Eye drop composition for preventing or treating eye diseases and method for producing the same

Abstract

Provided is an eye drop composition for preventing or treating an ophthalmic disease, comprising (a) a lyophilized preparation containing atropine or a pharma- ceutically acceptable salt thereof, and (b) a reconstitution diluent, wherein the lyophilized preparation and the reconstitution diluent are separated from each other.

Description

[Technical Field]

[0001] [Cross-reference to related application] This application claims priority to Patent Application No. 202110614105.6, filed June 2, 2021, the entire contents of which are incorporated herein by reference.

[0002] [Technical field] The present invention belongs to the field of ophthalmic pharmaceuticals, and specifically relates generally to eye drop compositions for preventing or treating ophthalmic diseases and methods for preparing the same. [Background technology]

[0003] In recent years, changes in the social environment, the accelerating pace of life, the widespread use of video terminals, and increased pressure from studying and working have led to an increasing trend in visual fatigue caused by excessive eye strain. The number of myopic patients is increasing, with a particularly notable increase in the prevalence among teenagers. According to a joint survey by the Chinese Ministry of Health and the Ministry of Education, the current prevalence of myopia among Chinese students is nearly 60%, second only to Japan in the world, and the number of patients exceeds 60 million, the highest in the world, with approximately 300,000 people becoming blind due to myopia. The incidence of myopia is also increasing in Western countries.

[0004] Current treatments are primarily health care and Western medicine. Atropine-based medications are currently the most commonly used in Western medicine. Years of clinical research by experts and scholars in Singapore, the United States, and other countries have confirmed that atropine is currently the most effective medication for preventing and treating myopia in adolescents and children. Atropine sulfate eye drops, USP, 1%, were approved by the FDA in 1960 and are available in 2ml: 20mg, 5ml: 50mg, and 15ml: 150mg doses. They are used to treat cycloplegia, mydriasis, and amblyopia. In Singapore, 0.01% atropine sulfate eye drops are used to treat myopia in children and adolescents.

[0005] However, current atropine sulfate eye drops have the following drawbacks: (1) The drug concentration is too high and the instantaneous dose to the eye is too large, resulting in relatively severe ocular side effects and making the drug's safety unreliable. On the other hand, if the drug concentration is too low or the instantaneous dose to the eye is too small, the effect is delayed, ineffective, or ineffective, limiting the scope of application of atropine eye drops. (2) Because atropine sulfate is an ester drug, it is easily decomposed in aqueous solution, and the pharmaceutical composition is easily hydrolyzed during storage, resulting in loss of efficacy. In the absence of elements capable of stabilizing hydroxide ions in aqueous solution, atropine sulfate is susceptible to the influence of hydroxide ions, resulting in the bond being broken and decomposition, producing belladonna phenol, tropic acid, and other related substances. Alternatively, hydroxide ions can easily bind to the chair structure of atropine sulfate, forming related substances such as 6-hydroxyscopolamine and 7-hydroxyscopolamine. Therefore, atropine sulfate aqueous solution is an active ingredient that is very sensitive to the buffer system, and even a slight difference in the buffer system can cause serious decomposition of atropine sulfate, resulting in loss of medicinal activity, drug malfunction, and the inability to exert therapeutic effects. In other words, all eye drops currently on the market have stability risks. Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to overcome the problem of poor hydrolysis that may occur during long-term storage of atropine solutions in the prior art, and to provide a novel eye drop composition for the prevention or treatment of eye diseases. [Means for solving the problem]

[0007] To achieve the above object, the present invention provides a freeze-dried preparation comprising: (a) atropine or a pharmaceutically acceptable salt thereof; and (b) a reconstituted lyophilized preparation. Seiki The freeze-dried preparation and the reconstituted SeikiThe present invention provides an eye drop composition for preventing or treating an ophthalmic disease, in which the lyophilized formulation and the diluent for reconstitution are separated. That is, the eye drop composition of the present invention is characterized by comprising two parts: the lyophilized formulation and the diluent for reconstitution.

[0008] First, the freeze-dried formulation contains atropine or a pharmaceutically acceptable salt thereof as an active ingredient. According to the present invention, the pharmaceutically acceptable salt may be a pharmaceutically acceptable acid addition salt, which means a salt formed with an inorganic or organic acid that can retain the efficacy of the free base without other side effects.

[0009] Specific examples of inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; specific examples of organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, decanoate, undecenoate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalenedisulfonate. These salts can be prepared by methods known in the art. In a preferred embodiment, the pharmaceutically acceptable salt may be a sulfate salt, i.e., the pharmaceutically acceptable salt of atropine is atropine sulfate, also referred to as atropine sulfate.

[0010] Furthermore, atropine or a pharmaceutically acceptable salt thereof is used as the active ingredient in the eye drop composition. However, as described above, if the drug concentration is too high, the instantaneous dose to the eye is too high, resulting in relatively severe ocular side effects of atropine, and the safety of the drug cannot be guaranteed. On the other hand, if the drug concentration is too low, resulting in a too small instantaneous dose to the eye, the effect will be delayed, poor, or ineffective. Therefore, in a preferred embodiment, the concentration of the atropine or a pharmaceutically acceptable salt thereof may be 0.001 to 2% (w / v), preferably 0.01 to 0.5% (w / v), and more preferably 0.01 to 0.08% (w / v), such as 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, and 0.07%, expressed in kg / L. Unless otherwise specified, all concentration percentages herein are in w / v (kg / L) units, which are the weight of the component in the corresponding formulation per unit volume. In particular, in the case of the lyophilized formulation, the percentage represents the weight of the component relative to the unit volume of the lyophilized formulation before lyophilization.

[0011] In addition to atropine or a pharmaceutically acceptable salt thereof as the active ingredient, the lyophilized formulation also contains a buffer salt system, Matrix Agent and stabilizers. In a preferred embodiment, the buffer salt system may be one or more selected from a citrate buffer system and a phosphate buffer system, preferably a citrate buffer system, and more preferably a buffer salt concentration of 0.01 to 1% (e.g., 0.05%, 0.1%, 0.2%, 0.5%, etc.). Here, the citrate buffer system may be a citrate buffer system containing anhydrous citric acid and / or sodium citrate dihydrate.

[0012] In another preferred embodiment, Matrix Agent Specifically, may be one or more selected from mannitol, sorbitol, sodium chloride and sucrose, preferably mannitol, more preferably Matrix AgentThe concentration may be 1 to 4% (for example, 1.5%, 2%, 2.5%, or 3%, etc.).

[0013] In another preferred embodiment, the stabilizer may be one or more selected from sorbitol and mannitol, preferably sorbitol, and more preferably the concentration of the stabilizer may be 0.05 to 1% (e.g., 0.1%, 0.2%, 0.5%, or 0.8%, etc.).

[0014] Next, regarding the reconstitution diluent, the reconstitution diluent may include one or more of a buffer salt system, an osmolality adjusting agent, a chelating agent, and a bacteriostatic agent.

[0015] In a preferred embodiment, the buffer salt system may be one or more selected from purified water, a phosphate buffer system, and a citrate buffer system, preferably a citrate buffer system, and more preferably, the concentration of the buffer salt may be 0.01 to 1% (e.g., 0.02%, 0.05%, 0.1%, 0.2%, 0.5%, etc.).

[0016] In another preferred embodiment, the osmotic pressure adjuster may be one or more selected from mannitol, sodium chloride, glucose, phosphate buffer, and borax, preferably mannitol, and more preferably, the concentration of the osmotic pressure adjuster may be 1 to 4% (e.g., 1.5%, 2%, 2.5%, 3%, etc.).

[0017] In another preferred embodiment, the chelating agent may specifically be edetate disodium, and preferably, the concentration of the chelating agent may be 0.01% to 0.03% (e.g., 0.015%, 0.02%, 0.025%, etc.).

[0018] In another preferred embodiment, the bacteriostatic agent may be one or more selected from benzalkonium chloride, ethylparaben, benzalkonium chloride, benzalkonium bromide, and polyquaternium-1, preferably benzalkonium chloride, and more preferably the concentration of the bacteriostatic agent is 0.005 to 0.1% (e.g., 0.01%, 0.02%, 0.05%, etc.).

[0019] It should be understood that, in addition to the active ingredient, the other reagents described above as additives in the lyophilized formulation and reconstitution diluent of the present invention can be set alone, optionally, or interchangeably in the lyophilized formulation and / or reconstitution diluent according to the actual situation and the conventional knowledge of those skilled in the art. In addition to the above-mentioned specific ingredients or compounds, the eye drop composition of the present invention may also contain other pharmaceutically acceptable excipients, carriers, or diluents according to actual needs. Regarding the pH of the eye drop composition of the present invention, the pH of the freeze-dried preparation and the pH of the reconstituted diluent may be independently 5.0 to 6.4, more preferably about 5.5, so that the eye drop composition of the present invention has an appropriate pH value.

[0020] On the other hand, the present invention further specifically relates to (a) a buffer salt system in the freeze-dried formulation, comprising atropine or a pharmaceutically acceptable salt thereof, and optionally Matrix Agent and stabilizer, and freeze-drying the mixture to obtain the freeze-dried formulation; and (b) re-recording A method for preparing the above-described ophthalmic solution composition is provided, comprising the step of contacting a buffer salt system in a reconstituted diluent with, optionally, one or more of an osmolality adjusting agent, a chelating agent, and a bacteriostatic agent to obtain the reconstituted diluent.

[0021] More specifically, the step (a) includes, for example, the steps of: (1) weighing a buffer salt into a dedicated container and preparing a solution (e.g., 10 to 25 mM concentration) while stirring; (2) sequentially adding mannitol and sorbitol, dissolving, adding atropine sulfate, adjusting the pH (e.g., 5.0 to 6.4), adjusting the volume to a constant volume; (3) sterile filtration; (4) filling; and (5) lyophilization, etc. The step (b) includes, for example, the steps of: (1) weighing a buffer salt into a dedicated container and preparing a solution (e.g., 10 to 25 mM concentration) while stirring; (2) sequentially adding solutions of mannitol, sodium chloride, and benzalkonium chloride, stirring to completely dissolve, adjusting the pH (e.g., 5.0 to 6.4), adjusting the volume to a constant volume; (3) sterile filtration; and (4) filling. Here, the pH can be adjusted by adding an acidic solution such as HCl or an alkaline solution such as NaOH, and the volume can be adjusted to a predetermined volume by adding water such as sterile water for injection.

[0022] Meanwhile, the present invention further provides a kit for preventing or treating an ophthalmic disease, comprising (a) a lyophilized formulation containing atropine or a pharmaceutically acceptable salt thereof, (b) a reconstitution diluent, and optionally (c) instructions for use, wherein the lyophilized formulation and the reconstitution diluent are separated.

[0023] On the other hand, the present invention further provides use of an effective amount of the eye drop composition in preparing an eye drop for treating the above-mentioned ophthalmic disease, which comprises mixing the freeze-dried formulation with the reconstitution diluent.

[0024] More specifically, in one embodiment of the invention, said ophthalmic disorder is selected from cycloplegia, mydriasis, amblyopia, myopia, or a combination thereof, in particular childhood and adolescent myopia. [Effects of the Invention]

[0025] The present inventors have conducted research to determine whether the eye drop composition of the present invention can be reconstituted with a freeze-dried preparation. SeikiBecause it consists of two parts, a solvent and a diluent, it has been found that the risk of moisture loss and decomposition of the solution-state atropine drug during long-term storage is reduced, ensuring the stability of the sample during long-term storage. DETAILED DESCRIPTION OF THE INVENTION

[0026] Specific embodiments of the present invention will be described in detail below. It should be understood that the specific embodiments described herein are used only to illustrate and explain the present invention, and are not intended to limit the present invention.

[0027] The endpoints of ranges and any values ​​disclosed herein are not limited to the exact range or value, but should be understood to include values ​​approaching such ranges or values. In the case of numerical ranges, it is possible to combine the endpoints of each range, the endpoints of each range and the individual point values, and the individual point values ​​with each other to obtain one or more new numerical ranges, and these numerical ranges shall be considered to be specifically disclosed herein.

[0028] Hereinafter, embodiments of the present invention will be described with reference to specific examples, but those skilled in the art will be able to easily understand other advantages and effects of the present invention from the contents disclosed in this specification, and it is clear that the described examples are only some of the examples of the present invention and do not represent all of the examples. All other examples that can be obtained by those skilled in the art based on the examples of the present invention without any creative work are all included in the scope of protection of the present invention.

[0029] In the following examples, stability criteria as set forth in the table below are used to measure the stability of the lyophilized formulation, reconstituted diluent, and reconstituted eye drops to determine the stability results of the formulations of the present invention. Stability criteria for lyophilized formulations:

[0030] [Table 1]

[0031] Diluent Stability Criteria:

[0032] [Table 2]

[0033] Stability criteria for eye drops:

[0034] [Table 3]

[0035] Example 1 Lyophilized formulation:

[0036] [Table 4]

[0037] A lyophilized formulation is prepared according to the above formula, and if the stability results still meet the requirements after 6 months, it indicates that both of the two formulas can meet the stability requirements.

[0038] Example 2 Reconstitution Diluent Formulation

[0039] [Table 5]

[0040] When the reconstituted diluent was prepared according to the above formula and adjusted to pH 6.0, the stability data showed that the samples were within the stability period and had better stability in both buffer systems.

[0041] Example 3 Determining the concentration of benzalkonium chloride in formulations The antimicrobial efficacy test (AET) was used to verify the concentration of benzalkonium chloride (BAK) in atropine sulfate eye drops. The lyophilized preparation was reconstituted with 8 ml of reconstitution diluent containing 100 ppm, 80 ppm, 50 ppm, 25 ppm, or 0 ppm BAK to obtain atropine sulfate eye drops (0.01%) with different benzalkonium chloride concentrations. The results of the antimicrobial efficacy test were found to be in compliance with the specifications for all test concentrations except 0 ppm.

[0042] [Table 6]

[0043] According to the standards of the Chinese Pharmacopoeia, if the concentration of benzalkonium chloride in the formulation exceeds 70 ppm, it can more effectively ensure that the standard requirements for antibacterial efficacy "A" are met during long-term storage.

[0044] Example 4 Eye drop composition 1. The formulation of the lyophilized formulation and reconstitution diluent is as shown in the table below.

[0045] [Table 7]

[0046] 2. Process flow: Preparation of lyophilized formulation: (1) Weigh out the buffer salts and add them to an appropriate container. Add water for injection and stir for 20 minutes until completely dissolved. Adjust the pH and add water for injection to the specified volume. (2) Weigh out a certain amount of buffer into a preparation container, add other excipients in order, visually confirm, add atropine sulfate, dissolve with stirring, and adjust the pH to the target value.

[0047] To prepare the reconstituted diluent: (1) Weigh out the buffer salts and place in a suitable container. Add water for injection and stir until completely dissolved. (2) Add the other excipients one by one and dissolve with stirring. (3) Adjust the pH and vol.

[0048] 3. Stability Results

[0049] According to the above stability criteria and measurement results, the lyophilized formulation and reconstituted diluent were left at 25°C ± 2°C / 60% RH ± 5% RH for 12 months and at 40°C ± 2°C / 75% RH ± 5% RH for 6 months, and both showed good stability results. After reconstitution, the eye drops were left at 25°C / 60% RH for 8 weeks, and also showed good stability results.

[0050] As can be seen from the results of Examples 1 to 4, the eye drop composition provided by the present invention has good stability. That is, the problem of decreased stability as a solution can be effectively solved by preparing atropine eye drops alone as a freeze-dried preparation.

[0051] Although the preferred embodiments of the present invention have been described in detail above, the present invention is not limited to the above embodiments, and various simple modifications are possible within the scope of the technical concept of the present invention, and all of these simple modifications fall within the scope of protection of the present invention.

[0052] Furthermore, the specific technical features described in the above specific embodiments can be combined in any appropriate manner as long as there is no contradiction, and in order to avoid unnecessary duplication, the present invention will omit separate descriptions of various possible combination methods.

[0053] Furthermore, various embodiments of the present invention can be arbitrarily combined, and as long as they are not contrary to the spirit of the present invention, they should also be considered as part of the disclosure of the present invention.

Claims

1. An eye drop composition for preventing or treating an ophthalmic disease, comprising: (a) a lyophilized formulation comprising atropine or a pharmaceutically acceptable salt thereof; and (b) a reconstitution diluent; the lyophilized formulation and the reconstitution diluent are separated; The lyophilized formulation comprises a buffer salt system, a matrix agent, and a stabilizer, and the reconstitution diluent comprises a buffer salt system, an osmotic pressure adjusting agent, a chelating agent, and a bacteriostatic agent.

2. 2. The eye drop composition of claim 1, wherein the pharmaceutically acceptable salt of atropine is atropine sulfate.

3. 2. The eye drop composition according to claim 1, wherein the concentration of the atropine or a pharmaceutically acceptable salt thereof is 0.001 to 2%.

4. 4. The eye drop composition according to claim 3, wherein the concentration of the atropine or a pharmaceutically acceptable salt thereof is 0.01 to 0.5%.

5. 5. The eye drop composition according to claim 4, wherein the concentration of the atropine or a pharmaceutically acceptable salt thereof is 0.01 to 0.08%.

6. 2. The eye drop composition according to claim 1, wherein the eye drop composition has a pH of 5.0 to 6.

4.

7. The buffer salt system of the freeze-dried preparation is one or more selected from a citrate buffer system and a phosphate buffer system. The eye drop composition of claim 1, wherein

8. 8. The eye drop composition of claim 7, wherein the buffer salt system of the lyophilized formulation is a citrate buffer system.

9. 9. The eye drop composition according to claim 7, wherein the concentration of the buffer salt system in the freeze-dried preparation is 0.01 to 1%.

10. 2. The eye drop composition according to claim 1, wherein the matrix agent is one or more selected from the group consisting of mannitol, sorbitol, sodium chloride, and sucrose.

11. The eye drop composition of claim 10, wherein the matrix agent is mannitol.

12. 12. The eye drop composition according to claim 10, wherein the concentration of the matrix agent is 1 to 4%.

13. 10. The method of claim 1, wherein the stabilizer is one or more selected from sorbitol and mannitol. The eye drop composition according to claim 1.

14. 14. The ophthalmic solution composition of claim 13, wherein the stabilizer is sorbitol.

15. 15. The eye drop composition according to claim 13, wherein the concentration of the stabilizer is 0.05 to 1%.

16. 2. The eye drop composition according to claim 1, wherein the buffer salt system of the reconstitution diluent is one or more selected from a phosphate buffer system and a citrate buffer system.

17. 17. The ophthalmic solution composition of claim 16, wherein the buffer salt system of the reconstitution diluent is a citrate buffer system.

18. 18. The eye drop composition according to claim 16 or 17, wherein the concentration of the buffer salt system in the reconstitution diluent is 0.01 to 1%.

19. 2. The eye drop composition according to claim 1, wherein the osmotic pressure adjusting agent is one or more selected from the group consisting of mannitol, sodium chloride, glucose, phosphate buffer, and borax.

20. 20. The eye drop composition of claim 19, wherein the osmolality adjusting agent is mannitol.

21. 21. The eye drop composition according to claim 19, wherein the concentration of the osmotic pressure adjusting agent is 1 to 4%.

22. 2. The eye drop composition of claim 1, wherein the chelating agent is edetate disodium.

23. 23. The eye drop composition of claim 22, wherein the chelating agent is present in a concentration of 0.01% to 0.03%.

24. 2. The eye drop composition according to claim 1, wherein the bacteriostatic agent is one or more selected from the group consisting of benzalkonium chloride, ethylparaben, benzalkonium chloride, benzalkonium bromide, and polyquaternium-1.

25. 25. The eye drop composition of claim 24, wherein the bacteriostatic agent is benzalkonium chloride.

26. 26. The eye drop composition according to claim 24 or 25, wherein the bacteriostatic agent has a concentration of 0.005 to 0.3%.

27. A method for preparing the eye drop composition according to any one of claims 1 to 26, comprising the steps of: (a) contacting the buffer salt system in the lyophilized formulation with atropine or a pharmaceutically acceptable salt thereof, a matrix agent, and a stabilizer, and lyophilizing to obtain the lyophilized formulation; (b) contacting the buffer salt system in the reconstituted diluent with an osmolality adjusting agent, a chelating agent, and a bacteriostatic agent to obtain the reconstituted diluent.

28. 28. The method of claim 27, wherein steps (a) and (b) each independently further comprise adjusting the pH of the mixed solution to 5.0 to 6.4 after the contacting is complete.

29. A kit for preventing or treating an ophthalmic disease, comprising: (a) a lyophilized formulation comprising atropine or a pharmaceutically acceptable salt thereof; and (b) a reconstitution diluent, wherein the lyophilized formulation and the reconstitution diluent are separated; The lyophilized formulation comprises a buffer salt system, a matrix agent, and a stabilizer; The reconstitution diluent comprises a buffer salt system, an osmolality adjusting agent, a chelating agent, and a bacteriostatic agent.

30. 30. The kit of claim 29, wherein the kit further comprises (c) instructions for use.

31. A method for preparing an eye drop for treating an ophthalmic disease, comprising using an effective amount of the eye drop composition according to any one of claims 1 to 26, the preparing comprising mixing the lyophilized formulation with the reconstitution diluent; the lyophilized formulation comprises atropine or a pharmaceutically acceptable salt thereof, and further comprises a buffer salt system, a matrix agent, and a stabilizer; The method of claim 1, wherein the reconstitution diluent comprises a buffer salt system, an osmolality adjusting agent, a chelating agent, and a bacteriostatic agent.

32. 32. The method of claim 31, wherein the ophthalmic condition is selected from cycloplegia, mydriasis, amblyopia, myopia, or a combination thereof.

33. 33. The method of claim 32, wherein the ophthalmic disease is childhood and adolescent myopia.

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