Pharmaceutical composition for treating glaucoma and application thereof

Abstract

According to the pharmaceutical composition for treating glaucoma and intraocular hypertension provided by the invention, the stability of the pharmaceutical composition is obviously improved through a salt changing technology; the pharmaceutical composition is prepared from netasdil free alkali or a pharmaceutically acceptable salt thereof, timolol free alkali or a pharmaceutically acceptable salt thereof, and dorzolamide free alkali or a pharmaceutically acceptable salt thereof. The pharmaceutical composition has excellent stability when the pH value is 4.5-5.4. According to the present invention, the effective dose of the pharmaceutical composition is applied to the eyes of the patient requiring the intraocular pressure at the sleeping time or at the time close to the sleeping time once a day, such that the intraocular pressure can be efficiently and rapidly reduced so as to maintain the intraocular pressure in the physiological range for a long time, the side effect is small, and the patient compliance is high.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to an ophthalmic pharmaceutical composition and use thereof in preparing a medicine for preventing or treating glaucoma or for reducing intraocular pressure. Background Art

[0002] Glaucoma is a common ophthalmological disease. Pathologically elevated intraocular pressure and insufficient blood supply to the optic nerve are primary risk factors. This elevated intraocular pressure compresses the optic nerve, causing thinning of the optic nerve fiber layer and damage to optic nerve cells, leading to decreased vision, visual field loss, and optic atrophy. Severe glaucoma can even lead to blindness. Therefore, glaucoma has become the leading cause of blindness in humans.

[0003] Currently, the commonly used single-ingredient preparations include the following categories: (1) Rho kinase inhibitors: IOP-lowering drugs that act directly on the trabecular meshwork, primarily by affecting the cytoskeleton to change trabecular meshwork cell morphology, cell motility, cytokinesis, and smooth muscle contraction, thereby increasing aqueous humor outflow and lowering intraocular pressure. At the same time, Rho kinase inhibitors have the effects of improving retinal vascular perfusion, promoting optic nerve regeneration, protecting the optic nerve, and reducing bleb scarring. The most commonly used drug in clinical practice is natriuretic peptide mesylate. (2) Adrenergic β-receptor blockers: These can reduce aqueous humor production and promote aqueous humor drainage and discharge by blocking β-receptors, resulting in a strong and sustained IOP-lowering effect and effective control of IOP. Commonly used drugs in clinical practice include timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, metipranolol hydrochloride, etc.; (3) Carbonic anhydrase inhibitors: by selectively binding to and blocking the α1A-adrenergic receptors in the eye, they reduce the release of catecholamines such as norepinephrine in the uveal tissue, thereby reducing the production of aqueous humor. Commonly used drugs in clinical practice include dorzolamide hydrochloride, etc.

[0004] Glaucoma is a chronic eye disease requiring long-term medication. Currently available single and compound formulations have numerous limitations, such as frequent dosing, high preservative exposure, and poor patient compliance. Based on this, the present invention combines timolol, natridil, and dorzolamide into a fixed triple compound formulation, which has the following advantages: (1) it can lower intraocular pressure through different mechanisms of action, with a significant and reliable therapeutic effect; (2) it can be administered once daily, reducing the number of doses, avoiding the use of preservatives, reducing the occurrence of ocular side effects, and significantly improving patient compliance.

[0005] With reference to the relevant literature, it can be seen that natridil has good stability in a boric acid-sodium borate buffer solution having a pH lower than 5.4, but maleic acid, hydrochloric acid, timolol maleate and dorzolamide hydrochloride all affect the stability of natridil in the solution. Based on this, the present invention improves the compatibility of timolol maleate, dorzolamide hydrochloride and natridil dimethanesulfonate by a salt engineering strategy, that is, by preparing natridil into natrid maleate or natrid hydrochloride, timolol, dorzolamide and natridil have good compatibility in an aqueous solution for injection having a pH value of 4.5-5.4. The triple compound preparation has the advantages of a strong intraocular pressure lowering effect and once-a-day administration, and is expected to solve the existing triple compound preparation (Krytantek Dorzolamide 2% / timolol 0.5% / brimonidine 0.2%) has serious adverse reactions and limited intraocular pressure-lowering effect. Summary of the Invention

[0006] In response to the shortcomings of existing single-ingredient preparations, dual-compound preparations, and triple-compound preparations for treating glaucoma, such as poor efficacy, multiple side effects, and poor patient compliance, the present invention provides a triple-compound pharmaceutical composition simultaneously comprising timolol, dorzolamide, and netadil. The incompatibility problem of timolol maleate, dorzolamide hydrochloride, and netadil mesylate is successfully solved through a salt engineering strategy. In addition, the pharmaceutical composition of the present invention can more significantly reduce intraocular pressure than commercially available compound ophthalmic preparations.

[0007] That is, the present invention relates to the following contents.

[0008] (1) In one aspect, the present invention provides an ophthalmic pharmaceutical composition comprising nepamidil, dorzolamide and timolol as active pharmaceutical ingredients and a certain amount of a buffer, a tonicity agent, a preservative and a pH adjuster.

[0009] (2) The pharmaceutical composition according to (1) above, wherein the timolol is maleate, the dorzolamide is hydrochloride, and the nepamidil is in the form of a free base or any pharmaceutically acceptable salt thereof (except mesylate).

[0010] Preferred are netamic acid silicium maleate, netamic acid silicium sulfate, netamic acid silicium dihydrobromide, netamic acid silicium dihydrochloride, netamic acid silicium diformate or netamic acid silicium dinitrate.

[0011] (3) The pharmaceutical composition according to the above (1), wherein the nepacidil is in the form of dimesylate, and the timolol is in the form of a free base or any pharmaceutically acceptable salt thereof (except maleate).

[0012] Preferred are timolol mesylate, timolol sulfate, timolol hydrobromide, timolol phosphate, timolol nitrate, timolol citrate or timolol tartrate.

[0013] (4) The pharmaceutical composition according to the above (1), wherein the tonicity agent includes but is not limited to glycerol, sorbitol, mannitol, propylene glycol, erythritol, arabitol, xylitol, ribitol, galactitol, polyethylene glycol, lactitol and other sugar alcohols, sodium chloride, potassium chloride and calcium chloride, or any combination thereof.

[0014] (5) The pharmaceutical composition according to the above (1), wherein the buffer includes but is not limited to boric acid or its salts, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, sodium phosphate anhydrate, citric acid or its salts, gluconic acid or its salts, acetic acid or its salts, phosphoric acid or its salts, various amino acids such as glutamic acid and ε-aminocaproic acid and tris(hydroxymethyl)aminomethane buffer, or any combination thereof.

[0015] (6) The pharmaceutical composition according to the above (1), wherein examples of the pH adjuster include but are not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium bicarbonate, hydrochloric acid, citric acid or its salts, phosphoric acid or its salts, acetic acid or its salts, and tartaric acid or its salts.

[0016] (7) The pharmaceutical composition according to (1) to (6) above, comprising 0.5% w / v timolol.

[0017] (8) The pharmaceutical composition according to any one of (1) to (7), comprising 0.02% w / v of netadil.

[0018] (9) The pharmaceutical composition according to any one of (1) to (8) above, comprising 2% w / v dorzolamide.

[0019] (10) The pharmaceutical composition according to any one of (1) to (9), comprising 1.0% w / v to 10.0% w / v mannitol.

[0020] (11) The pharmaceutical composition according to any one of (1) to (10), comprising 0.05% w / v boric acid.

[0021] (12) The pharmaceutical composition according to any one of (1) to (11), which has an osmotic pressure of 280-320 mOsmol / kg.

[0022] (13) The pharmaceutical composition according to any one of (1) to (12), wherein the pH thereof is 4.5 to 5.4.

[0023] (14) According to the pharmaceutical composition described in (1) to (13) above, when stored at 5°C for 24 months, the content of each active pharmaceutical ingredient did not change significantly compared with that at day 0, and remained consistent with the storage conditions of commercially available eye drops before opening.

[0024] (15) The pharmaceutical composition described in (1) to (13) above, when stored at 25°C for 6 weeks, showed no significant change in the content of each active pharmaceutical ingredient compared to day 0, thus meeting the storage conditions for commercially available eye drops after opening.

[0025] (16) The pharmaceutical composition described in (1) to (13) above, when stored at 40°C for 14 days, showed no significant change in the content of each active pharmaceutical ingredient compared to day 0, thus meeting the requirements for short-term deviation from storage conditions for commercially available eye drops.

[0026] (17) In another aspect, the present invention provides the use of the pharmaceutical composition described in the first aspect above in the preparation of a drug for preventing or treating eye diseases.

[0027] (18) The use according to (17) above, wherein the eye disease is glaucoma or symptoms related thereto.

[0028] (19) In a third aspect, the present invention provides a use of the pharmaceutical composition described in the first aspect in the preparation of a drug for reducing intraocular pressure.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The salt-forming species of natrium natrium was changed by salt engineering strategy to solve the problem of drug incompatibility, thereby obtaining a solution containing timolol, dorzolamide and natrium natrium with excellent stability.

[0031] (2) On the other hand, the pharmaceutical composition solution provided by the present invention is useful in the preparation of drugs for preventing or treating eye diseases (especially glaucoma or its related symptoms) and for reducing intraocular pressure. The pharmaceutical composition of the present invention can more significantly reduce intraocular pressure than commercially available compound ophthalmic preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The ophthalmic pharmaceutical composition solutions of Examples 1-5 and the positive control drug treatment group 1 Dosage regimen.

[0033] Figure 2 The ophthalmic pharmaceutical composition solutions of Examples 1-5 and the positive control drug The drug was administered once a day starting from the 10th day for 10 consecutive days. The intraocular pressure changes of the rabbits in each group were measured on the 15th and 20th days ( Figure 2 A) and measured intraocular pressure ( Figure 2 B) is a bar graph made from the data. Among them, on the 20th day: &&& : P < 0.001, treatment group 1 compared with Example 1-5 groups; *** : P<0.001 compared with Example 5 group in Example 1-4 group. DETAILED DESCRIPTION

[0034] In the ophthalmic pharmaceutical composition of the present invention, netadil is in the form of a dimethanesulfonate salt, timolol is preferably in the form of a salt formed with a pharmaceutically acceptable acid (except maleic acid), and dorzolamide is preferably in the form of a salt formed with a pharmaceutically acceptable acid (except hydrochloric acid). Specific acids include methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid, citric acid, and tartaric acid, with methanesulfonic acid being more preferred.

[0035] Alternatively, in the ophthalmic pharmaceutical composition of the present invention, when timolol is a maleate salt and dorzolamide is a hydrochloride salt, nepamidil is preferably in the form of a salt formed with a pharmaceutically acceptable acid (except methanesulfonic acid). Specific examples of the acid include maleic acid, sulfuric acid, hydrobromic acid, hydrochloric acid, formic acid, and nitric acid, with maleic acid and hydrochloric acid being more preferred.

[0036] In the ophthalmic pharmaceutical composition of the present invention, the concentration of timolol free base or its salt is 0.5% w / v.

[0037] In the ophthalmic pharmaceutical composition of the present invention, the concentration of nepamidil free base or its salt is 0.02% w / v.

[0038] In the ophthalmic pharmaceutical composition of the present invention, the concentration of dorzolamide is 2% w / v.

[0039] In the ophthalmic pharmaceutical composition of the present invention, a tonicity agent may be included. Examples of tonicity agents include, but are not limited to, sodium chloride, potassium chloride, mannitol, dextrose, glycerol, or propylene glycol. Suitably, the tonicity agent may be present in the ophthalmic pharmaceutical composition in an amount of from about 0.01% w / v to about 10% w / v, or from about 1% w / v to about 10% w / v, or from about 2.5% w / v to about 7.5% w / v, or from about 4% w / v to about 6% w / v. The tonicity agent may suitably be mannitol.

[0040] In the ophthalmic pharmaceutical composition of the present invention, a buffering agent may be included. Suitable buffering agents include, but are not limited to, acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, pharmaceutically acceptable salts thereof, tromethamine, and combinations thereof. The buffering agent may be present in the ophthalmic composition in an amount of from about 0.01% w / v to about 1% w / v, or from about 0.1% w / v to about 0.9% w / v, or from about 0.3% w / v to about 0.8% w / v, or from about 0.4% w / v to about 0.6% w / v. The buffering agent may suitably be boric acid.

[0041] In the ophthalmic pharmaceutical composition of the present invention, a pH adjuster may be included in an amount 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.

[0042] Example

[0043] The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0044] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0045] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0046] Examples 1-5: Formulations containing natridil, timolol and dorzolamide

[0047] Table 1. Topical ophthalmic pharmaceutical composition solutions for reducing intraocular pressure were prepared and formulated as follows:

[0048]

[0049] The preparation process is as follows: weigh 95 mL of the prescribed amount of water for injection, add the prescribed amount of natriuretic peptide, timolol, dorzolamide and excipients, stir until completely dissolved, and adjust the pH to 4.5-5.4 with sodium hydroxide solution (10%). Add water for injection to the full prescribed amount, stir evenly and make the volume reach 100%, place it into a low-density polyethylene medicinal eye drop bottle, and study its stability under different storage temperature conditions.

[0050] Table 2. Content of each main drug component in Example 1-2 when stored at 5°C for 24 months

[0051]

[0052]

[0053] Table 3. Commercially available eye drops stored at 5°C for 24 months Content of each main drug component

[0054]

[0055] According to Examples 1-2, the preparation containing natriuretic acid, timolol and dorzolamide has good stability for 24 months under storage conditions of 5°C, which meets the requirements of commercially available eye drops. Requirements for storage conditions before opening.

[0056] Table 4. Content of each main drug component in Example 1-2 when stored at 25°C for 6 weeks

[0057]

[0058] Table 5. Commercially available eye drops stored at 25°C for 6 weeks Content of each main drug component

[0059]

[0060]

[0061] According to Examples 1-2, the preparation containing natriuretic acid, timolol and dorzolamide has good stability under storage conditions of 25°C for 6 weeks, which meets the requirements of commercially available eye drops. Requirements for storage conditions after opening.

[0062] Table 6. Content of each main drug component in Example 1-2 when stored at 40°C for 14 days

[0063]

[0064] Table 7. Commercially available eye drops stored at 40°C for 14 days. Content of each main drug ingredient

[0065]

[0066] According to Examples 1-5, the preparation containing natriuretic acid, timolol and dorzolamide has good stability for 14 days under storage conditions of 40°C, which meets the requirements of commercially available eye drops. Short-term deviations from storage conditions.

[0067] Example 6: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solutions of Examples 1-5 using the Japanese white rabbit glaucoma model

[0068] Experimental animals: Healthy male Japanese white rabbits (Shenyang Pharmaceutical University, license number: SYXK(Liao)2018-0009), initial body weight 2.5-3.0 kg, 3 rabbits / group.

[0069] Experimental groups:

[0070] Normal control group: no treatment.

[0071] Model group: The intraocular hypertension model was established without any eye drops.

[0072] Treatment group 1: establish an intraocular hypertension model and administer commercially available dorzolamide hydrochloride and timolol maleate eye drops

[0073] Group 1 of Example: A model of intraocular hypertension was established, and the ophthalmic pharmaceutical composition solution of Example 1 was administered.

[0074] Group 2 of Example: A model of intraocular hypertension was established, and the ophthalmic pharmaceutical composition solution of Example 2 was administered.

[0075] Group 3 of Example: A model of intraocular hypertension was established, and the ophthalmic pharmaceutical composition solution of Example 3 was administered.

[0076] Group 4 of Example: A model of intraocular hypertension was established, and the ophthalmic pharmaceutical composition solution of Example 4 was administered.

[0077] Group 5 of Example: An intraocular hypertension model was established, and the ophthalmic pharmaceutical composition solution of Example 5 was administered.

[0078] Model establishment: The normal control group rabbits did not receive any treatment. On day 0, rabbits in the other groups were injected with urethane 0.8-1g / kg into the ear vein. Under general anesthesia, 10μL of aqueous humor was removed from each anterior chamber of the eye using a 1mL syringe. 10μL of compound carbomer solution (containing 0.3% by weight of the main drug carbomer and 0.025% by weight of dexamethasone) was then injected. Intraocular pressure was measured every two days and clinical manifestations were observed. In a successful model, turbidity appeared in the anterior chamber and intraocular pressure was significantly increased. After 10 days, a rabbit model of intraocular hypertension was successfully established.

[0079] Dosage regimen: Based on the currently available dorzolamide hydrochloride and timolol maleate eye drops The clinical dosing regimen of this experiment was mainly divided into the following groups: (1) Treatment group 1: commercially available dorzolamide hydrochloride and timolol maleate eye drops 50 μL per eye, once a day (9:00 PM); (2) Example 1-5 group: Example 1-5 eye drops, 50 μL per eye, once a day (9:00 PM). All groups started to receive medication on the 10th day after the successful establishment of the model, and continued for 10 consecutive days. The normal control group and the model group did not receive any treatment. The medication regimen is as follows Figure 1 shown.

[0080] Detection indicators and methods:

[0081] Intraocular Pressure: IOP 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. Gently pull apart the upper and lower eyelids, place the tonometer close to the rabbit's eye, adjust the distance, and gently press the measurement button without touching the eyelid. Six measurements were performed sequentially to obtain the individual and average values (mmHg).

[0082] Experimental results:

[0083] Intraocular Pressure: At all post-dose time points during the study, IOP values were significantly lower in all treatment groups and the Example group compared to the Model group (Student paired t-test). Furthermore, IOP was significantly lower in Example 1, 2, 3, 4, and 5 groups compared to Treatment Group 1.

[0084] Table 8. Differences between the measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (measured intraocular pressure on the 10th day) after drug administration for 10 consecutive days starting from the 10th day

[0085]

[0086] Table 9. Intraocular pressure values of rabbits in each group on the 10th, 15th, and 20th days after drug administration for 10 consecutive days starting from the 10th day.

[0087]

[0088] Comparative Example 1: Preparation containing natacidil dimesylate, timolol maleate and dorzolamide hydrochloride

[0089] Table 10. Topical ophthalmic pharmaceutical composition solutions for reducing intraocular pressure were prepared and formulated as follows:

[0090]

[0091]

[0092] Preparation process: Refer to the preparation process described in Examples 1-5.

[0093] Table 11. Content of each main drug component in Comparative Example 1 when stored at 5°C for 7 days

[0094]

[0095] According to Comparative Example 1, the preparation containing netapidil dimethanesulfonate, timolol maleate and dorzolamide hydrochloride was incompatible under storage conditions of 5° C., and netapidil dimethanesulfonate precipitated.

[0096] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications fall within the scope of the claims and their equivalents, the present invention is intended to include such changes and modifications.

Claims

1. An ophthalmic pharmaceutical composition, characterized in that: The pharmaceutical composition is prepared from the following: (1) 0.5% w / v of (S)-1-(tert-butylamino)-3-[(4-morpholinyl-1,2,5-thiadiazol-3-yl)oxy]-2-propanol (timolol) free base or a pharmaceutically acceptable salt thereof; (2) 0.02% w / v of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (netacidil) free base or a pharmaceutically acceptable salt thereof; (3) 2% w / v of (2R,4R)-2-ethylamino-4-methyl-5,5-dioxo-5,7-dithiabicyclo[4.3.0]nona-8,10-diene-8-sulfonamide (dorzolamide) free base or a pharmaceutically acceptable salt thereof; (4) 0.01% w / v to 1.0% w / v buffer; (5) 0.01% w / v to 10.0% w / v tonicity agent; (6) pH adjuster; and (7) Water for injection.

2. The ophthalmic pharmaceutical composition according to claim 1, wherein: In the pharmaceutical composition, the nepamidil is dimethanesulfonate, the timolol or a pharmaceutically acceptable salt thereof is selected from timolol methanesulfonate, timolol sulfate, timolol hydrobromide, timolol phosphate, timolol nitrate, timolol citrate or timolol tartrate; the dorzolamide or a pharmaceutically acceptable salt thereof is selected from dorzolamide methanesulfonate, dorzolamide sulfate, dorzolamide hydrobromide, dorzolamide phosphate, dorzolamide nitrate, dorzolamide citrate or dorzolamide tartrate; or, In the pharmaceutical composition, the timolol is maleate, the dorzolamide is hydrochloride, and the nepamidil or its pharmaceutically acceptable salt is selected from nepamidil maleate, nepamidil sulfate, nepamidil dihydrobromide, nepamidil dihydrochloride, nepamidil diformate or nepamidil dinitrate.

3. The pharmaceutical composition according to claim 1 or claim 2, characterized in that: The osmotic pressure of the pharmaceutical composition is 280 to 320 mOsmol / kg.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that: The buffer is boric acid or a salt thereof, the tonicity agent is mannitol, and the pH regulator is selected from sodium hydroxide and / or hydrochloric acid.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The pharmaceutical composition contains no precipitate after being stored at 5°C for 24 months, and the content of each active pharmaceutical ingredient has no significant change compared with that at day zero; contains no precipitate after being stored at 25°C for 6 weeks, and the content of each active pharmaceutical ingredient has no significant change compared with that at day zero; and / or, contains no precipitate after being stored at 40°C for 14 days, and the content of each active pharmaceutical ingredient has no significant change compared with that at day zero.

6. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a medicament for preventing or treating an eye disease.

7. The use according to claim 6, wherein the eye disease is glaucoma or related symptoms thereof.

8. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a medicament for reducing intraocular pressure.

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