 mOsmol / kg.

[0038] Preferably, the pH of the composition solution is 4.5-5.4.

[0039] Preferably, the composition solution provided by the present invention has undergone stability testing. The results show that, compared to day 0, after storage at 5℃±3℃ for 24 months, the content of each active pharmaceutical ingredient showed no significant change, consistent with the storage conditions of commercially available eye drops before opening.

[0040] Preferably, the composition solution provided by the present invention has undergone stability testing. The results show that, compared to day 0, after storage at 25℃±2℃ for 6 weeks, the content of each active pharmaceutical ingredient showed no significant change, meeting the requirements for storage conditions of commercially available eye drops after opening.

[0041] Preferably, the composition solution provided by the present invention has undergone stability testing. The results show that, compared to day 0, after storage at 40℃±2℃ for 14 days, the content of each active pharmaceutical ingredient showed no significant change compared to day 0, meeting the requirements for short-term deviation from storage conditions for commercially available eye drops.

[0042] The present invention further provides the use of the aforementioned dual-combination pharmaceutical composition in the preparation of a medicament for the prevention or treatment of eye diseases. Preferably, the eye disease is glaucoma, intraocular pressure, and / or related symptoms.

[0043] The aforementioned compound eye drops for the treatment of glaucoma, high intraocular pressure, and / or related symptoms comprise a solution of the aforementioned ophthalmic pharmaceutical composition administered once daily to the eye of a patient in need.

[0044] The beneficial effects of the technical solution of the present invention are: (1) Due to the incompatibility of the salt forms of netardil dimethylsulfonate and the adrenaline β-receptor blocker carteolol hydrochloride, the development of compound eye drops prepared from the two drugs is limited; the present invention successfully solves the problem of incompatibility between the two drugs by adding a pH adjuster to the free base of netardil and the free base of carteolol. The preparation process is simple and provides a method to solve the incompatibility of the salt forms of the two drugs. This method is expected to provide a solution for the dissolution of other incompatible drugs; (2) Intraocular pressure can be reduced through different mechanisms of action, and the therapeutic effect is obvious and definite; (3) The thickener provides a longer retention time on the ocular surface. Compared with traditional prescription eye drops, the present invention can reduce the amount of ocular surface loss of eye drops, and is expected to allow more drugs to penetrate the cornea and provide a stronger effect in lowering intraocular pressure; compared with commercially available single-component preparations ( Compared to eye drops, once-daily administration significantly enhances the intraocular pressure-lowering effect; (4) once-daily administration not only reduces the frequency of administration, but also eliminates preservative exposure due to the preservative-free formula, reducing the occurrence of ocular side effects and significantly improving patient compliance. Furthermore, the pharmaceutical composition solution provided by this invention is useful as a treatment for glaucoma, high intraocular pressure, and / or related symptoms. Therefore, the ophthalmic pharmaceutical composition of this invention provides the possibility for safely and effectively lowering intraocular pressure and treating glaucoma in clinical practice. Attached Figure Description

[0045] Figure 1 is a diagram showing the dosing regimens of the ophthalmic drug composition solution, positive control drug treatment group 1, and positive control drug treatment group 2 of Examples 1-30 of the present invention.

[0046] Figure 2 is a bar chart showing the measured intraocular pressure (IOP) values ​​(Figure 2-1) and the IOP difference (Figure 2-2) after administration of the ophthalmic drug composition solutions and positive control drugs of Examples 1-30 of the present invention.

[0047] Figure 3 is a diagram showing the dosing regimens of the ophthalmic drug composition solution, positive control drug treatment group 1, and positive control drug treatment group 2 of Examples 31-60 of the present invention.

[0048] Figure 4 is a bar chart showing the measured intraocular pressure (Figure 4-1) and intraocular pressure change (Figure 4-2) after administration of the ophthalmic drug composition solution and positive control drug of Examples 31-60 of the present invention.

[0049] Figure 5 is a diagram showing the dosing regimens of the ophthalmic drug composition solution, positive control drug treatment group 1, and positive control drug treatment group 2 of Examples 61-90 of this invention.

[0050] Figure 6 is a bar chart showing the intraocular pressure changes (Figure 6-1) and measured intraocular pressure values ​​(Figure 6-2) of each group of rabbits in Examples 61-90 of this invention, including the ophthalmic drug composition solution and the positive control drug.

[0051] Figure 7 is a diagram showing the dosing regimens of the ophthalmic drug composition solution, positive control drug treatment group 1, and positive control drug treatment group 2 of Examples 91-120 of the present invention.

[0052] Figure 8 is a bar chart (Figure 8-1) showing the intraocular pressure changes of the ophthalmic drug composition solutions and positive control drugs in Examples 91-120 of the present invention without the addition of a thickener, and a bar chart (Figure 8-2) showing the measured intraocular pressure values.

[0053] Figure 9 shows the significant difference in intraocular pressure changes on day 20 between the group without thickener and the group with hydroxypropyl methylcellulose (HPMC) ophthalmic drug composition solution.

[0054] Figure 10 shows the significant difference in intraocular pressure changes on day 20 between the ophthalmic drug composition solution without thickener and the group with polyethylene glycol (PEG). Figure 10-1 shows the ophthalmic drug composition solution with 1% carteolol, and Figure 10-2 shows the ophthalmic drug composition solution with 2% carteolol.

[0055] Figure 11 shows the significant difference in intraocular pressure changes on day 20 between the group without thickener and the group with sodium hyaluronate (HA). Figure 11-1 shows the ophthalmic drug composition solution with 1% carteolol, and Figure 11-2 shows the ophthalmic drug composition solution with 2% carteolol.

[0056] Figure 12 is a diagram showing the dosing regimens of ophthalmic drug composition solutions, positive control drug treatment group 1, and positive control drug treatment group 3 in Examples 126-129 of the present invention.

[0057] Figure 13 shows the ophthalmic pharmaceutical composition solution and positive control drug of Examples 126-129 of the present invention with added hydroxypropyl methylcellulose (HPMC). The intraocular pressure (IOP) was administered once a day for 10 consecutive days starting from day 10. A bar chart was created using the data of the changes in IOP in each group of rabbits on day 20 (Figure 13-1) and the measured IOP (Figure 13-2).

[0058] Figure 14 shows the significant difference in intraocular pressure changes on day 20 between the group without thickener and the group with hydroxypropyl methylcellulose (HPMC) ophthalmic drug composition solution. Figure 14-1 shows the ophthalmic drug composition solution with 0.25% timolol, and Figure 14-2 shows the ophthalmic drug composition solution with 0.5% timolol. Detailed Implementation

[0059] The present invention will be further described in detail below with reference to embodiments, but is not limited thereto.

[0060] This invention relates to a therapeutic agent for glaucoma, high intraocular pressure, and / or related symptoms, comprising an ophthalmic dual-combination drug composition solution containing the adrenaline beta-receptor blocker carteolol free base or timolol free base and neltadil free base.

[0061] This invention successfully solves the problem of immiscibility between nedadil methanesulfonate and carteolol hydrochloride salts or timolol maleate by adding different pH adjusters to directly form salts from nedadil free base and carteolol free base or timolol maleate free base.

[0062] In the ophthalmic pharmaceutical composition solution of the present invention, the concentration of the adrenergic β-receptor blocker carteolol free base is from 0.02% w / v to 4.0% w / v, more preferably from 0.3% w / v to 2.0% w / v, and most preferably 2.0% w / v; the concentration of the timolol free base is from 0.02% w / v to 4.0% w / v, more preferably from 0.1% w / v to 2.0% w / v, and most preferably 0.5% w / v.

[0063] In the ophthalmic pharmaceutical composition solution of the present invention, the concentration of netardil free base is from 0.005% w / v to 0.1% w / v, more preferably from 0.02% w / v to 0.04% w / v, and most preferably 0.02% w / v.

[0064] The ophthalmic pharmaceutical composition solution of the present invention may contain a tensile agent. The tensile or osmolality of the composition can be adjusted to hypotonic, isotonic, or hypertonic relative to normal tears by using conventional materials known in the art. The tensile agent is typically a nonionic compound. Examples of tensile agents include, but are not limited to, sodium chloride, potassium chloride, mannitol, dextran, glycerol, and propylene glycol. Suitably, the tensile agent may be present in the ophthalmic composition in an amount from about 0.01% w / v to about 10% w / v. In the embodiments, the tensioning agent may be present in the ophthalmic composition in amounts of about 1.0% w / v, about 1.1% w / v, about 1.2% w / v, about 1.3% w / v, about 1.4% w / v, about 1.5% w / v, about 1.6% w / v, about 1.7% w / v, about 1.8% w / v, about 1.9% w / v, about 2.0% w / v, about 2.1% w / v, about 2.2% w / v, about 2.3% w / v, about 2.4% w / v, about 2.5% w / v, about 2.6% w / v, about 2.7% w / v, about 2.8% w / v, about 2.9% w / v, or about 3.0% w / v. The tensioning agent may suitably be mannitol.

[0065] The ophthalmic pharmaceutical composition solution of the present invention may contain a buffer. The buffer can be used to minimize pH drift of the composition and to help stabilize the composition. Suitable buffers include, but are not limited to, acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, their pharmaceutically acceptable salts, tromethorphan, and combinations thereof. The buffer may be present in the ophthalmic composition in an amount of about 0.01% w / v to about 1% w / v. In embodiments, the buffer may be present in the ophthalmic composition in an amount of about 0.01% w / v, about 0.02% w / v, about 0.03% w / v, about 0.04% w / v, about 0.05% w / v, about 0.06% w / v, about 0.07% w / v, about 0.08% w / v, about 0.09% w / v, or about 0.1% w / v. The buffer may suitably be boric acid.

[0066] The ophthalmic pharmaceutical composition solution of the present invention may contain a thickener. The thickener can increase the retention time of the drug on the ocular surface to improve efficacy. Suitable thickeners include, but are not limited to, hydroxypropyl methylcellulose, sodium hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, sodium hyaluronate, hyaluronic acid, chitosan, etc. The thickener may be present in the ophthalmic composition in an amount from about 0.1% w / v to 1.0% w / v. In embodiments, a buffer may be present in the ophthalmic composition in an amount of about 0.3% w / v, about 0.4% w / v, about 0.5% w / v, about 0.6% w / v, about 0.7% w / v, about 0.8% w / v, or about 0.9% w / v. Suitable thickeners are hydroxypropyl methylcellulose, polyethylene glycol, and sodium hyaluronate.

[0067] The ophthalmic pharmaceutical composition solution of the present invention may contain a pH adjuster, the amount of which is sufficient to adjust the pH of the composition to about 4 to about 9. Suitably, the pH of the ophthalmic composition may be about 4.5 to about 5.4. Suitable pH adjusters include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium bicarbonate, methanesulfonic acid, hydrobromic acid, phosphoric acid, hydrochloric acid, citric acid, tartaric acid, malic acid, lactic acid, succinic acid, hydroiodic acid, formic acid, acetic acid, benzoic acid, ethanesulfonic acid, and oxalic acid.

[0068] Examples 1-30: Dual-compound eye drops prepared using hydroxypropyl methylcellulose as a thickener and different pH adjusters

[0069] Table 1. The preparation and formulation methods of topical ophthalmic drug composition solutions for lowering intraocular pressure are as follows:

[0070] The preparation process is as follows: (1) Weigh 90% of the prescribed amount of water for injection, add the prescribed amounts of carteolol, boric acid, mannitol, natedadil and hydroxypropyl methylcellulose, add different pH adjusters, stir and adjust the pH to 4.5-5.4; (2) Add water for injection to the full prescribed amount, stir evenly and make the volume reach 100%; (3) Put the solution from step 2 into a low-density polyethylene pharmaceutical eye drop bottle and study its stability under different storage temperature conditions. Table 2. Content of each active pharmaceutical ingredient in Examples 1-30 when stored at 5℃ for 24 months.

[0071] Table 3. Commercially available eye drops stored at 5°C for 24 months (…) Content of each active ingredient in eye drops

[0072] According to Examples 1-30, formulations containing netardil and carteolol exhibited good stability for 24 months under storage conditions at 5°C, meeting the requirements for commercially available eye drops ( Requirements for storage conditions of eye drops before opening.

[0073] Table 4. Content of each active pharmaceutical ingredient in Examples 1-30 after storage at 25°C for 6 weeks.

[0074] Table 5. Commercially available eye drops stored at 25°C for 6 weeks ( Content of each active ingredient in eye drops

[0075] According to Examples 1-30, formulations containing netardil and carteolol exhibited good stability for 6 weeks under storage conditions at 25°C, meeting the requirements for commercially available eye drops ( Requirements for storage conditions of eye drops after opening.

[0076] Table 6. Content of each active pharmaceutical ingredient in Examples 1-30 after storage at 40°C for 14 days.

[0077] Table 7. Commercially available eye drops stored at 40℃ for 14 days (…) Content of each main ingredient in eye drops

[0078] According to Examples 1-30, formulations containing netardil and carteolol showed good stability for 14 days under storage conditions at 40°C, meeting the requirements for commercially available eye drops ( (Eye drops) Short-term deviation from storage requirements.

[0079] Examples 31-60: Dual-compound eye drops prepared using polyethylene glycol as a thickener and different pH adjusters

[0080] Table 8. The preparation and formulation methods of topical ophthalmic drug composition solutions for lowering intraocular pressure are as follows:

[0081] The preparation process is as follows: (1) Weigh 90% of the prescription amount of water for injection, add the prescription amount of carteolol, boric acid, mannitol, nertadil and polyethylene glycol, add different pH adjusters, stir and adjust the pH to 4.5-5.4; (2) Add water for injection to the full prescription amount, stir evenly and make the volume reach 100%; (3) Put the solution from step 2 into a low-density polyethylene pharmaceutical eye drop bottle and study its stability under different storage temperature conditions.

[0082] Examples 61-90: Dual-compound eye drops prepared using sodium hyaluronate as a thickener and different pH adjusters

[0083] Table 15. The preparation and formulation methods of topical ophthalmic drug composition solutions for lowering intraocular pressure are as follows:

[0084] The preparation process is as follows: (1) Weigh 90% of the prescription amount of water for injection, add the prescription amount of carteolol, boric acid, mannitol, nertadil and sodium hyaluronate, add different pH adjusters, stir and adjust the pH to 4.5-5.4; (2) Add water for injection to the full prescription amount, stir evenly and make the volume reach 100%; (3) Put the solution from step 2 into a low-density polyethylene pharmaceutical eye drop bottle and study its stability under different storage temperature conditions.

[0085] Examples 91-120: Non-thickening dual-compound eye drops prepared with different pH adjusters

[0086] Table 22. The preparation and formulation methods of topical ophthalmic drug composition solutions for lowering intraocular pressure are as follows:

[0087] The preparation process is as follows: (1) Weigh 90% of the prescription amount of water for injection, add the prescription amount of carteolol, boric acid, mannitol and natedil, add different pH adjusters, stir and adjust the pH to 4.5-5.4; (2) Add water for injection to the full prescription amount, stir evenly and make the volume reach 100%; (3) Put the solution in step 2 into a low-density polyethylene pharmaceutical eye drop bottle. After testing, the composition under different storage temperature conditions has good stability.

[0088] Example 121: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using a Japanese white rabbit glaucoma model.

[0089] In this embodiment, a high intraocular pressure model was established by injecting compound carbomer (containing 0.3% carbomer and 0.025% dexamethasone by weight) into the anterior chamber. The eye drops prepared in Examples 1-30 were administered once a day to evaluate the treatment effect.

[0090] Experimental animals: 102 healthy male Japanese white rabbits, with an initial weight of 2.5-3.0 kg.

[0091] Experimental Groups:

[0092] Normal control group: No treatment was given.

[0093] Model group: A high intraocular pressure model was established, and no eye drops were administered.

[0094] Treatment Group 1: A high intraocular pressure model was established, and commercially available natedil eye drops were administered. Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the active ingredient netardil.

[0095] Treatment Group 2: A high intraocular pressure model was established, and commercially available carteolol hydrochloride eye drops were administered. Eye drops, a single-component preparation containing 2.0 parts by weight of the active ingredient carteolol.

[0096] Example 1 group: an ophthalmic drug composition solution with hydroxypropyl methylcellulose as the thickener and mesylate as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0097] Example 2: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of natedil as the pH adjuster (a dual-combination preparation). The thickener is hydroxypropyl methylcellulose and the pH adjuster is mesylate.

[0098] Example 3: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and hydrobromic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0099] Example 4: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of natedil as the pH adjuster (a dual-combination preparation). The thickener is hydroxypropyl methylcellulose and the pH adjuster is hydrobromic acid.

[0100] Example 5 group: an ophthalmic drug composition solution with hydroxypropyl methylcellulose as the thickener and phosphoric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0101] Example 6: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of natedil as the pH adjuster (a dual-combination preparation).

[0102] Example 7: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and hydrochloric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0103] Example 8: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of natedil as the pH adjuster (a dual-combination preparation). The thickener is hydroxypropyl methylcellulose and the pH adjuster is hydrochloric acid.

[0104] Example 9: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and citric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0105] Example 10: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of natedil as the pH adjuster (a dual-combination preparation).

[0106] Example 11: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and tartaric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0107] Example 12: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of retardil as the pH adjuster (a dual-combination preparation).

[0108] Example 13: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and malic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0109] Example 14: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and malic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0110] Example 15: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and lactic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0111] Example 16: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and lactic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0112] Example 17: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and succinic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0113] Example 18: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and succinic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0114] Example 19: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and hydroiodic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0115] Example 20: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil as the pH adjuster.

[0116] Example 21: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and formic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0117] Example 22: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and formic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0118] Example 23: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and acetic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0119] Example 24: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of natedil as the pH adjuster (a dual-combination preparation).

[0120] Example 25: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and benzoic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0121] Example 26: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of nestadil as the pH adjuster (a dual-combination preparation). The thickener is hydroxypropyl methylcellulose and the pH adjuster is benzoic acid.

[0122] Example 27: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and ethanesulfonic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0123] Example 28: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and ethanesulfonic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0124] Example 29: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and oxalic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0125] Example 30: An ophthalmic drug composition solution containing 2.0 parts by weight of carteolol and 0.02 parts by weight of natedil as the pH adjuster (a dual-combination preparation).

[0126] Model establishment: Rabbits in the normal control group received no treatment. The remaining 33 groups of white rabbits were anesthetized on day 0 by intravenous injection of urethane (0.8-1 g / kg) via the ear. Using a 1 ml syringe, 10 μl of aqueous humor was extracted from each anterior chamber, followed by the injection of 10 μl of a combined carbomer solution. Intraocular pressure was measured every two days, and clinical manifestations were observed. A successful model was characterized by anterior chamber opacity and significantly elevated intraocular pressure. A rabbit model of high intraocular pressure was successfully established after 10 days.

[0127] Dosage regimen: Based on currently available natedadil eye drops ( eye drops) and commercially available carteolol hydrochloride eye drops ( The clinical dosing regimen for eye drops was divided into the following groups in this experiment: (1) Treatment group 1: commercially available natedadil eye drops ( (1) Eye drops), 50 μL per eye each time, once a day (9:00 PM); (2) Treatment group 2: commercially available carteolol hydrochloride eye drops ( (3) Examples 1-30: 50 μL per eye, once daily (9:00 AM and 9:00 PM). All groups successfully established the model on day 10 and started administration for 10 days. No eye drops were given to the normal control group and the model group. The administration regimen is shown in Figure 1.

[0128] Detection indicators and methods:

[0129] Intraocular pressure: Intraocular pressure was measured once daily (9:00 PM) on days 0, 2, 4, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of the experiment. The rabbit's upper and lower eyelids were gently pulled apart, the tonometer was brought close to the rabbit's eye, the distance was adjusted, and the measurement button was pressed lightly. The eyelids were not touched during the measurement. Six measurements were completed sequentially to obtain the individual measurement value and the average value (mmHg).

[0130] Experimental results:

[0131] Intraocular pressure (IOP): At all time points following drug administration during the study period, IOP values ​​in all treatment groups and example groups were significantly lower than those in the model group (Student paired t-test). Furthermore, compared to treatment group 1 and treatment group 2, the IOP of the ophthalmic composition solutions in examples 1-30 were all significantly lower. Among these, the ophthalmic drug compositions in examples 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, and 30 showed significantly better intraocular pressure-lowering effects than those in examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, and 25. The ophthalmic drug compositions in groups 27 and 29; however, there were no significant differences in the measured values ​​and changes in IOP between groups 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, and 29, and no significant differences in the measured values ​​and changes in IOP between groups 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, and 30.

[0132] Table 29. Measured intraocular pressure values ​​in rabbits of each group after 10 consecutive days of drug administration, starting from day 10.

[0133] Table 30. Differences between measured intraocular pressure (IOP) values ​​and initial IOP (measured IOP on day 10) in each group of rabbits after 10 consecutive days of drug administration starting from day 10.

[0134] Figures 2-1 and 2-2 show the ophthalmic pharmaceutical composition solution and positive control drug of Examples 1-30 ( The intraocular pressure and intraocular pressure difference after administration of eye drops were plotted as bar graphs based on the measured intraocular pressure values ​​(Figure 2-1) and intraocular pressure difference values ​​(Figure 2-2) of each group of rabbits, starting from day 10 and administered once a day for 10 consecutive days. Among them, the results of intraocular pressure change differences showed that on day 20: compared with groups 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, and 29, treatment group 2 showed *** P<0.001; compared with groups 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, and 30, treatment group 2 showed *** P<0.0001; compared with groups 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, and 29, groups 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, and 30 showed *** P<0.001.

[0135] Example 122: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using a Japanese white rabbit glaucoma model.

[0136] In this embodiment, a high intraocular pressure model was established by injecting compound carbomer (containing 0.3% carbomer by weight and 0.025% dexamethasone by weight) into the anterior chamber. The eye drops prepared in Examples 31-60 were administered once a day to evaluate the treatment effect.

[0137] Experimental animals: 102 healthy male Japanese white rabbits, with an initial weight of 2.5-3.0 kg.

[0138] Experimental Groups:

[0139] Normal control group: No treatment was given.

[0140] Model group: A high intraocular pressure model was established, and no eye drops were administered.

[0141] Treatment Group 1: A high intraocular pressure model was established, and commercially available natedil eye drops were administered. Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the active ingredient netardil.

[0142] Treatment Group 2: A high intraocular pressure model was established, and commercially available carteolol hydrochloride eye drops were administered. Eye drops, a single-component preparation containing 2.0 parts by weight of the active ingredient carteolol.

[0143] Example 31: An ophthalmic drug composition solution with polyethylene glycol as the thickener and mesylate as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0144] Example 32: An ophthalmic drug composition solution with polyethylene glycol as the thickener and mesylate as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0145] Example 33: An ophthalmic drug composition solution with polyethylene glycol as the thickener and hydrobromic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0146] Example 34: An ophthalmic drug composition solution with polyethylene glycol as the thickener and hydrobromic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0147] Example 35: An ophthalmic drug composition solution with polyethylene glycol as the thickener and phosphoric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0148] Example 36: An ophthalmic drug composition solution with polyethylene glycol as the thickener and phosphoric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0149] Example 37: An ophthalmic drug composition solution with polyethylene glycol as the thickener and hydrochloric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0150] Example 38: An ophthalmic drug composition solution with polyethylene glycol as the thickener and hydrochloric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0151] Example 39: An ophthalmic drug composition solution with polyethylene glycol as the thickener and citric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0152] Example 40: An ophthalmic drug composition solution with polyethylene glycol as the thickener and citric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0153] Example 41: An ophthalmic drug composition solution with polyethylene glycol as the thickener and tartaric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0154] Example 42: An ophthalmic drug composition solution with polyethylene glycol as the thickener and tartaric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0155] Example 43: An ophthalmic drug composition solution with polyethylene glycol as the thickener and malic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0156] Example 44: An ophthalmic drug composition solution with polyethylene glycol as the thickener and malic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0157] Example 45: An ophthalmic drug composition solution with polyethylene glycol as the thickener and lactic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0158] Example 46: An ophthalmic drug composition solution with polyethylene glycol as the thickener and lactic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0159] Example 47: An ophthalmic drug composition solution with polyethylene glycol as the thickener and succinic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0160] Example 48: An ophthalmic drug composition solution with polyethylene glycol as the thickener and succinic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0161] Example 49: An ophthalmic drug composition solution with polyethylene glycol as the thickener and hydroiodic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0162] Example 50: An ophthalmic drug composition solution with polyethylene glycol as the thickener and hydroiodic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0163] Example 51: An ophthalmic drug composition solution with polyethylene glycol as the thickener and formic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0164] Example 52: An ophthalmic drug composition solution with polyethylene glycol as the thickener and formic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0165] Example 53: An ophthalmic drug composition solution with polyethylene glycol as the thickener and acetic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0166] Example 54: An ophthalmic drug composition solution containing polyethylene glycol as the thickener and acetic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0167] Example 55: An ophthalmic drug composition solution with polyethylene glycol as the thickener and benzoic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0168] Example 56: An ophthalmic drug composition solution with polyethylene glycol as the thickener and benzoic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0169] Example 57: An ophthalmic drug composition solution with polyethylene glycol as the thickener and ethanesulfonic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0170] Example 58: An ophthalmic drug composition solution with polyethylene glycol as the thickener and ethanesulfonic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0171] Example 59: An ophthalmic drug composition solution with polyethylene glycol as the thickener and oxalic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0172] Example 60: An ophthalmic drug composition solution with polyethylene glycol as the thickener and oxalic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0173] Model establishment: Rabbits in the normal control group received no treatment. The remaining 33 groups of white rabbits were anesthetized on day 0 by intravenous injection of urethane (0.8-1 g / kg) via the ear. Using a 1 ml syringe, 10 μl of aqueous humor was extracted from each anterior chamber, followed by the injection of 10 μl of a combined carbomer solution. Intraocular pressure was measured every two days, and clinical manifestations were observed. A successful model was characterized by anterior chamber opacity and significantly elevated intraocular pressure. A rabbit model of high intraocular pressure was successfully established after 10 days.

[0174] Dosage regimen: Based on currently available natedadil eye drops ( eye drops) and commercially available carteolol hydrochloride eye drops ( The clinical dosing regimen for eye drops was divided into the following groups in this experiment: (1) Treatment group 1: commercially available natedadil eye drops ( (1) Eye drops), 50 μL per eye each time, once a day (9:00 PM); (2) Treatment group 2: commercially available carteolol hydrochloride eye drops ( (3) Examples 1-30: 50 μL per eye, once daily (9:00 AM and 9:00 PM). All groups successfully established the model on day 10 and started administration for 10 days. No eye drops were given to the normal control group and the model group. The administration regimen is shown in Figure 1.

[0175] Detection indicators and methods:

[0176] Intraocular pressure: Intraocular pressure was measured once daily (9:00 PM) on days 0, 2, 4, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of the experiment. The rabbit's upper and lower eyelids were gently pulled apart, the tonometer was brought close to the rabbit's eye, the distance was adjusted, and the measurement button was pressed lightly. The eyelids were not touched during the measurement. Six measurements were completed sequentially to obtain the individual measurement value and the average value (mmHg).

[0177] Experimental results:

[0178] Intraocular pressure (IOP): At all time points following drug administration during the study period, IOP values ​​in all treatment groups and example groups were significantly lower than those in the model group (Student paired t-test). Furthermore, compared to treatment group 1 and treatment group 2, the IOP of the ophthalmic composition solutions in examples 31-60 was significantly lower. Specifically, the intraocular pressure-lowering effects of the ophthalmic drug compositions in examples 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60 were significantly better than those in examples 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, and 55. The ophthalmic drug compositions in groups 57 and 59; however, there were no significant differences in the measured values ​​and changes in IOP among groups 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, and no significant differences in the measured values ​​and changes in IOP among groups 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60.

[0179] Table 31. Measured intraocular pressure values ​​in rabbits of each group after 10 consecutive days of drug administration, starting from day 10.

[0180] Table 32. Changes in intraocular pressure in rabbits in each group after 10 consecutive days of drug administration, starting from day 10.

[0181] Figures 4-1 and 4-2 show the ophthalmic pharmaceutical composition solutions and positive control drugs of Examples 31-60 of the present invention. The eye drops were administered once a day starting from day 10 for 10 consecutive days. The measured intraocular pressure (IOP) values ​​(Figure 4-1) and IOP changes (Figure 4-2) of each group of rabbits were obtained on day 20. Among them, the results of intraocular pressure changes on day 20 showed that: compared with groups 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, treatment group 2 showed ****: P<0.0001; compared with groups 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60, treatment group 2 showed ****: P<0.0001; compared with groups 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60, groups 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, *: P<0.05.

[0182] Example 123: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using a Japanese white rabbit glaucoma model.

[0183] In this embodiment, a high intraocular pressure model was established by injecting compound carbomer (containing 0.3% carbomer and 0.025% dexamethasone by weight) into the anterior chamber. The eye drops prepared in Examples 61-90 were administered once a day to evaluate the treatment effect.

[0184] Experimental animals: 102 healthy male Japanese white rabbits, with an initial weight of 2.5-3.0 kg.

[0185] Experimental Groups:

[0186] Normal control group: No treatment was given.

[0187] Model group: A high intraocular pressure model was established, and no eye drops were administered.

[0188] Treatment Group 1: A high intraocular pressure model was established, and commercially available natedil eye drops were administered. Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the active ingredient netardil.

[0189] Treatment Group 2: A high intraocular pressure model was established, and commercially available carteolol hydrochloride eye drops were administered. Eye drops, a single-component preparation containing 2.0 parts by weight of the active ingredient carteolol.

[0190] Example 61: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and mesylate as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0191] Example 62: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and mesylate as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0192] Example 63: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and hydrobromic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0193] Example 64: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and hydrobromic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0194] Example 65: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and phosphoric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0195] Example 66: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and phosphoric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0196] Example 67: An ophthalmic drug composition solution containing sodium hyaluronate as the thickener and hydrochloric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0197] Example 68: An ophthalmic drug composition solution containing sodium hyaluronate as the thickener and hydrochloric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0198] Example 69: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and citric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0199] Example 70: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and citric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0200] Example 71: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and tartaric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0201] Example 72: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and tartaric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0202] Example 73: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and malic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0203] Example 74: An ophthalmic drug composition solution containing sodium hyaluronate as the thickener and malic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0204] Example 75: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and lactic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0205] Example 76: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and lactic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0206] Example 77: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and succinic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0207] Example 78: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and succinic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0208] Example 79: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and hydroiodic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0209] Example 80: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and hydroiodic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0210] Example 81: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and formic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0211] Example 82: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and formic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0212] Example 83: An ophthalmic drug composition solution containing sodium hyaluronate as the thickener and acetic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0213] Example 84: An ophthalmic drug composition solution containing sodium hyaluronate as the thickener and acetic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0214] Example 85: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and benzoic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0215] Example 86: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and benzoic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0216] Example 87: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and ethanesulfonic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0217] Example 88: An ophthalmic drug composition solution with sodium hyaluronate as the thickener and ethanesulfonic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0218] Example 89: An ophthalmic drug composition solution containing sodium hyaluronate as the thickener and oxalic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0219] Example 90: An ophthalmic drug composition solution containing sodium hyaluronate as the thickener and oxalic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0220] Model establishment: Rabbits in the normal control group received no treatment. The remaining 33 groups of white rabbits were anesthetized on day 0 by intravenous injection of urethane (0.8-1 g / kg) via the ear. Using a 1 ml syringe, 10 μl of aqueous humor was extracted from each anterior chamber, followed by the injection of 10 μl of a combined carbomer solution. Intraocular pressure was measured every two days, and clinical manifestations were observed. A successful model was characterized by anterior chamber opacity and significantly elevated intraocular pressure. A rabbit model of high intraocular pressure was successfully established after 10 days.

[0221] Dosage regimen: Based on currently available natedadil eye drops ( eye drops) and commercially available carteolol hydrochloride eye drops ( The clinical dosing regimen for eye drops was divided into the following groups in this experiment: (1) Treatment group 1: commercially available natedadil eye drops ( (1) Eye drops), 50 μL per eye each time, once a day (9:00 PM); (2) Treatment group 2: commercially available carteolol hydrochloride eye drops ( (3) Examples 1-30: 50 μL per eye, once daily (9:00 AM and 9:00 PM). All groups successfully established the model on day 10 and started administration for 10 days. No eye drops were given to the normal control group and the model group. The administration regimen is shown in Figure 1.

[0222] Detection indicators and methods:

[0223] Intraocular pressure: Intraocular pressure was measured once daily (9:00 PM) on days 0, 2, 4, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of the experiment. The rabbit's upper and lower eyelids were gently pulled apart, the tonometer was brought close to the rabbit's eye, the distance was adjusted, and the measurement button was pressed lightly. The eyelids were not touched during the measurement. Six measurements were completed sequentially to obtain the individual measurement value and the average value (mmHg).

[0224] Experimental results:

[0225] Intraocular pressure (IOP): At all time points following drug administration during the study period, IOP values ​​in all treatment groups and example groups were significantly lower than those in the model group (Student paired t-test). Furthermore, compared to treatment group 1 and treatment group 2, the IOP of the ophthalmic composition solutions in examples 61-90 was significantly lower. Specifically, the intraocular pressure-lowering effects of the ophthalmic drug compositions in examples 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, and 90 were significantly better than those in examples 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, and 85. The ophthalmic drug compositions in groups 87 and 89; however, there were no significant differences in the measured values ​​and changes in IOP among groups 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, and 89, and no significant differences in the measured values ​​and changes in IOP among groups 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, and 90.

[0226] Table 33. Measured intraocular pressure values ​​in rabbits of each group after 10 consecutive days of drug administration, starting from day 10.

[0227] Table 34. Changes in intraocular pressure in rabbits in each group after 10 consecutive days of drug administration, starting from day 10.

[0228] Figures 6-1 and 6-2 show the ophthalmic pharmaceutical composition solution and positive control drug of Examples 61-90 of the present invention. The eye drops were administered once a day starting from day 10 for 10 consecutive days. The changes in intraocular pressure (IOP) in each group of rabbits were measured on day 20 (Figure 6-1) and the measured IOP values ​​(Figure 6-2) were plotted in a bar graph. Among them, the intraocular pressure changes showed that on day 20: compared with groups 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, and 89, treatment group 2 showed a significant difference (P<0.001); compared with groups 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, and 90, treatment group 2 showed a significant difference (P<0.0001); compared with groups 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, and 90, treatment group 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, and 90, treatment group 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, and 89, treatment group 61, 63, 65, 67, 69, treatment group 61, 73, 75, 77, 79, 81, 83, 85, 87, and 89, treatment group 61, 63, 65, 67, and 89 showed a significant difference (P<0.05).

[0229] Example 124: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using a Japanese white rabbit glaucoma model.

[0230] In this embodiment, a high intraocular pressure model was established by injecting compound carbomer (containing 0.3% carbomer and 0.025% dexamethasone by weight) into the anterior chamber. The eye drops prepared in Examples 91-120 were administered once a day to evaluate the treatment effect.

[0231] Experimental animals: 102 healthy male Japanese white rabbits, with an initial weight of 2.5-3.0 kg.

[0232] Experimental Groups:

[0233] Normal control group: No treatment was given.

[0234] Model group: A high intraocular pressure model was established, and no eye drops were administered.

[0235] Treatment Group 1: A high intraocular pressure model was established, and commercially available natedil eye drops were administered. Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the active ingredient netardil.

[0236] Treatment Group 2: A high intraocular pressure model was established, and commercially available carteolol hydrochloride eye drops were administered. Eye drops, a single-component preparation containing 2.0 parts by weight of the active ingredient carteolol.

[0237] Example 91: An ophthalmic drug composition solution without thickeners and with mesylic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0238] Example 92: An ophthalmic pharmaceutical composition solution without thickeners and with mesylate as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0239] Example 93: An ophthalmic drug composition solution without thickeners and with hydrobromic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0240] Example 94: An ophthalmic drug composition solution without thickeners and with hydrobromic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0241] Example 95: An ophthalmic pharmaceutical composition solution without thickeners and with phosphoric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of natedil).

[0242] Example 96: An ophthalmic drug composition solution without thickener and with phosphoric acid as pH adjuster (a dual-combination preparation containing 2.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0243] Example 97: An ophthalmic drug composition solution without thickeners and with hydrochloric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0244] Example 98: An ophthalmic drug composition solution without thickeners and with hydrochloric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0245] Example 99: An ophthalmic pharmaceutical composition solution without thickeners and with citric acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0246] Example 100: An ophthalmic pharmaceutical composition solution without thickeners and with citric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0247] Example 101: An ophthalmic drug composition solution without thickener and with tartaric acid as pH adjuster (a dual-combination preparation containing 1.0 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0248] Example 102: An ophthalmic pharmaceutical composition solution without thickeners and with tartaric acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0249] Example 103: An ophthalmic drug composition solution without thickeners and with malic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0250] Example 104: An ophthalmic pharmaceutical composition solution without thickeners and with malic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0251] Example 105: An ophthalmic drug composition solution without thickeners and with lactic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0252] Example 106: An ophthalmic drug composition solution without thickeners and with lactic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0253] Example 107: An ophthalmic drug composition solution without thickeners and with succinic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0254] Example 108: An ophthalmic drug composition solution without thickeners and with succinic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0255] Example 109: An ophthalmic drug composition solution without thickeners and with hydroiodic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0256] Example 110: An ophthalmic drug composition solution without thickeners and with hydroiodic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0257] Example 111: An ophthalmic drug composition solution without thickeners and with formic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0258] Example 112: An ophthalmic drug composition solution without thickeners and with formic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0259] Example 113: An ophthalmic drug composition solution without thickener and with acetic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0260] Example 114: An ophthalmic pharmaceutical composition solution without thickeners and with acetic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0261] Example 115: An ophthalmic drug composition solution without thickener and with benzoic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0262] Example 116: An ophthalmic drug composition solution without thickeners and with benzoic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0263] Example 117: An ophthalmic drug composition solution without thickeners and with ethanesulfonic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0264] Example 118: An ophthalmic drug composition solution without thickeners and with ethanesulfonic acid as the pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0265] Example 119: An ophthalmic drug composition solution without thickeners and with oxalic acid as the pH adjuster (a dual-combination preparation containing 1.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0266] Example 120: An ophthalmic drug composition solution without thickener and with oxalic acid as pH adjuster (a dual-combination preparation containing 2.0 parts by weight of the active ingredient carteolol and 0.02 parts by weight of netardil).

[0267] Model establishment: Rabbits in the normal control group received no treatment. The remaining 33 groups of white rabbits were anesthetized on day 0 by intravenous injection of urethane (0.8-1 g / kg) via the ear. Using a 1 ml syringe, 10 μl of aqueous humor was extracted from each anterior chamber, followed by the injection of 10 μl of a combined carbomer solution. Intraocular pressure was measured every two days, and clinical manifestations were observed. A successful model was characterized by anterior chamber opacity and significantly elevated intraocular pressure. A rabbit model of high intraocular pressure was successfully established after 10 days.

[0268] Dosage regimen: Based on currently available natedadil eye drops ( eye drops) and commercially available carteolol hydrochloride eye drops ( The clinical dosing regimen for eye drops was divided into the following groups in this experiment: (1) Treatment group 1: commercially available natedadil eye drops ( (1) Eye drops), 50 μL per eye each time, once a day (9:00 PM); (2) Treatment group 2: commercially available carteolol hydrochloride eye drops ( (3) Examples 1-30: 50 μL per eye, once daily (9:00 AM and 9:00 PM). All groups successfully established the model on day 10 and started administration for 10 days. No eye drops were given to the normal control group and the model group. The administration regimen is shown in Figure 1.

[0269] Detection indicators and methods:

[0270] Intraocular pressure: Intraocular pressure was measured once daily (9:00 PM) on days 0, 2, 4, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of the experiment. The rabbit's upper and lower eyelids were gently pulled apart, the tonometer was brought close to the rabbit's eye, the distance was adjusted, and the measurement button was pressed lightly. The eyelids were not touched during the measurement. Six measurements were completed sequentially to obtain the individual measurement value and the average value (mmHg).

[0271] Experimental results:

[0272] Intraocular pressure (IOP): At all time points following administration during the study period, IOP values ​​in all treatment groups and example groups were significantly lower than in the model group (Student paired t-test). Furthermore, compared to treatment group 1 and treatment group 2, the IOP of the ophthalmic composition solutions in examples 91-120 was significantly lower. Specifically, the intraocular pressure-lowering effects of the ophthalmic drug compositions in examples 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, and 120 were significantly better than those in examples 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, and 1... The ophthalmic drug compositions in groups 17 and 119; however, there were no significant differences in the measured values ​​and changes in IOP of groups 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, and 119, and no significant differences in the measured values ​​and changes in IOP of groups 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, and 120.

[0273] Table 35 shows the measured intraocular pressure values ​​of rabbits in each group after 10 consecutive days of drug administration, starting from day 10.

[0274] Table 36 shows the changes in intraocular pressure in rabbits in each group after 10 consecutive days of drug administration, starting from day 10.

[0275] Figures 8-1 and 8-2 show the ophthalmic pharmaceutical composition solutions of Examples 91-120 of the present invention without the addition of a thickener and the positive control drug. The eye drops were administered once daily for 10 consecutive days, starting on day 10. A bar chart was created using the intraocular pressure changes (Figure 8-1) and measured intraocular pressure (Figure 8-2) data for each group of rabbits on day 20. The results showed that on day 20: Treatment group 2 was significantly different from groups 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, and 119*: P < 0.05; Treatment group 2 was also significantly different from groups 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, and 116. Compared with groups 118 and 120**: P<0.01; Compared with groups 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, and 119*: P<0.05.

[0276] Figures 9-1 and 9-2 show the significant differences in intraocular pressure changes on day 20 between the ophthalmic drug composition solutions without thickener and those with hydroxypropyl methylcellulose (HPMC). Figure 9-1 represents the ophthalmic drug composition solution with 1% carteolol, and Figure 9-2 represents the ophthalmic drug composition solution with 2% carteolol. The results indicate that the 1% carteolol HPMC group was significantly different from the group without thickener (P<0.01); the 2% carteolol HPMC group was significantly different from the group without thickener (P<0.01).

[0277] Figures 10-1 and 10-2 show the significant differences in intraocular pressure changes on day 20 between the ophthalmic drug composition solutions without thickener and those with polyethylene glycol (PEG). Figure 10-1 represents the ophthalmic drug composition solution with 1% carteolol, and Figure 10-2 represents the ophthalmic drug composition solution with 2% carteolol. The results indicate that the 1% carteolol PEG group was significantly different from the group without thickener (P < 0.001); the 2% carteolol PEG group was significantly different from the group without thickener (P < 0.01).

[0278] Figures 11-1 and 11-2 show the significant differences in intraocular pressure changes on day 20 between the ophthalmic drug composition solutions without thickener and those with sodium hyaluronate (HA). Figure 11-1 shows the ophthalmic drug composition solution with 1% carteolol, and Figure 11-2 shows the ophthalmic drug composition solution with 2% carteolol. The results indicate that compared to the group without thickener, the 1% carteolol HA group**: P < 0.01; compared to the group without thickener, the 2% carteolol HA group*: P < 0.05. All references to this invention are incorporated herein by reference as if each reference were individually incorporated by reference.

[0279] Examples 126-129: Dual-compound eye drops prepared using hydroxypropyl methylcellulose as a thickener and different pH adjusters

[0280] Table 37. The preparation and formulation methods of topical ophthalmic drug composition solutions for lowering intraocular pressure are as follows:

[0281] The preparation process is as follows: (1) Weigh 90% of the prescription amount of water for injection, add the prescription amount of timolol, boric acid, mannitol, natedil and hydroxypropyl methylcellulose, add different pH adjusters, stir and adjust the pH to 4.5-5.4; (2) Add water for injection to the full prescription amount, stir evenly and make the volume reach 100%; (3) Put the solution from step 2 into a low-density polyethylene pharmaceutical eye drop bottle and study its stability under different storage temperature conditions.

[0282] Table 38. Content of each active pharmaceutical ingredient in Examples 126-129 after storage at 5°C for 24 months.

[0283] Table 39. Commercially available eye drops stored at 5°C for 24 months (…) Content of each active ingredient in eye drops

[0284] According to Examples 126-129, formulations containing netardil and timolol exhibited good stability for 24 months under storage conditions at 5°C, meeting the requirements for commercially available eye drops ( Requirements for storage conditions of eye drops before opening.

[0285] Table 4. Content of each active pharmaceutical ingredient in Examples 126-129 after storage at 25°C for 6 weeks.

[0286] Table 40. Commercially available eye drops stored at 25°C for 6 weeks (…) Content of each active ingredient in eye drops

[0287] According to Examples 126-129, formulations containing netardil and timolol exhibited good stability for 6 weeks under storage conditions at 25°C, meeting the requirements for commercially available eye drops ( Requirements for storage conditions of eye drops after opening.

[0288] Table 41. Content of each active pharmaceutical ingredient in Examples 126-129 after storage at 40°C for 14 days.

[0289] Table 42. Commercially available eye drops stored at 40℃ for 14 days (…) Content of each main ingredient in eye drops

[0290] According to Examples 126-129, formulations containing netardil and timolol exhibited good stability for 14 days under storage conditions at 40°C, meeting the requirements for commercially available eye drops ( (Eye drops) Short-term deviation from storage requirements.

[0291] Examples 130-133: Two-component eye drops without thickeners prepared with different pH adjusters

[0292] Table 43. The preparation and formulation methods of topical ophthalmic drug composition solutions for lowering intraocular pressure are as follows:

[0293] The preparation process is as follows: (1) Weigh 90% of the prescription amount of water for injection, add the prescription amount of timolol, boric acid, mannitol and natedil, add different pH adjusters, stir and adjust the pH to 4.5-5.4; (2) Add water for injection to the full prescription amount, stir evenly and make the volume reach 100%; (3) Put the solution in step 2 into a low-density polyethylene pharmaceutical eye drop bottle. After testing, the composition under different storage temperature conditions has good stability.

[0294] Example 134: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using a Japanese white rabbit glaucoma model.

[0295] In this embodiment, a high intraocular pressure model was established by injecting compound carbomer (containing 0.3% carbomer and 0.025% dexamethasone by weight) into the anterior chamber. The eye drops prepared in Examples 126-129 were administered once a day to evaluate the treatment effect.

[0296] Experimental animals: 102 healthy male Japanese white rabbits, with an initial weight of 2.5-3.0 kg.

[0297] Experimental Groups:

[0298] Normal control group: No treatment was given.

[0299] Model group: A high intraocular pressure model was established, and no eye drops were administered.

[0300] Treatment Group 1: A high intraocular pressure model was established, and commercially available natedil eye drops were administered. Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the active ingredient netardil.

[0301] Treatment group 3: A high intraocular pressure model was established, and commercially available timolol maleate eye drops were administered. Eye drops, a single-ingredient preparation containing 0.5 parts by weight of the active ingredient timolol.

[0302] Example 126: An ophthalmic drug composition solution containing hydroxypropyl methylcellulose as the thickener and mesylate as the pH adjuster (a dual-combination preparation containing 0.25 parts by weight of carteolol and 0.02 parts by weight of netardil).

[0303] Example 127: An ophthalmic drug composition solution containing 0.5 parts by weight of carteolol and 0.02 parts by weight of natedil as the pH adjuster (a dual-combination preparation). The thickener is hydroxypropyl methylcellulose and the pH adjuster is mesylate.

[0304] Example 128: An ophthalmic drug composition solution containing 0.25 parts by weight of carteolol and 0.02 parts by weight of netardil as the pH adjuster.

[0305] Example 129: An ophthalmic drug composition solution containing 0.5 parts by weight of carteolol and 0.02 parts by weight of netardil as the pH adjuster (a dual-combination preparation). The thickener is hydroxypropyl methylcellulose and the pH adjuster is maleic acid.

[0306] Model establishment: Rabbits in the normal control group received no treatment. The remaining seven groups of white rabbits were anesthetized on day 0 by intravenous injection of urethane (0.8-1 g / kg) via the ear. Using a 1 ml syringe, 10 μl of aqueous humor was extracted from each anterior chamber, followed by the injection of 10 μl of a combined carbomer solution. Intraocular pressure was measured every two days, and clinical manifestations were observed. A successful model was characterized by anterior chamber opacity and significantly elevated intraocular pressure. A rabbit model of high intraocular pressure was successfully established after 10 days.

[0307] Dosage regimen: Based on currently available natedadil eye drops ( Eye drops) and commercially available timolol maleate eye drops ( The clinical dosing regimen for eye drops was divided into the following groups in this experiment: (1) Treatment group 1: commercially available natedadil eye drops ( (1) Eye drops), 50 μL per eye each time, once a day (9:00 PM); (2) Treatment group 3: commercially available timolol maleate eye drops ( (3) Examples 126-129: 50 μL per eye, once daily (9:00 PM). All groups successfully established the model on day 10 and started administration for 10 days. The normal control group and the model group did not receive eye drops. The administration regimen is shown in Figure 1.

[0308] Detection indicators and methods:

[0309] Intraocular pressure: Intraocular pressure was measured once daily (9:00 PM) on days 0, 2, 4, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of the experiment. The rabbit's upper and lower eyelids were gently pulled apart, the tonometer was brought close to the rabbit's eye, the distance was adjusted, and the measurement button was pressed lightly. The eyelids were not touched during the measurement. Six measurements were completed sequentially to obtain the individual measurement value and the average value (mmHg).

[0310] Experimental results:

[0311] Intraocular pressure (IOP): At all post-drug administration time points during the study period, IOP values ​​in all treatment groups and example groups were significantly reduced compared to the model group (Student paired t-test). Simultaneously, compared to treatment groups 1 and 3, the IOP of the ophthalmic composition solutions in examples 126-129 was significantly reduced. Specifically, the intraocular pressure-lowering effects of the ophthalmic drug compositions in examples 127 and 129 were significantly better than those in examples 126 and 128. However, there were no significant differences in the measured IOP values ​​and IOP changes between examples 126 and 128, and between examples 127 and 129.

[0312] Table 44. Measured intraocular pressure values ​​in rabbits of each group after 10 consecutive days of drug administration, starting from day 10.

[0313] Table 45. Differences between measured intraocular pressure (IOP) values ​​and initial IOP (measured IOP on day 10) in each group of rabbits after 10 consecutive days of drug administration starting from day 10.

[0314] Figure 12 shows the ophthalmic pharmaceutical composition solutions of Examples 126-129 and the positive control drug ( Intraocular pressure (IOP) and IOP differential were measured after administration of the eye drops. The medication was administered once daily for 10 consecutive days, and a bar chart was created on day 20 showing the measured IOP values ​​(Figure 2-1) and IOP differential values ​​(Figure 2-2) for each group of rabbits. The IOP differential values ​​showed that on day 20: Treatment group 3 was significantly lower than groups 126 and 128 (P<0.001); Treatment group 3 was significantly lower than groups 127 and 129 (P<0.0001); Groups 127 and 129 were significantly lower than groups 126 and 128 (P<0.001).

[0315] Example 135: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using a Japanese white rabbit glaucoma model.

[0316] In this embodiment, a high intraocular pressure model was established by injecting compound carbomer (containing 0.3% carbomer and 0.025% dexamethasone by weight) into the anterior chamber. The eye drops prepared in Examples 130-133 were administered once a day to evaluate the treatment effect.

[0317] Experimental animals: 102 healthy male Japanese white rabbits, with an initial weight of 2.5-3.0 kg.

[0318] Experimental Groups:

[0319] Normal control group: No treatment was given.

[0320] Model group: A high intraocular pressure model was established, and no eye drops were administered.

[0321] Treatment Group 1: A high intraocular pressure model was established, and commercially available natedil eye drops were administered. Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the active ingredient netardil.

[0322] Treatment group 3: A high intraocular pressure model was established, and commercially available timolol maleate eye drops were administered. Eye drops, a single-component preparation containing 0.5 parts by weight of the active ingredient carteolol.

[0323] Example 130: An ophthalmic pharmaceutical composition solution without thickeners and with mesylate as the pH adjuster (a dual-combination preparation containing 0.25 parts by weight of the active ingredient timolol and 0.02 parts by weight of netardil).

[0324] Example 131: An ophthalmic pharmaceutical composition solution without thickeners, with mesylate as the pH adjuster (a dual-combination preparation containing 0.5 parts by weight of the active ingredient timolol and 0.02 parts by weight of netardil).

[0325] Example 132: An ophthalmic drug composition solution without thickeners and with maleic acid as the pH adjuster (a dual-combination preparation containing 0.25 parts by weight of the active ingredient timolol and 0.02 parts by weight of netardil).

[0326] Example 133: An ophthalmic drug composition solution without thickeners and with maleic acid as the pH adjuster (a dual-combination preparation containing 0.5 parts by weight of the active ingredient timolol and 0.02 parts by weight of netardil).

[0327] Model establishment: Rabbits in the normal control group received no treatment. The remaining seven groups of white rabbits were anesthetized on day 0 by intravenous injection of urethane (0.8-1 g / kg) via the ear. Using a 1 ml syringe, 10 μl of aqueous humor was extracted from each anterior chamber, followed by the injection of 10 μl of a combined carbomer solution. Intraocular pressure was measured every two days, and clinical manifestations were observed. A successful model was characterized by anterior chamber opacity and significantly elevated intraocular pressure. A rabbit model of high intraocular pressure was successfully established after 10 days.

[0328] Dosage regimen: Based on currently available natedadil eye drops ( Eye drops) and commercially available timolol maleate eye drops ( The clinical dosing regimen for eye drops was divided into the following groups in this experiment: (1) Treatment group 1: commercially available natedadil eye drops ( (1) Eye drops), 50 μL per eye each time, once a day (9:00 PM); (2) Treatment group 3: commercially available timolol maleate eye drops ( (3) Examples 1-30: 50 μL per eye, once daily (9:00 AM and 9:00 PM). All groups successfully established the model on day 10 and started administration for 10 days. No eye drops were given to the normal control group and the model group. The administration regimen is shown in Figure 1.

[0329] Detection indicators and methods:

[0330] Intraocular pressure: Intraocular pressure was measured once daily (9:00 PM) on days 0, 2, 4, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of the experiment. The rabbit's upper and lower eyelids were gently pulled apart, the tonometer was brought close to the rabbit's eye, the distance was adjusted, and the measurement button was pressed lightly. The eyelids were not touched during the measurement. Six measurements were completed sequentially to obtain the individual measurement value and the average value (mmHg).

[0331] Experimental results:

[0332] Intraocular pressure (IOP): At all time points following drug administration during the study period, IOP values ​​in all treatment groups and example groups were significantly reduced compared to the model group (Student paired t-test). Furthermore, compared to treatment groups 1 and 3, the IOP of the ophthalmic composition solutions in examples 130-133 was significantly reduced. Specifically, the intraocular pressure-lowering effects of the ophthalmic drug compositions in examples 131 and 133 were significantly better than those in examples 130 and 132. However, there were no significant differences in the measured IOP values ​​and IOP changes between examples 130 and 132, and between examples 131 and 133.

[0333] Table 46 shows the measured intraocular pressure values ​​of rabbits in each group after 10 consecutive days of drug administration, starting from day 10.

[0334] Table 47 shows the changes in intraocular pressure in rabbits in each group after 10 consecutive days of drug administration, starting from day 10.

[0335] Figures 13-1 and 13-2 show the ophthalmic drug composition solutions of Examples 126-129 of the present invention with added hydroxypropyl methylcellulose (HPMC) and the positive control drug ( The eye drops were administered once daily for 10 consecutive days, starting on day 10. A bar chart was created using the intraocular pressure changes (Figure 13-1) and measured intraocular pressure (Figure 13-2) data for each group of rabbits on day 20. The results showed that on day 20: Treatment group 3 was significantly different from groups 126 and 128 (P<0.001); Treatment group 3 was significantly different from groups 127 and 129 (P<0.001); Group 126 was significantly different from group 127 (P<0.05); Group 128 was significantly different from group 129 (P<0.05).

[0336] Figures 14-1 and 14-2 show the significant differences in intraocular pressure changes on day 20 between the ophthalmic drug composition solutions without thickener and those with hydroxypropyl methylcellulose (HPMC). Figure 14-1 represents the ophthalmic drug composition solution with 0.25% timolol, and Figure 14-2 represents the ophthalmic drug composition solution with 0.5% timolol. The results indicate that the 0.25% timolol HPMC group was significantly different from the group without thickener (P < 0.001); the 0.5% timolol HPMC group was significantly different from the group without thickener (P < 0.001). All references to this invention are incorporated herein by reference as if each reference were individually incorporated by reference.

Claims

1. A combination pharmaceutical composition for treating glaucoma, characterized by comprising, The pharmaceutical composition comprises: carteolol or timolol, netardil, buffer, tension agent, pH adjuster, thickener, and water for injection.

2. The double combination pharmaceutical composition according to claim 1, wherein The ophthalmic drug composition comprises (1) 0.02% w / v to 4.0% w / v of free carteolol base or free timolol base; (2) Nettadil free base at 0.005% w / v to 0.1% w / v; (3) Tensioning agents ranging from 0.01% w / v to 10.0% w / v; (4) 0.01% w / v to 1.0% w / v buffer; (5) Thickener of 0.1% w / v to 1.0% w / v; v is the volume of the composition system after the addition of water for injection; (6) Adjust the pH to 4.5 to 5.4 using a pH adjuster; (7) The osmotic pressure is 280 to 320 mOsmol / kg.

3. The combination drug composition of claim 2, wherein The ophthalmic drug composition comprises (1) 0.02% w / v to 2.0% w / v of free carteolol base or free timolol base; (2) Nettadil free base from 0.005% w / v to 0.02% w / v; (3) Tensioning agents ranging from 0.01% w / v to 10.0% w / v; (4) 0.01% w / v to 1.0% w / v buffer; (5) Thickener of 0.1% w / v to 1.0% w / v; v is the volume of the composition system after the addition of water for injection; (6) Adjust the pH to 4.5 to 5.4 using a pH adjuster; (7) The osmotic pressure is 280 to 320 mOsmol / kg.

4. The combination drug composition of claim 1, wherein The buffer is selected from boric acid and borates, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous sodium phosphate, citric acid or its salts, carbonic acid, gluconic acid or its salts, acetic acid or its salts, phosphoric acid or its salts, or any combination thereof.

5. The combination drug composition of claim 1, wherein The borate is borax.

6. The dual-combination drug composition as described in claim 1, characterized in that, The tensioning agent is selected from glycerol, sorbitol, mannitol, propylene glycol, erythritol, arabinitol, xylitol, ribitol, galactitol, polyethylene glycol, lactotol, mannitol, dextrose, sodium chloride, potassium chloride and calcium chloride, or any combination thereof.

7. The dual-combination drug composition as described in claim 1, characterized in that, The pH adjuster is selected from one or more of the following: methanesulfonic acid, hydrobromic acid, phosphoric acid, hydrochloric acid, citric acid, tartaric acid, malic acid, lactic acid, succinic acid, hydroiodic acid, formic acid, acetic acid, benzoic acid, ethanesulfonic acid, oxalic acid, sodium oxychloride, and tromethamine.

8. The dual-combination drug composition as described in claim 1, characterized in that, The thickener is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium hydroxyethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, sodium alginate, chitosan, and polyvinylpyrrolidone.

9. Use of the dual-combination pharmaceutical composition according to any one of claims 1-8 in the preparation of a medicament for the prevention or treatment of eye diseases.

10. The use as described in claim 9, characterized in that, The eye disease is glaucoma, high intraocular pressure, and / or related symptoms.

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