Transparent composite eye drops containing carbonic anhydrase inhibitor and timolol and preparation method thereof

Abstract

The present invention relates to a transparent composite eye drop containing a carbonic anhydrase inhibitor, timolol or a pharmaceutically acceptable salt thereof, and cyclodextrin or a derivative thereof as an anti-recrystallization agent, and to a method for preparing the same. The present invention relates to a transparent composite eye drop containing a carbonic anhydrase inhibitor, timolol or a pharmaceutically acceptable salt thereof, and cyclodextrin or a derivative thereof as an anti-recrystallization agent.

Description

Technical Field

[0001] This invention relates to a transparent compound eye drop containing a carbonic anhydrase inhibitor and timolol. Background Technology

[0002] Glaucoma is an eye disease characterized by a gradual increase in intraocular pressure. If left untreated, glaucoma can cause serious structural defects in the eye, particularly leading to reduced visual field and optic nerve atrophy due to damage to the optic disc. In some cases, the pathological phenomena are related to insufficient drainage of aqueous humor from the eye. Other factors, including aqueous humor production and pressure in the superior scleral veins, can also contribute to the development of the disease.

[0003] Dozolemide is an aromatic sulfonamide derivative, known as an effective carbonic anhydrase inhibitor in the treatment of elevated intraocular pressure. When carbonic anhydrase in the ciliary processes is inhibited, the rate of bicarbonate ion formation slows down, leading to the secretion of an aqueous humor into the eye. It is usually used in glaucoma treatment in the form of acid addition salts such as hydrochloride.

[0004] On the other hand, timolol is an effective β-adrenergic receptor blocker in the treatment of intraocular pressure, inhibiting the production of aqueous humor by reducing the inflow of aqueous humor. It is usually used in the maleate form in the treatment of glaucoma.

[0005] In 1998, a glaucoma treatment formulation containing 2.0% dazolamide and 0.5% timolol (product name: Cosopt, Merck & Co., Ltd. (MSD)) received FDA approval and is currently used clinically. Cosopt is a formulation obtained by dissolving dazolamide hydrochloride and timolol maleate in sterile water with hydroxyethyl cellulose, mannitol, sodium citrate, sodium hydroxide, and benzalkonium chloride. It is used to treat glaucoma patients, and common side effects include burning, stinging, redness, blurred vision, tearing, or itching. When administered to patients, side effects such as burning and stinging may reduce medication adherence, presumably due to the acidic pH and pain originating from the active ingredients.

[0006] Carbonic anhydrase inhibitors include not only dzodamine hydrochloride, but also methazolamide, brinzolamide, dichlorphenamide, and acetazolamide. When these drugs are administered, burning and stinging sensations are usually present.

[0007] Furthermore, dzodamine hydrochloride has very high solubility under acidic conditions (pH less than 6.0), but it is difficult to solubilize about 2.0 (w / v)% of dzodamine at pH above 6.0. In fact, Cosopt has a pH of about 5.5.

[0008] Furthermore, brinzolamide tartrate, a drug in the same series, also exhibits pH-dependent solubility, with high solubility under acidic conditions and decreasing solubility as pH increases, thus showing properties similar to dzodamine hydrochloride.

[0009] Therefore, studies are needed to solubilize 2.0 (w / v)% docoxam at pH 6.0 and above. Summary of the Invention

[0010] Technical issues

[0011] The purpose of this invention is to provide a transparent composite eye drop comprising a carbonic anhydrase inhibitor, timolol or a pharmaceutically acceptable salt thereof, and cyclodextrin or a derivative thereof as an anti-recrystallization agent, and a method thereof for preparing the same.

[0012] However, the technical problem to be solved by the present invention is not limited to the technical problems mentioned above. Those skilled in the art to which the present invention pertains can clearly understand other technical problems not mentioned through the following description.

[0013] Technical solution

[0014] This invention provides a transparent compound eye drop comprising: a carbonic anhydrase inhibitor; timolol or a pharmaceutically acceptable salt thereof; and cyclodextrin or a derivative thereof as an anti-recrystallization agent.

[0015] The carbonic anhydrase inhibitor may be dorzolamide, metronidazole, brinzolamide, diclofenac, acetazolamide, or a pharmaceutically acceptable salt thereof.

[0016] The anti-recrystallization agent may also contain amino acids or their salts.

[0017] The transparent composite eye drops can maintain a pH of 6.0 to 8.0.

[0018] The concentration of the carbonic anhydrase inhibitor may be from 10 mg / mL to 30 mg / mL, and the concentration of timolol or a pharmaceutically acceptable salt thereof may be from 1 mg / mL to 10 mg / mL.

[0019] The cyclodextrin or its derivatives may include one or more selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-α-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether-γ-cyclodextrin.

[0020] The concentration of the cyclodextrin or its derivative may be from 10 mg / mL to 200 mg / mL (preferably from 100 mg / mL to 130 mg / mL).

[0021] The amino acid or its salt may include one or more selected from the group consisting of arginine, lysine, histidine, aspartic acid, glycine, alanine, valine, carnitine, L-carnitine, proline, leucine, and their salts.

[0022] The concentration of the amino acid or its salt may be from 0.1 mg / mL to 10 mg / mL (preferably from 1 mg / mL to 5 mg / mL).

[0023] The transparent composite eye drops can be either a reusable type or a single-use type.

[0024] An example of the present invention provides a method for preparing a transparent composite eye drop, comprising: step (a) adding cyclodextrin or a derivative thereof to a carbonic anhydrase inhibitor and stirring to prepare a first solution; step (b) adding timolol or a pharmaceutically acceptable salt thereof to the prepared first solution and stirring to prepare a second solution; and step (c) adjusting the pH of the prepared second solution.

[0025] In step (b), after adding timolol or a pharmaceutically acceptable salt thereof, an amino acid or a salt thereof may also be added.

[0026] In step (c), the pH can be adjusted to 6.0 to 8.0.

[0027] The effects of the invention

[0028] The transparent composite eye drops of the present invention are characterized by comprising: a carbonic anhydrase inhibitor; timolol or a pharmaceutically acceptable salt thereof; and cyclodextrin or a derivative thereof as an anti-recrystallization agent. At a pH of 6.0 to 8.0 (preferably, pH greater than 6.0 and less than or equal to 8.0), the colorless and transparent properties can be maintained without precipitation of the main component or substantial formation of a soft substance.

[0029] In particular, in the transparent composite eye drops of the present invention, the use of a combination of cyclodextrin or its derivatives and amino acids or their salts as the anti-recrystallization agent has the advantage of improving storage stability. Attached Figure Description

[0030] Figure 1 Photographs showing the properties of the dazolamide-timolol transparent composite eye drops in Examples 1 and 2 during preparation.

[0031] Figure 2 Photographs showing the properties of the dazolamide-timolol transparent composite eye drops of Example 12 after 8 weeks of storage at room temperature (1-30°C) by the naked eye.

[0032] Figure 3a Photographs showing the properties of the dazolamide-timolol transparent composite eye drops of Examples 13 to 20 during preparation.

[0033] Figure 3b Photographs showing the properties of the dazolamide-timolol transparent composite eye drops of Example 13 after 2 weeks of storage at room temperature (1-30°C) by the naked eye. Detailed Implementation

[0034] The inventors conducted research to achieve a transparent state for carbonic anhydrase inhibitor-timolol compound eye drops under conditions of pH 6.0 or higher (preferably, pH greater than 6.0 and less than or equal to 8.0). The results confirmed that using cyclodextrin or its derivatives (especially combinations of cyclodextrin or its derivatives with amino acids or their salts) as an anti-recrystallization agent can maintain a colorless and transparent state and improve storage stability without precipitating the main component or substantially producing a soft substance, thus completing this invention.

[0035] The present invention will now be described in detail.

[0036] Carbonic anhydrase inhibitor - timolol transparent compound eye drops

[0037] This invention provides a transparent compound eye drop comprising: a carbonic anhydrase inhibitor; timolol or a pharmaceutically acceptable salt thereof; and cyclodextrin or a derivative thereof as an anti-recrystallization agent.

[0038] The transparent composite eye drops are used to prevent side effects under acidic conditions. Preferably, the pH is maintained at a level greater than 6.0 and less than or equal to 8.0. More preferably, the pH is maintained at a level between 6.2 and 8.0. Most preferably, the pH is maintained at a level between 6.5 and 8.0, but not limited thereto.

[0039] First, the transparent composite eye drops of the present invention contain a carbonic anhydrase inhibitor.

[0040] Specifically, the carbonic anhydrase inhibitor may be dorzolamine, metronidazole, brinzolamine, diclofenac, acetazolamine, or a pharmaceutically acceptable salt thereof. In particular, dorzolamine, brinzolamine, or a pharmaceutically acceptable salt thereof (e.g., dorzolamine hydrochloride or brinzolamine tartrate) exhibiting pH-dependent solubility is preferred, and dorzolamine or a pharmaceutically acceptable salt thereof (e.g., dorzolamine hydrochloride) is more preferred, but not limited thereto.

[0041] More specifically, dorzolamine or a pharmaceutically acceptable salt thereof, as an aromatic sulfonamide derivative, is known as an effective carbonic anhydrase inhibitor in the treatment of elevated intraocular pressure, and is a drug commonly used in the treatment of glaucoma in the form of acid addition salts such as hydrochloride. In one embodiment of the invention, dorzolamine hydrochloride is used. In this case, dorzolamine can be represented by the following chemical formula 1.

[0042] Chemical Formula 1

[0043]

[0044] In the transparent compound eye drops of the present invention, the concentration of the carbonic anhydrase inhibitor is high, ranging from 10 mg / mL to 30 mg / mL, preferably from 20 mg / mL to 30 mg / mL, but not limited thereto. If the pH of the aqueous solution containing doxorylamine hydrochloride is below 6.0, there is a problem of inducing pain in the user due to both doxorylamine hydrochloride and acidic pH. On the other hand, if the pH is above 6.0 (preferably, the pH is in the range of greater than 6.0 and less than or equal to 8.0), there is a problem of a significant decrease in the solubility of doxorylamine hydrochloride. Therefore, only by increasing the solubility of doxorylamine hydrochloride with an anti-recrystallization agent can the compound eye drops be made transparent.

[0045] Then, the transparent composite eye drops of the present invention contain timolol or a pharmaceutically acceptable salt thereof.

[0046] Specifically, timolol or a pharmaceutically acceptable salt thereof is a β-adrenergic receptor blocker that reduces aqueous humor production in the eye and can be used as a topical treatment for chronic open-angle glaucoma. In one embodiment of the invention, timolol maleate is used. In this case, timolol can be represented by the following chemical formula 2.

[0047] Chemical formula 2

[0048]

[0049] Timolol maleate is fully soluble in aqueous solution. Therefore, in the transparent compound eye drops of the present invention, the concentration of timolol or its pharmaceutically acceptable salt is not limited, but from the perspective of optimal efficacy, the concentration can be from 1 mg / mL to 10 mg / mL, more preferably from 5 mg / mL to 10 mg / mL, but is not limited thereto.

[0050] Then, the transparent composite eye drops of the present invention contain cyclodextrin or its derivatives as an anti-recrystallization agent.

[0051] Specifically, the anti-recrystallization agent may comprise cyclodextrin or its derivatives. The cyclodextrin or its derivatives may include one or more selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-α-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether-γ-cyclodextrin. In one embodiment of the present invention, hydroxypropyl-γ-cyclodextrin is used. The concentration of the hydroxypropyl-γ-cyclodextrin may be from 10 mg / mL to 200 mg / mL, preferably from 100 mg / mL to 130 mg / mL, more preferably from 120 mg / mL to 130 mg / mL, but is not limited thereto. Maintaining the high concentration of hydroxypropyl-γ-cyclodextrin as described above can preserve its colorless and transparent properties and improve storage stability without precipitating the main component or substantially producing a soft substance. On the other hand, if the concentration of hydroxypropyl-γ-cyclodextrin is less than 100 mg / mL, there is a problem of precipitating a large amount of the main component; if the concentration of hydroxypropyl-γ-cyclodextrin is greater than 130 mg / mL, which is too high, there is a problem of large particles forming during long-term storage at room temperature.

[0052] Optionally, the anti-recrystallization agent may also selectively contain amino acids or their salts. These amino acids or their salts can activate eye metabolism, relieve eye fatigue, and alleviate inflammation. In this invention, they also have the advantage of increasing the solubility of carbonic anhydrase inhibitors.

[0053] Therefore, using a combination of cyclodextrin or its derivatives with amino acids or their salts as the anti-recrystallization agent is preferred from the perspective of improving storage stability. The amino acids or their salts may include one or more selected from the group consisting of arginine, lysine, histidine, aspartic acid, glycine, alanine, valine, carnitine, L-carnitine, proline, leucine, and their salts, preferably one or more selected from the group consisting of arginine, lysine, and histidine, which are equivalent to basic amino acids, but are not limited thereto. In one embodiment of the invention, L-arginine or potassium L-aspartate is used. The concentration of the amino acids or their salts may be from 0.1 mg / mL to 10 mg / mL, preferably from 1 mg / mL to 5 mg / mL. If the concentration is too high, it may cause allergic reactions, irritate the eyes, and induce foreign body sensation, etc.

[0054] The transparent composite eye drops of the present invention may further include a thickener or stabilizer as needed. The thickener may be hydroxypropyl methylcellulose, methylcellulose, sodium chondroitin sulfate, sodium carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, or polyethylene glycol; preferably, hydroxypropyl methylcellulose is used, but it is not limited thereto. In this case, the concentration of the thickener may be from 1 mg / mL to 10 mg / mL. The stabilizer may be ethylenediaminetetraacetic acid (EDTA) or its derivatives, ascorbic acid, phosphates, sulfites, citrates, etc.; preferably, EDTA or its derivatives are used, but it is not limited thereto. In this case, the concentration of the stabilizer may be from 0.1 mg / mL to 5 mg / mL. Thus, storage stability can be improved without changing the main components or substantially producing a softening substance.

[0055] Furthermore, the transparent composite eye drops of the present invention may also contain a nonionic surfactant. In one example of the present invention, polysorbate 80, PEG 400, or tylosap is used as the nonionic surfactant. When additionally containing the above-mentioned surfactant, it is more preferably at a concentration of 0.1 mg / mL to 10 mg / mL, but not limited thereto. Among the above-mentioned nonionic surfactants, polysorbate 80, in particular, can suppress the formation of softening substances, thereby improving storage stability.

[0056] In addition, the transparent composite eye drops of the present invention may also contain other pharmaceutically acceptable additives. The characteristics of other additives to be considered include compatibility with carbonic anhydrase inhibitors and timolol, biocompatibility, processing temperature, etc., but are not limited thereto.

[0057] On the other hand, the transparent composite eye drops can be either a reusable type or a single-use type. If the transparent composite eye drops are a reusable type, they may also contain preservatives such as benzalkonium chloride as other additives; if the transparent composite eye drops are a single-use type, preservatives such as benzalkonium chloride can be omitted.

[0058] Furthermore, the osmotic pressure of the transparent composite eye drops of the present invention can be from 200 mOsmol / kg to 400 mOsmol / kg, preferably from 250 mOsmol / kg to 350 mOsmol / kg, but is not limited thereto.

[0059] Meanwhile, the dosage of the transparent composite eye drops of the present invention can be determined by medical professionals or related general technicians, who can determine the optimal actual dosage based on the patient's age, weight, gender, response, and the condition to be treated.

[0060] The transparent composite eye drops of the present invention can be supplied in a sterile container, and may include instructions for use thereof, which may be physically attached to the container that fills the eye drops or a second container that packages the container, or packaged inside the second container.

[0061] Alternatively, the present invention provides the use of a transparent compound eye drop comprising a carbonic anhydrase inhibitor, timolol or a pharmaceutically acceptable salt thereof, and cyclodextrin or a derivative thereof as an anti-recrystallization agent.

[0062] Alternatively, the present invention provides a method for preventing or treating eye diseases (especially glaucoma) or for lowering intraocular pressure, comprising the step of administering to an individual a clear compound eye drop containing a carbonic anhydrase inhibitor, timolol or a pharmaceutically acceptable salt thereof, and cyclodextrin or a derivative thereof as an anti-recrystallization agent. In this case, "individual" refers to a person requiring treatment for a disease, more specifically, to mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cattle. Furthermore, "administration" is a local administration, meaning eye drops.

[0063] As described above, the transparent composite eye drops of the present invention are characterized by comprising: a carbonic anhydrase inhibitor; timolol or a pharmaceutically acceptable salt thereof; and cyclodextrin or a derivative thereof as an anti-recrystallization agent. At a pH of 6.0 to 8.0 (preferably, pH greater than 6.0 and less than or equal to 8.0), the colorless and transparent properties can be maintained without precipitation of the main component or substantial formation of a soft substance.

[0064] In particular, in the transparent composite eye drops of the present invention, the use of a combination of cyclodextrin or its derivatives and amino acids or their salts as the anti-recrystallization agent has the advantage of improving storage stability.

[0065] Preparation method of transparent composite eye drops

[0066] The present invention provides a method for preparing a transparent composite eye drop, comprising: step (a) adding cyclodextrin or a derivative thereof to a carbonic anhydrase inhibitor and stirring to prepare a first solution; step (b) adding timolol or a pharmaceutically acceptable salt thereof to the prepared first solution and stirring to prepare a second solution; and step (c) adjusting the pH of the prepared second solution.

[0067] First, the method for preparing the transparent composite eye drops of the present invention includes the step of adding cyclodextrin or its derivative to a carbonic anhydrase inhibitor and then stirring to prepare a first solution (step (a)).

[0068] The types and concentrations of the carbonic anhydrase inhibitors are as described above, and will not be repeated here. Furthermore, the cyclodextrins or their derivatives act as anti-recrystallization agents, preventing the precipitation of doxorylamine hydrochloride. The types and concentrations of the cyclodextrins or their derivatives are as described above, and will not be repeated here.

[0069] The stirring can be carried out at a temperature of 60°C to 90°C and a speed of 100 RPM to 1000 RPM. After thorough stirring, stabilizers such as hydroxypropyl methylcellulose can be added.

[0070] Next, the method for preparing the transparent composite eye drops of the present invention includes the step of preparing a second solution by adding timolol or a pharmaceutically acceptable salt thereof to the first solution and stirring. (Step (b))

[0071] The types and concentrations of timolol or its pharmaceutically acceptable salts are as described above, and will not be repeated here. Optionally, after adding timolol or its pharmaceutically acceptable salts, amino acids such as L-arginine and L-aspartate potassium or their salts may also be added, or thickeners, stabilizers, nonionic surfactants, and other additives may be added as needed.

[0072] The stirring can be carried out at a temperature of 60°C to 90°C and a speed of 100 RPM to 1000 RPM.

[0073] Next, the method for preparing the transparent composite eye drops of the present invention includes the step of adjusting the pH of the prepared second solution (step (c)).

[0074] The pH adjustment can be achieved by adding appropriate amounts of pH adjusters such as hydrochloric acid and sodium hydroxide. Thus, the pH can be adjusted to 6.0 to 8.0, preferably to a value greater than 6.0 and less than or equal to 8.0, more preferably to a value of 6.2 to 8.0, and most preferably to a value of 6.5 to 8.0, but is not limited thereto.

[0075] The following preferred embodiments are provided to aid in understanding the present invention. However, these embodiments are provided merely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited to these embodiments.

[0076] Example

[0077] Examples 1-2 and Comparative Examples 1-2: Comparison of dzodamine-timolol transparent composites with and without anti-recrystallization agent eye drops

[0078] As shown in Table 1, the first solution (20% of the total volume of pure water) was prepared by adding dzoxamine hydrochloride and hydroxypropyl-γ-cyclodextrin to pure water at 80°C and stirring at 500 RPM. When the first solution was completely dissolved, hydroxypropyl methylcellulose was added, followed by pure water, and the mixture was stirred at 500 RPM while maintaining the temperature at 80°C. After uniform dispersion, the solution was cooled to room temperature, and then pure water was added, followed by timolol maleate and then benzalkonium chloride, and stirred at 500 RPM to prepare the second solution (an additional 20% of the total volume of pure water). After confirming the second solution was clear, pure water was added, and an appropriate amount of sodium hydroxide was added to adjust to the target pH (95% of the total volume of pure water). After adjusting to the target pH, the solution was brought to volume with pure water to finally prepare the dzoxamine-timolol transparent composite eye drops.

[0079] On the other hand, Comparative Example 1 was Cosopt product (pH=5.5) sold by Merck & Co., Ltd. of South Korea. The pH of Comparative Example 1 was adjusted to 7.0 to prepare Comparative Example 2.

[0080] Table 1

[0081]

[0082]

[0083] As shown in Table 1 and Figure 1 As shown in (a), in the cases of dzodamine-timolol transparent composite eye drops with hydroxypropyl-γ-cyclodextrin as an anti-recrystallization agent added in Examples 1-2, the eye drops remained colorless and transparent when the pH was 7.0 or 6.5.

[0084] On the other hand, in Comparative Example 1, although the product remained colorless and transparent during preparation, the pH was 5.5, maintaining acidic conditions, which limited its effectiveness due to the side effect of pain. However, in Comparative Example 2, where the pH of Comparative Example 1 was adjusted to 7.0, precipitation was observed to the naked eye during preparation.

[0085] Examples 3-12: Comparison of dzodamine-timolol transparent composite drops with optimized anti-recrystallization agent content eye drops

[0086] Dozolam-timolol transparent composite eye drops were prepared according to the composition shown in Table 2. In this case, benzalkonium chloride was added, or alternatively, disodium EDTA hydrate, sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate hydrate (monohydrogen), and tyloxapine were selectively added.

[0087] Table 2

[0088]

[0089]

[0090] As shown in Table 2, in the cases of dazolamine-timolol transparent composite eye drops in Examples 7-12, where hydroxypropyl-γ-cyclodextrin was added at a high concentration as an anti-recrystallization agent, a colorless and transparent appearance was observed during preparation at pH 6.5. However, in Example 3, when only 20 mg / mL of hydroxypropyl-γ-cyclodextrin was added as an anti-recrystallization agent, the problem of dazolamine not dissolving was observed. Furthermore, in Example 4, when only 40 mg / mL of hydroxypropyl-γ-cyclodextrin was added as an anti-recrystallization agent, although dazolamine dissolved during preparation, precipitation occurred during filling.

[0091] Then, taking Examples 7-12 as examples, the properties of the samples after being stored at room temperature (1-30°C) for a total of 4 weeks were observed by the naked eye, and the results are shown in Table 3.

[0092] Table 3

[0093]

[0094] As shown in Table 3, in the cases of dzodamine-timolol transparent compound eye drops of Examples 7-12, in which hydroxypropyl-γ-cyclodextrin as an anti-recrystallization agent was added at a high concentration of 100 mg / mL or more, the colorless and transparent properties were observed to be maintained after 2 weeks at pH 6.5. In particular, in the cases of dzodamine-timolol transparent compound eye drops of Examples 9-12, in which hydroxypropyl-γ-cyclodextrin as an anti-recrystallization agent was added at an even higher concentration of 130 mg / mL or more, the colorless and transparent properties were still observed to be maintained after 4 weeks at pH 6.5, thus proving to be more preferred.

[0095] However, in the cases of Examples 3 and 4, problems arose from the preparation process. In the cases of Examples 5 and 6, when hydroxypropyl-γ-cyclodextrin was added at a concentration of 60-80 mg / mL, precipitation was observed to occur after one week.

[0096] On the other hand, such as Figure 2 As shown, in the case of dzodamine-timolol transparent compound eye drops of Example 12, in which hydroxypropyl-γ-cyclodextrin as an anti-recrystallization agent was added at a concentration greater than 130 mg / mL, large particles were observed to form after being stored at room temperature (1-30°C) for 8 weeks.

[0097] Examples 13-20: Comparison of optimal anti-recrystallization agent content and the presence or absence of amino acid addition in dolezamine-thiazolinone Morolol Transparent Compound Eye Drops

[0098] The final dorzodamine-timolol transparent composite eye drops were prepared using the components shown in Table 4. In this case, when adding benzalkonium chloride, L-arginine, potassium L-aspartate, polysorbate 80, and PEG 400 were selectively added.

[0099] Table 4

[0100]

[0101]

[0102] As shown in Table 4 and Figure 3a As shown, in the case of dzodamine-timolol transparent composite eye drops of Examples 13-20 with hydroxypropyl-γ-cyclodextrin added at the optimal concentration as an anti-recrystallization agent, the colorless and transparent properties were visually confirmed during preparation at pH 6.5.

[0103] Then, using Examples 13-20 as subjects, the properties of the samples stored at room temperature (1-30°C) for a total of 8 weeks were observed by the naked eye. The results are shown in Table 5. Figure 3b As shown.

[0104] Table 5

[0105]

[0106] As shown in Table 5, in the dazolamide-timolol transparent compound eye drops of Examples 13-17, where the combination of hydroxypropyl-γ-cyclodextrin and L-arginine was added as an anti-recrystallization agent, the eye drops maintained a colorless and transparent appearance after 8 weeks at pH 6.5, thus confirming it as the optimal combination. In particular, in Examples 14-15, it was confirmed that even when the L-arginine content in the combination of hydroxypropyl-γ-cyclodextrin and L-arginine as an anti-recrystallization agent was reduced, the eye drops still maintained a colorless and transparent appearance after 8 weeks, even without preservatives such as benzalkonium chloride.

[0107] In Examples 18-19, where the combination of hydroxypropyl-γ-cyclodextrin and L-arginine was added as an anti-recrystallization agent, the dzodamine-timolol clear compound eye drops maintained a colorless and transparent appearance until 6 weeks, but precipitation occurred after 8 weeks. This can still be considered as having considerable shelf-life stability. In Example 20, only hydroxypropyl-γ-cyclodextrin was added as an anti-recrystallization agent, excluding combinations of amino acids or their salts. In this case, it was still confirmed that the eye drops maintained a colorless and transparent appearance until 6 weeks, but precipitation occurred only after 8 weeks.

[0108] In particular, such as Figure 3b As shown, in Example 13, at pH 6.5, after 2 weeks, it was visually confirmed that it still maintained a colorless and transparent appearance.

[0109] Then, taking Examples 15 and 17 as examples, the changes in the content of the main components during preparation and after 8 weeks of storage at room temperature (1-30°C) were analyzed and compared by dazolamine analysis and timolol analysis, respectively. The results are shown in Table 6.

[0110] Dozolemine analysis

[0111] A. Preparation of standard stock solution for soft substances

[0112] Accurately weigh approximately 10 mg of dzodamine-related compound B standard and approximately 10 mg of dzodamine-related compound D standard and place them in a 200 mL brown volumetric flask. Dissolve them in diluent and bring the volume to a final volume (*Diluent: Use a mixture of 50 mL acetonitrile and 950 mL phosphate buffer as the diluent).

[0113] B. Preparation of standard solutions

[0114] Accurately weigh approximately 11 mg of dzodamine hydrochloride standard into a brown volumetric flask and add 50 mL of diluent. After sonication, add 1 mL of the soft substance standard stock solution and dilute to volume with the diluent.

[0115] C. Preparation of the test solution

[0116] Accurately weigh approximately 0.27g of this product and place it in a 50mL brown volumetric flask. Dissolve the product in diluent and bring the volume to a final volume.

[0117] D. Instrument operating conditions

[0118] High performance liquid chromatography (HPLC) was used.

[0119] 1) Mobile phase A: Acetonitrile

[0120] 2) Mobile phase B: Phosphate buffer (*Phosphate buffer: 2 mL of 85% phosphate dissolved in 1000 mL of water)

[0121] 3) Mobile phase concentration gradient

[0122] Time (minutes) Mobile phase A (%) Mobile phase B (%) 20.0 5.0 95.0 15.0 5.0 95.0 15.1 95.0 5.0 20.0 95.0 5.0 20.1 5.0 95.0 30.0 5.0 95.0

[0123] 4) Instruments and testing equipment: LC / UV detector (253nm)

[0124] 5) Column: C18, 4.6*250mm, 5μm

[0125] 6) Flow rate: 1.2 mL / min

[0126] 7) Injection volume: 20 μL

[0127] Timolol analysis

[0128] A. Preparation of standard solutions

[0129] Accurately weigh approximately 35 mg of timolol maleate standard into a 100 mL brown volumetric flask, add diluent, sonicate, and then dilute to volume with diluent.

[0130] B. Preparation of the test solution

[0131] Accurately weigh approximately 1.32 g of this product and place it in a 25 mL brown volumetric flask. Dissolve the product in diluent and bring the volume to a final volume.

[0132] C. Instrument operating conditions

[0133] HPLC was used.

[0134] 1) Mobile phase: A mixture of methanol and phosphate buffer (40:60) (*Phosphate buffer: Dissolve 22g of sodium hydrogen phosphate in 1995mL of pure water, adjust the pH to 2.8 with phosphoric acid, and then bring the volume to a final volume with pure water.)

[0135] 2) Instruments and testing equipment: LC / UV detector (295nm)

[0136] 3) Column: C18, 4.6*250mm, 5μm

[0137] 4) Flow rate: 1 mL / min

[0138] 5) Injection volume: 20μL

[0139] 6) Column temperature: 40℃

[0140] Table 6

[0141]

[0142] As shown in Table 6, in the cases of dzodamine-timolol transparent compound eye drops of Examples 15 and 17, where the combination of hydroxypropyl-γ-cyclodextrin and L-arginine was added at the optimal concentration as an anti-recrystallization agent, at pH 6.5, it was confirmed that the content of the main component remained unchanged after 8 weeks.

[0143] Furthermore, using Examples 15 and 17 as examples, the method was the same as that used for analyzing the change in the content of the main component to analyze whether a soft substance was produced after 12 weeks of storage at room temperature (1-30°C).

[0144] Analysis of the results showed that, in the cases of dzodamine-timolol transparent composite eye drops in Examples 15 and 17, where the combination of hydroxypropyl-γ-cyclodextrin and L-arginine was added at the optimal concentration as an anti-recrystallization agent, the softening agents of dzodamine all met the appropriate criteria of cis-dzodamine ≤ 2.0%, other individual softening agents ≤ 0.5%, and total softening agent ≤ 3.0%. Furthermore, the softening agents of timolol all met the appropriate criteria of individual softening agent ≤ 0.5% and total softening agent ≤ 1.0%.

[0145] The foregoing description of the present invention is for illustrative purposes only. Those skilled in the art will understand that other specific forms can be easily derived without altering the technical concept or essential features of the invention. Therefore, the embodiments described above should be interpreted in all respects as illustrative only and not as limiting.

Claims

1. A transparent composite eye drop, characterized in that, Include: Carbonic anhydrase inhibitor; Timolol or its pharmaceutically acceptable salts; and Cyclodextrin or its derivatives as anti-recrystallization agents.

2. The transparent composite eye drops according to claim 1, characterized in that, The carbonic anhydrase inhibitor is dolzoamine, metronidazole, brinzolamide, diclofenac, acetazolamide, or a pharmaceutically acceptable salt thereof.

3. The transparent composite eye drops according to claim 1, characterized in that, The anti-recrystallization agent also contains amino acids or their salts.

4. The transparent composite eye drops according to claim 1, characterized in that, The transparent composite eye drops maintain a pH of 6.0 to 8.

0.

5. The transparent composite eye drops according to claim 1, characterized in that, The concentration of the carbonic anhydrase inhibitor is from 10 mg / mL to 30 mg / mL. The concentration of timolol or a pharmaceutically acceptable salt thereof is from 1 mg / mL to 10 mg / mL.

6. The transparent composite eye drops according to claim 1, characterized in that, The cyclodextrin or its derivatives comprise one or more selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-α-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether-γ-cyclodextrin.

7. The transparent composite eye drops according to claim 1, characterized in that, The concentration of the cyclodextrin or its derivative is from 10 mg / mL to 200 mg / mL.

8. The transparent composite eye drops according to claim 1, characterized in that, The concentration of the cyclodextrin or its derivative is from 100 mg / mL to 130 mg / mL.

9. The transparent composite eye drops according to claim 3, characterized in that, The amino acid or its salt comprises one or more selected from the group consisting of arginine, lysine, histidine, aspartic acid, glycine, alanine, valine, carnitine, L-carnitine, proline, leucine, and their salts.

10. The transparent composite eye drops according to claim 3, characterized in that, The concentration of the amino acid or its salt is from 0.1 mg / mL to 10 mg / mL.

11. The transparent composite eye drops according to claim 3, characterized in that, The concentration of the amino acid or its salt is from 1 mg / mL to 5 mg / mL.

12. The transparent composite eye drops according to claim 1, characterized in that, The transparent composite eye drops are either reusable or single-use.

13. A method for preparing a transparent composite eye drop, characterized in that, include: Step (a) involves adding cyclodextrin or its derivative to a carbonic anhydrase inhibitor and stirring to prepare a first solution; Step (b) involves adding timolol or a pharmaceutically acceptable salt thereof to the first solution and stirring to prepare a second solution; as well as Step (c) involves adjusting the pH of the prepared second solution.

14. The method for preparing the transparent composite eye drops according to claim 13, characterized in that, In step (b), after adding timolol or a pharmaceutically acceptable salt thereof, an amino acid or a salt thereof is also added.

15. The method for preparing the transparent composite eye drops according to claim 13, characterized in that, In step (c), the pH is adjusted to 6.0 to 8.0.

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