Transparent composite eye drop containing carbonic anhydrase inhibitors and timolol and preparation method therefor

Abstract

The present invention relates to: a transparent composite eye drop containing carbonic anhydrase inhibitors, timolol or a pharmaceutically acceptable salt thereof, and cyclodextrin or a derivative thereof as an anti-recrystallization agent; and a preparation method therefor.

Description

Transparent composite eye drop containing carbonic anhydrase inhibitor and timolol and method for preparing the same

[0001] The present invention relates to a transparent combination eye drop containing a carbonic anhydrase inhibitor and timolol.

[0002] Glaucoma is an eye disease often characterized by a gradual increase in intraocular pressure. If left untreated, glaucoma can lead to serious structural defects in the eye, particularly damage to the optic nerve head, leading to decreased visual field and optic nerve atrophy. In some cases, the pathology is associated with inadequate drainage of aqueous humor from the eye. Other factors, including aqueous humor production and pressure in the episcleral vein, can also contribute to the development of this condition.

[0003] Dorzolamide is an aromatic sulfonamide derivative known as a carbonic anhydrase inhibitor useful for the treatment of elevated intraocular pressure. It inhibits carbonic anhydrase in the ciliary process, thereby reducing the rate of bicarbonate ion formation and increasing the secretion of aqueous humor. It is a drug generally used to treat glaucoma in the form of acid addition salts such as hydrochloride.

[0004] Meanwhile, timolol is a beta-adrenergic receptor blocker useful for treating elevated intraocular pressure. It inhibits aqueous humor inflow and thus reduces aqueous humor production. It is commonly used in the treatment of glaucoma in the maleate form.

[0005] In 1998, a glaucoma treatment formulation containing dorzolamide 2.0% and timolol 0.5% (trade name: Cosopt, MSD) was approved by the U.S. FDA and is currently in clinical use. At that time, Cosopt was a formulation obtained by dissolving dorzolamide hydrochloride and timolol maleate, along with hydroxyethyl cellulose, mannitol, sodium citrate, sodium hydroxide, and benzalkonium chloride in sterile water, and was used for the treatment of patients with glaucoma. Common side effects listed include burning, stinging, eye redness, blurred vision, tearing, or itching. These side effects can lead to low medication compliance due to the burning and stinging sensation when taking the medication, and it is thought that this is due to the acidic pH and pain derived from the active ingredient.

[0006] Carbonic anhydrase inhibitors include dorzolamide hydrochloride, as well as methazolamide, brinzolamide, dichlorphenamide, and acetazolamide, and these drugs generally cause a burning and stinging sensation when administered.

[0007] In addition, the solubility of dorzolamide hydrochloride is shown to be very high under acidic conditions (pH less than 6.0), and it is judged that it is difficult to solubilize about 2.0 (w / v)% of dorzolamide at pH 6.0 or higher, and in fact, the pH of the cosop is about 5.5.

[0008] In addition, among drugs in the same class, brinzolamide tartrate also exhibits pH-dependent solubility, with high solubility in acidic conditions and decreasing solubility as pH increases, thus exhibiting properties similar to dorzolamide hydrochloride.

[0009] Accordingly, research is needed to solubilize 2.0 (w / v)% of dorzolamide at pH 6.0 or higher.

[0010] The present invention provides a transparent composite eye drop containing carbonic anhydrase inhibitors; timolol or a pharmaceutically acceptable salt thereof; and cyclodextrin or a derivative thereof as a recrystallization inhibitor, and a method for producing the same.

[0011] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

[0012] The present invention provides a transparent composite eye drop containing carbonic anhydrase inhibitors; timolol or a pharmaceutically acceptable salt thereof; and cyclodextrin or a derivative thereof as a recrystallization inhibitor.

[0013] The above carbonic anhydrase inhibitor may be dorzolamide, methazolamide, brinzolamide, dichlorphenamide, acetazolamide or a pharmaceutically acceptable salt thereof.

[0014] The above recrystallization inhibitor may additionally include an amino acid or a salt thereof.

[0015] The above transparent composite eye drop can maintain a pH of 6.0 to 8.0.

[0016] The concentration of the carbonic anhydrase inhibitor may be 10 mg / mL to 30 mg / mL, and the concentration of timolol or a pharmaceutically acceptable salt thereof may be 1 mg / mL to 10 mg / mL.

[0017] The cyclodextrin or derivative thereof may include at least one selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl-beta-cyclodextrin, dimethyl-gamma-cyclodextrin, hydroxyethyl-alpha-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, hydroxypropyl-alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfurbutylether-alpha-cyclodextrin, sulfurbutylether-beta-cyclodextrin, and sulfurbutylether-gamma-cyclodextrin.

[0018] The concentration of the cyclodextrin or its derivative may be 10 mg / mL to 200 mg / mL (preferably, 100 mg / mL to 130 mg / mL).

[0019] The above amino acid or salt thereof may include at least one selected from the group consisting of arginine, lysine, histidine, aspartic acid, glycine, alanine, valine, carnitine, levocarnitine, proline, leucine, and salts thereof.

[0020] The concentration of the amino acid or its salt may be 0.1 mg / mL to 10 mg / mL (preferably 1 mg / mL to 5 mg / mL).

[0021] The above transparent composite eye drops may be multi-use or single-use.

[0022] In one embodiment of the present invention, a method for preparing a transparent composite eye drop is provided, comprising the steps of: (a) preparing a first solution by adding cyclodextrin or a derivative thereof to a carbonic anhydrase inhibitor and stirring the same; (b) preparing a second solution by adding timolol or a pharmaceutically acceptable salt thereof to the prepared first solution and stirring the same; and (c) adjusting the pH of the prepared second solution.

[0023] After the addition of timolol or a pharmaceutically acceptable salt thereof in step (b) above, an amino acid or a salt thereof may be additionally added.

[0024] In the above step (c), the pH can be adjusted to 6.0 to 8.0.

[0025] The transparent composite eye drop according to the present invention is characterized by containing a carbonic anhydrase inhibitor; timolol or a pharmaceutically acceptable salt thereof; and a cyclodextrin or a derivative thereof as a recrystallization inhibitor, so that even when the pH is 6.0 to 8.0 (preferably, more than pH 6.0 to 8.0), the transparent composite eye drop can maintain a colorless and transparent state without precipitating the main component and without substantially generating a volatile substance.

[0026] In particular, in the transparent composite eye drop according to the present invention, when a combination of cyclodextrin or a derivative thereof and an amino acid or a salt thereof is applied as the recrystallization prevention agent, there is an advantage in that storage stability can be improved.

[0027] Figure 1 is a photograph showing the appearance of a transparent combination eye drop of dorzolamide-timolol according to Examples 1 and 2.

[0028] Figure 2 is a photograph of the appearance of a dorzolamide-timolol transparent combination eye drop according to Example 12 observed with the naked eye over time for 8 weeks when stored at room temperature (1-30°C).

[0029] Figure 3(a) is a photograph showing the appearance of a transparent combination eye drop of dorzolamide-timolol according to Examples 13 to 20.

[0030] Figure 3(b) is a photograph of the appearance of the transparent combination eye drop of dorzolamide-timolol according to Example 13 observed with the naked eye over time for two weeks when stored at room temperature (1-30°C).

[0031] The present inventors studied to implement a carbonic anhydrase inhibitor-timolol combination eye drop in a transparent form at a pH of 6.0 or higher (preferably, pH 6.0 to 8.0), and as a result, confirmed that by applying cyclodextrin or a derivative thereof (particularly, a combination of cyclodextrin or a derivative thereof and an amino acid or a salt thereof) as an anti-recrystallization agent, it is possible to improve storage stability while maintaining a colorless and transparent state without precipitation of the main component and without substantially generating flexible substances, thereby completing the present invention.

[0032]

[0033] Hereinafter, the present invention will be described in detail.

[0034]

[0035] Carbonic anhydrase inhibitors (Timolol) clear combination eye drops

[0036]

[0037] The present invention provides a transparent composite eye drop containing a carbonic anhydrase inhibitor; timolol or a pharmaceutically acceptable salt thereof; and a cyclodextrin or a derivative thereof as an anti-recrystallization agent.

[0038] The above transparent composite eye drops are intended to prevent side effects due to acidic conditions, and it is preferable to maintain a pH of 6.0 to 8.0, more preferably a pH of 6.2 to 8.0, and most preferably a pH of 6.5 to 8.0, but the present invention is not limited thereto.

[0039]

[0040] First, the transparent composite eye drop according to the present invention includes a carbonic anhydrase inhibitor.

[0041] Specifically, the carbonic anhydrase inhibitor may be dorzolamide, methazolamide, brinzolamide, dichlorphenamide, acetazolamide or a pharmaceutically acceptable salt thereof. In particular, it is preferable that it is dorzolamide, brinzolamide or a pharmaceutically acceptable salt thereof (e.g., dorzolamide hydrochloride or brinzolamide tartrate) exhibiting pH-dependent solubility, and it is more preferable that it is dorzolamide or a pharmaceutically acceptable salt thereof (e.g., dorzolamide hydrochloride), but is not limited thereto.

[0042] More specifically, the dorzolamide or a pharmaceutically acceptable salt thereof is an aromatic sulfonamide derivative known as a carbonic anhydrase inhibitor useful for treating elevated intraocular pressure, and is a drug generally used for the treatment of glaucoma in the form of an acid addition salt such as a hydrochloride. In one embodiment of the present invention, dorzolamide hydrochloride was used. In this case, dorzolamide can be represented by the following chemical formula 1:

[0043] [Chemical Formula 1]

[0044]

[0045] In the transparent composite eye drop according to the present invention, the concentration of the carbonic anhydrase inhibitor is a high concentration, and may be 10 mg / mL to 30 mg / mL, and preferably 20 mg / mL to 30 mg / mL, but is not limited thereto. If the pH of the aqueous solution containing dorzolamide hydrochloride is lower than 6.0, there is a problem that the user experiences pain derived from dorzolamide hydrochloride and pain derived from acidic pH. On the other hand, if the pH is 6.0 or higher (preferably, when the pH is in the range of more than 6.0 to 8.0), there is a problem that the solubility of dorzolamide hydrochloride is greatly reduced, and therefore, the solubility of dorzolamide hydrochloride must be increased using a recrystallization inhibitor in order to implement the composite eye drop in a transparent form.

[0046]

[0047] Next, the transparent composite eye drop according to the present invention comprises timolol or a pharmaceutically acceptable salt thereof.

[0048] Specifically, timolol or a pharmaceutically acceptable salt thereof is a beta-adrenergic receptor blocker that has the effect of reducing aqueous humor production in the eye and can be used as a topical treatment for chronic open-angle glaucoma. In one embodiment of the present invention, timolol maleate was used. In this case, timolol can be represented by the following chemical formula 2:

[0049] [Chemical Formula 2]

[0050]

[0051] Since timolol maleate is sufficiently soluble in an aqueous solution, the concentration of timolol or a pharmaceutically acceptable salt thereof in the transparent composite eye drop according to the present invention is not limited, but may be 1 mg / mL to 10 mg / mL in terms of optimal efficacy, and is more preferably 5 mg / mL to 10 mg / mL, but is not limited thereto.

[0052]

[0053] Next, the transparent composite eye drop according to the present invention contains cyclodextrin or a derivative thereof as an anti-recrystallization agent.

[0054] Specifically, the recrystallization inhibitor may include cyclodextrin or a derivative thereof. The cyclodextrin or derivative thereof may include at least one selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl-beta-cyclodextrin, dimethyl-gamma-cyclodextrin, hydroxyethyl-alpha-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, hydroxypropyl-alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfurbutylether-alpha-cyclodextrin, sulfurbutylether-beta-cyclodextrin, and sulfurbutylether-gamma-cyclodextrin, and in one embodiment of the present invention, hydroxypropyl-gamma-cyclodextrin was used. The concentration of the above hydroxypropyl-gamma-cyclodextrin may be 10 mg / mL to 200 mg / mL, preferably 100 mg / mL to 130 mg / mL, and more preferably 120 mg / mL to 130 mg / mL, but is not limited thereto. By maintaining the concentration of the above hydroxypropyl-gamma-cyclodextrin at such a high level, storage stability can be improved while maintaining a colorless and transparent appearance without substantially generating volatile substances and without precipitation of the main component. On the other hand, when the concentration of the above hydroxypropyl-gamma-cyclodextrin is less than 100 mg / mL, there is a problem that a large amount of the main component precipitates, and when the concentration of the above hydroxypropyl-gamma-cyclodextrin is excessively high exceeding 130 mg / mL, there is a problem that large granules are generated during long-term storage at room temperature.

[0055]

[0056] Optionally, the above-described recrystallization inhibitor may further comprise an amino acid or its salt. Such amino acids or their salts can stimulate eye metabolism, relieve eye fatigue, and alleviate inflammation. In the present invention, they have the advantage of enhancing the solubility of the carbonic anhydrase inhibitor.

[0057] Therefore, it is preferable to use a combination of cyclodextrin or a derivative thereof and an amino acid or a salt thereof as the recrystallization inhibitor in terms of improving storage stability. The amino acid or its salt may include at least one selected from the group consisting of arginine, lysine, histidine, aspartic acid, glycine, alanine, valine, carnitine, levocarnitine, proline, leucine, and salts thereof, and preferably includes at least one selected from the group consisting of arginine, lysine, and histidine, which are basic amino acids, but is not limited thereto. In one embodiment of the present invention, L-arginine or potassium L-aspartate was used. The concentration of the amino acid or its salt may be 0.1 mg / mL to 10 mg / mL, preferably 1 mg / mL to 5 mg / mL, and if the concentration is too high, an allergic reaction may occur, and problems such as irritation to the eyes and a foreign body sensation may occur.

[0058]

[0059] If necessary, the transparent composite eye drop according to the present invention may further include a thickener or a stabilizer. The thickener may be hypromellose, methylcellulose, sodium chondroitin sulfate, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, etc., and hypromellose is preferably used, but is not limited thereto. At this time, the concentration of the thickener may be 1 mg / mL to 10 mg / mL. The stabilizer may be edetic acid or a derivative thereof, ascorbic acid, phosphate, sulfite, citrate, etc., and edetic acid or a derivative thereof is preferably used, but is not limited thereto. At this time, the concentration of the stabilizer may be 0.1 mg / mL to 5 mg / mL. As a result, storage stability can be improved without substantially generating reactive substances and without changing the main ingredient content.

[0060] In addition, the transparent composite eye drop according to the present invention may additionally contain a nonionic surfactant. In one embodiment of the present invention, polysorbate 80, PEG 400, or tyloxapol is used as the nonionic surfactant. When the nonionic surfactant is additionally contained, the concentration is more preferably 0.1 mg / mL to 10 mg / mL, but is not limited thereto. Among these nonionic surfactants, the use of polysorbate 80 in particular can suppress the generation of volatile substances, thereby improving storage stability.

[0061] In addition, the transparent composite eye drop according to the present invention may additionally include other pharmaceutically acceptable additives, and the characteristics to be considered in the other additives include, but are not limited to, compatibility with carbonic anhydrase inhibitors and timolol, biocompatibility, processing temperature, etc.

[0062] Meanwhile, the transparent combination eye drops may be multi-use or single-use. If the transparent combination eye drops are multi-use, they may additionally include a preservative such as benzalkonium chloride as the other additives. If the transparent combination eye drops are single-use, the preservative such as benzalkonium chloride may be omitted.

[0063]

[0064] In addition, the osmotic pressure of the transparent composite eye drop according to the present invention may be 200 to 400 mOsmol / kg, and is preferably 250 to 350 mOsmol / kg, but is not limited thereto.

[0065]

[0066] In addition, the dosage of the transparent composite eye drop according to the present invention can be routinely determined by a medical professional or a person skilled in the art, and the medical professional or a person skilled in the art can determine the most appropriate actual dosage based on the age, weight, sex, and response of the patient to be treated, as well as the condition to be treated.

[0067] The transparent composite eye drop according to the present invention can be provided by filling it in a sterile container, and can be provided including instructions for its use, and the instructions can be physically attached to the container filled with the eye drop or a second container packaging the container, or can be packaged together inside the second container.

[0068]

[0069] Alternatively, the present invention provides a use for a transparent composite eye drop containing a carbonic anhydrase inhibitor; timolol or a pharmaceutically acceptable salt thereof; and a cyclodextrin or a derivative thereof as an anti-recrystallization agent.

[0070] Alternatively, the present invention provides a method for preventing or treating an eye disease (particularly, glaucoma) or a method for lowering intraocular pressure, comprising administering to a subject a transparent composite eye drop containing a carbonic anhydrase inhibitor; timolol or a pharmaceutically acceptable salt thereof; and a cyclodextrin or a derivative thereof as an anti-recrystallization agent. Here, the term "subject" refers to a subject in need of treatment for a disease, and more specifically, refers to mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cows. In addition, "administration" refers to topical administration, that is, eye drops.

[0071]

[0072] As reviewed above, the transparent composite eye drop according to the present invention is characterized by containing a carbonic anhydrase inhibitor; timolol or a pharmaceutically acceptable salt thereof; and a cyclodextrin or a derivative thereof as a recrystallization inhibitor, so that even when the pH is 6.0 to 8.0 (preferably, more than pH 6.0 to 8.0), the transparent composite eye drop can maintain a colorless and transparent state without substantially generating flexible substances and without precipitation of the main component.

[0073] In particular, in the transparent composite eye drop according to the present invention, when a combination of cyclodextrin or a derivative thereof and an amino acid or a salt thereof is applied as the recrystallization prevention agent, there is an advantage in that storage stability can be improved.

[0074]

[0075] Method for manufacturing transparent composite eye drops

[0076]

[0077] The present invention provides a method for preparing a transparent composite eye drop, comprising the steps of: (a) preparing a first solution by adding cyclodextrin or a derivative thereof to a carbonic anhydrase inhibitor and stirring the same; (b) preparing a second solution by adding timolol or a pharmaceutically acceptable salt thereof to the first solution thus prepared and stirring the same; and (c) adjusting the pH of the second solution thus prepared.

[0078]

[0079] First, the method for manufacturing a transparent composite eye drop according to the present invention includes a step [step (a)] of preparing a first solution by adding cyclodextrin or a derivative thereof to a carbonic anhydrase inhibitor and then stirring.

[0080] The type and concentration of the carbonic anhydrase inhibitor have been previously described, and therefore, a detailed explanation thereof will be omitted. Furthermore, the cyclodextrin or its derivative acts as a recrystallization inhibitor, preventing the precipitation of dorzolamide hydrochloride. The type and concentration of the cyclodextrin or its derivative have been previously described, and therefore, a detailed explanation thereof will be omitted.

[0081] The above stirring can be performed at a temperature of 60°C to 90°C and a speed of 100 RPM to 1,000 RPM. After the above stirring is sufficiently performed, a stabilizer such as hypromellose can be added.

[0082]

[0083] Next, the method for manufacturing a transparent composite eye drop according to the present invention includes a step [step (b)] of adding timolol or a pharmaceutically acceptable salt thereof to the first solution manufactured above and stirring to prepare a second solution.

[0084] The type and concentration of the timolol or its pharmaceutically acceptable salt have been described above, so a duplicate description will be omitted. Optionally, after the addition of the timolol or its pharmaceutically acceptable salt, an amino acid such as L-arginine or potassium L-aspartate or a salt thereof may be additionally added, or a thickener, stabilizer, nonionic surfactant, or other additives may be additionally added as needed.

[0085] The above stirring can be performed at a temperature of 60°C to 90°C and a speed of 100 RPM to 1,000 RPM.

[0086]

[0087] Next, the method for manufacturing a transparent composite eye drop according to the present invention includes a step [step (c)] of adjusting the pH of the second solution manufactured above.

[0088] The above pH adjustment can be achieved by adding an appropriate amount of a pH adjusting agent such as hydrochloric acid or sodium hydroxide. As a result, the pH can be adjusted to 6.0 to 8.0, preferably to a pH higher than 6.0 to 8.0, more preferably to a pH of 6.2 to 8.0, and most preferably to a pH of 6.5 to 8.0, but is not limited thereto.

[0089]

[0090] Hereinafter, preferred examples are presented to aid in understanding the present invention. However, the following examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following examples.

[0091]

[0092] [Example]

[0093] Example 1-2 and Comparative Example 1-2: Comparison of dorzolamide-timolol transparent combination eye drops with and without an anti-recrystallization agent

[0094] As shown in the composition in Table 1, dorzolamide hydrochloride and hydroxypropyl gammadex were added to purified water at 80°C, and stirred at 500 RPM to prepare a first solution (20% of the total purified water was collected). When the first solution was completely dissolved, hypromellose was added, and additional purified water was collected, and stirred at 500 RPM while maintaining the temperature at 80°C. After evenly dispersing the solution, additional purified water was collected while cooling at room temperature, and then timolol maleate was added, followed by benzalkonium chloride, and stirred at 500 RPM to prepare a second solution (20% of the total purified water was collected). After confirming that the second solution was clear, additional purified water was collected, and an appropriate amount of sodium hydroxide was added to adjust the pH to the target pH (water was collected so that the total purified water amount was 95%). After adjusting to the target pH, the final dorzolamide-timolol transparent combination eye drop was manufactured by adding purified water to the final pH.

[0095] Meanwhile, Comparative Example 1 is a Cosopt product (pH = 5.5) commercially available from MSD Korea, and Comparative Example 2 was prepared by adjusting the pH of the product according to Comparative Example 1 to 7.0.

[0096] Raw material nameExample 1Example 2Comparative Example 1Comparative Example 2Dorzolamide hydrochloride22.26 mg22.26 mg22.26 mg22.26 mgTimolol maleate6.83 mg6.83 mg6.83 mg6.83 mgSodium citrate hydrate--0.1~100.0 mg0.1~100.0 mgHydroxyethylcellulose--0.1~100.0 mg0.1~100.0 mgD-mannitol--0.1~100.0 mg0.1~100.0 mgSodium hydroxideAmountAmountAmountAmountAmountHydroxypropyl gammadex130.00 mg130.00 mg--Hypromellose5.00 mg5.00 mg--Benzalkonium chloride2.00 mg2.00 mg0.1~100.0 mg0.1~100.0 mgPurified waterAmountAmountAmountAmountTotal amount1mL1mL1mL1mLpHpH 7.0pH 6.5pH 5.5pH 7.0Osmolality(mOsmol / kg)200~400200~400200~400200~400Appearance during manufacturingColorless transparentColorless transparentColorless transparentPrecipitation occurs

[0097] As shown in Table 1 and Fig. 1(a), in the case of the dorzolamide-timolol transparent composite eye drop to which hydroxypropyl gammadex is added as an anti-recrystallization agent as in Example 1-2, it is visually confirmed that the transparent and colorless appearance is maintained during manufacture at pH 7.0 or pH 6.5.

[0098] Meanwhile, in the case of Comparative Example 1, although it maintains a colorless and transparent appearance during manufacturing, there is a limitation that side effects such as pain occur due to maintaining acidic conditions at pH 5.5. However, in the case of Comparative Example 2, where the pH was adjusted to 7.0 in Comparative Example 1, precipitation was confirmed to occur during manufacturing with the naked eye.

[0099]

[0100] Example 3-12: Comparison of dorzolamide-timolol transparent combination eye drops with optimized content of anti-recrystallization agent

[0101] A transparent combination eye drop of dorzolamide-timolol was prepared according to the composition shown in Table 2. At this time, when benzalkonium chloride was added or replaced, sodium edetate hydrate, sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate monohydrate, and tyloxapol were selectively added.

[0102] Raw material nameExample 3Example 4Example 5Example 6Example 7Example 8Example 9Example 10Example 11Example 12Dorzolamide hydrochloride22.26 mg22.26 mg22.26 mg22.26 mg22.26 mg22.26 mg22.26 mg22.26 mg22.26 mg22.26 mgTimolol maleate6.83 mg6.83 mg6.83 mg6.83 mg6.83 mg6.83 mg6.83 mg6.83 mgHydroxypropyl gammadex20 mg40 mg60 mg80 mg100 mg120 mg130 mg130 mg150 mgHypromellose5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg Sodium edetate monohydrate1.00mg1.00mg1.00mg1.00mg1.00mg1.00mg1.00mg1.00mg1.00mg1.00mg Sodium dihydrogen phosphate monohydrate0.10mg0.10mg0.10mg0.10mg0.10mg0.10mg0.10mg0.10mg Sodium hydrogen phosphate monohydrate (monohydrogen)2.00mg2.00mg2.00mg2.00mg2.00 mg2.00mg2.00mg2.00mg2.00mg2.00mgTyloxapol------0.5mg---Benzalkonium chloride0.2mg0.2mg0.2mg0.2mg0.2mg0.2mg0.2mg0.2mg-0.2mgSodium hydroxideAmountAmountAmountAmountAmountAmountAmountAmountAmountAmountAmountAmountAmountAmountAmountAmountPurified waterAmountAmountAmountAmountAmountAmountAmountAmountAmountAmountAmountTotal amount1mL1mL1mL1mL1mL1mL1mL1mL1mL1mL1mL1mLpHpH 6.5pH 6.5pH 6.5pH 6.5pH 6.5pH 6.5pH 6.5pH 6.5pH 6.5pH 6.5pH Osmolarity (mOsmol / kg) 200~40 ...

[0103] As shown in Table 2, in the case of the dorzolamide-timolol transparent combination eye drops to which hydroxypropyl gammadex was added at a high concentration as a recrystallization inhibitor, as in Examples 7-12, it was visually confirmed that the solution maintained a colorless and transparent appearance at pH 6.5 during manufacture. However, in the case of Example 3, since only 20 mg / mL of hydroxypropyl gammadex was added as a recrystallization inhibitor, a problem was identified in which dorzolamide did not dissolve. In addition, in the case of Example 4, since only 40 mg / mL of hydroxypropyl gammadex was added as a recrystallization inhibitor, a problem was identified in which dorzolamide dissolved during preparation but precipitated during filling.

[0104]

[0105] Afterwards, for Examples 7-12, the properties were visually observed over time for a total of 4 weeks when stored at room temperature (1-30°C), and the results are shown in Table 3.

[0106] Storage at room temperature (1-30℃) Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 When manufacturing, Dorzolamide does not dissolve. When prepared, it is dissolved, but when filling, precipitation occurs. Colorless and transparent. Colorless and transparent. Colorless and transparent. Colorless and transparent. Colorless and transparent. Colorless and transparent. Colorless and transparent. After 1 week, precipitation occurs. Precipitation occurs. Colorless and transparent. Colorless and transparent. Colorless and transparent. Colorless and transparent. Colorless and transparent. After 2 weeks, precipitation occurs. Colorless and transparent. Colorless and transparent. Colorless and transparent. Colorless and transparent. Colorless and transparent. After 4 weeks, precipitation occurs. Precipitation occurs. Colorless and transparent ...

[0107] As shown in Table 3, in the case of the dorzolamide-timolol transparent combination eye drop to which hydroxypropyl gammadex was added at a high concentration of 100 mg / mL or more as an anti-recrystallization agent, as in Examples 7-12, it was visually confirmed that the colorless and transparent appearance was maintained for up to 2 weeks at pH 6.5. In particular, in the case of the dorzolamide-timolol transparent combination eye drop to which hydroxypropyl gammadex was added at an even higher concentration of 130 mg / mL or more as an anti-recrystallization agent, as in Examples 9-12, it was visually confirmed that the colorless and transparent appearance was maintained even after 4 weeks at pH 6.5, and thus it was confirmed to be more preferable.

[0108] However, in the case of Examples 3-4, problems occur from the time of manufacturing, and in the case of Examples 5-6, as hydroxypropyl gammadex is added at a concentration of 60-80 mg / mL, precipitation is visually confirmed to occur after one week.

[0109] Meanwhile, as shown in Fig. 2, in the case of the dorzolamide-timolol transparent combination eye drop to which hydroxypropyl gammadex as an anti-recrystallization agent is added in excess of 130 mg / mL as in Example 12, a problem of large granules being generated after 8 weeks of storage at room temperature (1-30°C) is visually confirmed.

[0110]

[0111] Example 13-20: Comparison of dorzolamide-timolol transparent combination eye drops according to the optimization of the content of anti-recrystallization agent and the presence or absence of amino acid addition.

[0112] A transparent dorzolamide-timolol combination eye drop was finally manufactured according to the composition shown in Table 4. At this time, when benzalkonium chloride was added, L-arginine, potassium L-aspartate, polysorbate 80, and PEG 400 were selectively added.

[0113] Raw material nameExample 13Example 14Example 15Example 16Example 17Example 18Example 19Example 20Dorzolamide hydrochloride22.26 mg22.26 mg22.26 mg22.26 mg22.26 mg22.26 mg22.26 mg22.26 mgTimolol maleate6.83 mg6.83 mg6.83 mg6.83 mg6.83 mg6.83 mg6.83 mgHydroxypropyl gammadex130.00 mg130.00 mg130.00 mg130.00 mg130.00 mg130.00 mg130.00 mg130.00 mgHypromellose5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mg5.00 mgSodium edetate hydrate--0.50 mg-----L-arginine5.00 mg1.80 mg1.80 mg5.00 mg5.00 mg---L-potassium aspartate-----1.00 mg5.00 mg-Polysorbate 80---5.00 mg10.00 mg---PEG 400-------3.00 mgBenzalkonium chloride2.00 mg--2.00 mg2.00 mg2.00 mg2.00 mg2.00 mgSodium hydroxideQuantityQuantityQuantityQuantityQuantityQuantityQuantityQuantityQuantityQuantityQuantityTotal 1mL1mL1mL1mL1mL1mL1mL1mL1mLpHpH 6.5pH 6.5pH 6.5pH 6.5pH 6.5pH 6.5pH 6.5pH 6.5Osmolality (mOsmol / kg)200~400200~400200~400200~400200~400200~400200~400200~400Appearance at time of manufactureColorless transparentColorless transparentColorless transparentColorless transparentColorless transparentColorless transparentColorless transparentColorless transparent

[0114] As shown in Table 4 and Fig. 3(a), in the case of the dorzolamide-timolol transparent composite eye drop to which hydroxypropyl gammadex as an anti-recrystallization agent was added at an optimal concentration as in Example 13-20, it was visually confirmed that the transparent and colorless appearance was maintained during manufacture at pH 6.5.

[0115]

[0116] Afterwards, for Examples 13-20, the properties were visually observed over time for a total of 8 weeks when stored at room temperature (1-30°C), and the results are shown in Table 5 and Fig. 3(b).

[0117] Storage at room temperature (1-30℃) Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 At the time of manufacturing Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent After 1 week Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent After 2 weeks Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent After 4 weeks Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent After 6 weeks Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent After 8 weeks Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Transparent Colorless Precipitation occurred Precipitation occurred Precipitation occurred After 12 weeks Colorless Transparent Colorless Transparent Colorless Transparent, colorless, transparent, colorless, transparent---

[0118] As shown in Table 5, in the case of the dorzolamide-timolol transparent combination eye drop with the combination of hydroxypropyl gammadex and L-arginine added as a recrystallization inhibitor, as in Examples 13-17, it was confirmed that the colorless and transparent state was maintained for up to 8 weeks at pH 6.5, which is an optimal combination. In particular, in the case of the combination of hydroxypropyl gammadex and L-arginine as a recrystallization inhibitor, as in Examples 14-15, it was confirmed that the colorless and transparent state could be maintained for up to 8 weeks even when the content of L-arginine was reduced and a preservative such as benzalkonium chloride was omitted.

[0119] Of course, in the case of the dorzolamide-timolol transparent combination eye drop to which a combination of hydroxypropyl gammadex and potassium L-aspartate as anti-recrystallization agents was added, as in Examples 18-19, the colorless and transparent appearance was maintained for up to 6 weeks, and precipitation only occurred after 8 weeks, so it can be seen that it has storage stability for a considerable period of time. Even in the case where only hydroxypropyl gammadex was added as an anti-recrystallization agent, as in Example 20, but the combination of amino acids or their salts was excluded, it was confirmed that the colorless and transparent appearance was maintained for up to 6 weeks, and precipitation only occurred after 8 weeks.

[0120] In particular, as shown in Fig. 3(b), in the case of Example 13, it is visually confirmed that the colorless and transparent properties are maintained even after two weeks at pH 6.5.

[0121]

[0122] Afterwards, for Examples 15 and 17, the changes in the main ingredient content were analyzed using the <dorzolamide analysis method> and the <timolol analysis method>, respectively, at the time of manufacture vs. after 8 weeks of storage at room temperature (1-30°C), and the results are shown in Table 6.

[0123]

[0124] Dorzolamide Analysis Method

[0125] A. Preparation of standard stock solutions of flexible substances

[0126] Weigh accurately about 10 mg of dorzolamide-related compound B standard and about 10 mg of dorzolamide-related compound D standard, place in a 200 mL brown volumetric flask, add diluent to dissolve, and mark (* Diluent: Use a solution of 50 mL of acetonitrile and 950 mL of phosphate buffer as the diluent).

[0127] B. Preparation of standard solution

[0128] Weigh accurately about 11 mg of dorzolamide hydrochloride standard, place in a brown volumetric flask, add 50 mL of diluent, sonicate, then add 1 mL of the standard stock solution of flexible substances and measure with the diluent.

[0129] C. Preparation of test solution

[0130] Weigh approximately 0.27 g accurately, place in a 50 mL brown volumetric flask, add dilution solution, dissolve, and mark.

[0131] D. Device operating conditions

[0132] Use HPLC.

[0133] 1) Mobile phase A: Acetonitrile

[0134] 2) Mobile phase B: Phosphate buffer (* Phosphate buffer: Add 2 mL of 85% phosphoric acid to water to make 1000 mL)

[0135] 3) Mobile phase concentration gradient

[0136]

[0137] 4) Device and detector: LC / UV detector (253 nm)

[0138] 5) Column: C18, 4.6*250 mm, 5μm

[0139] 6) Flow rate: 1.2 mL / min

[0140] 7) Injection volume: 20 μL

[0141]

[0142] Timolol analysis method

[0143] A. Preparation of standard solution

[0144] Weigh accurately about 35 mg of timolol maleate standard, place in a 100 mL brown volumetric flask, add dilution solution, sonicate, and then mark with the dilution solution.

[0145] B. Preparation of test solution

[0146] Weigh approximately 1.32 g accurately, place in a 25 mL brown volumetric flask, add dilution solution, dissolve, and mark.

[0147] C. Device operating conditions

[0148] Use HPLC.

[0149] 1) Mobile phase: Mixture of methanol and phosphate buffer (40:60) (*Phosphate buffer: Dissolve 22g of sodium dihydrogen phosphate in 1995 mL, adjust to pH 2.8 with phosphoric acid, and adjust to the mark with purified water)

[0150] 2) Device and detector: LC / UV detector (295 nm)

[0151] 3) Column: C18, 4.6*250 mm, 5μm

[0152] 4) Flow rate: 1 mL / min

[0153] 5) Injection volume: 20 μL

[0154] 6) Column temperature: 40 ℃

[0155] Sample main ingredient content (%) Dorzolamide Timolol 8 weeks after manufacturing 8 weeks after manufacturing Example 1599.899.598.598.4 Example 17100.9101.399.499.6

[0156] As shown in Table 6, in the case of the dorzolamide-timolol transparent combination eye drops in which a combination of hydroxypropyl gammadex and L-arginine as anti-recrystallization agents was added at an optimal concentration, as in Examples 15 and 17, it was confirmed that the main ingredient content was maintained without significant change for up to 8 weeks at pH 6.5.

[0157]

[0158] In addition, for Examples 15 and 17, the occurrence of flexible substances was analyzed after 12 weeks of storage at room temperature (1-30°C) using the same method as the analysis of changes in main ingredient content.

[0159] As a result of the analysis, in the case of the dorzolamide-timolol transparent combination eye drop in which the combination of hydroxypropyl gammadex and L-arginine as an anti-recrystallization agent was added at the optimal concentration as in Examples 15 and 17, all of the following criteria were met: cis-dorzolamide of 2.0% or less, other individual elastic substances of 0.5% or less, and total elastic substances of 3.0% or less as a dorzolamide-related substance. In addition, all of the criteria were met: 0.5% or less of individual elastic substances and 1.0% or less as a timolol-related substance.

[0160]

[0161] The foregoing description of the present invention is for illustrative purposes only. Those skilled in the art will readily appreciate that modifications to other specific embodiments can be made without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. Carbonic anhydrase inhibitors; Timolol or a pharmaceutically acceptable salt thereof; and As a recrystallization inhibitor, containing cyclodextrin or a derivative thereof Transparent combination eye drops.

2. In paragraph 1, A transparent combination eye drop, characterized in that the carbonic anhydrase inhibitor is dorzolamide, methazolamide, brinzolamide, dichlorphenamide, acetazolamide or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, A transparent composite eye drop, characterized in that the above recrystallization inhibitor additionally contains an amino acid or a salt thereof.

4. In paragraph 1, A transparent composite eye drop characterized in that the transparent composite eye drop maintains a pH of 6.0 to 8.

0.

5. In paragraph 1, The concentration of the above carbonic anhydrase inhibitor is 10 mg / mL to 30 mg / mL, A transparent combination eye drop, characterized in that the concentration of timolol or a pharmaceutically acceptable salt thereof is 1 mg / mL to 10 mg / mL.

6. In paragraph 1, A transparent composite eye drop, characterized in that the cyclodextrin or derivative thereof comprises at least one selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl-beta-cyclodextrin, dimethyl-gamma-cyclodextrin, hydroxyethyl-alpha-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, hydroxypropyl-alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfurbutylether-alpha-cyclodextrin, sulfurbutylether-beta-cyclodextrin, and sulfurbutylether-gamma-cyclodextrin.

7. In paragraph 1, A transparent composite eye drop, characterized in that the concentration of the cyclodextrin or its derivative is 10 mg / mL to 200 mg / mL.

8. In paragraph 1, A transparent composite eye drop, characterized in that the concentration of the cyclodextrin or its derivative is 100 mg / mL to 130 mg / mL.

9. In paragraph 3, A transparent composite eye drop, characterized in that the amino acid or salt thereof comprises at least one selected from the group consisting of arginine, lysine, histidine, aspartic acid, glycine, alanine, valine, carnitine, levocarnitine, proline, leucine, and salts thereof.

10. In paragraph 3, A transparent composite eye drop, characterized in that the concentration of the amino acid or its salt is 0.1 mg / mL to 10 mg / mL.

11. In paragraph 3, A transparent composite eye drop, characterized in that the concentration of the amino acid or its salt is 1 mg / mL to 5 mg / mL.

12. In paragraph 1, The transparent composite eye drop is characterized in that it is a multi-use or disposable transparent composite eye drop. 13.(a) A step of preparing a first solution by adding cyclodextrin or a derivative thereof to a carbonic anhydrase inhibitor and stirring; (b) a step of preparing a second solution by adding timolol or a pharmaceutically acceptable salt thereof to the first solution prepared above and stirring the mixture; and (c) A method for producing a transparent composite eye drop, comprising a step of adjusting the pH of the second solution produced above.

14. In paragraph 13, A method for producing a transparent composite eye drop, characterized in that after adding timolol or a pharmaceutically acceptable salt thereof in the step (b), an amino acid or a salt thereof is additionally added.

15. In paragraph 13, A method for manufacturing a transparent composite eye drop, characterized in that in the step (c) above, the pH is adjusted to 6.0 to 8.0.

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