Naphthalene derivative-based therapeutic agents for ophthalmic diseases

Abstract

The present invention relates to a formulation comprising KUS121 that can be internally administered into the vitreous body.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical product comprising KUS121 which can be administered into the vitreous. Background of the Invention

[0002] Sodium 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonate dihydrate (hereinafter also referred to as "KUS121") is a compound having a naphthalene structure, which has now been developed as a drug for treating retinal ischemic diseases and retinal degenerative diseases (Patent Document 1). One of the recommended administration methods for KUS121 is injection directly into the vitreous body of the eye.

[0003] When KUS121 is injected into the vitreous, phosphate buffered saline (PBS buffer) is considered to be very suitable as an administration vehicle considering the physical properties of the vitreous fluid, such as pH (about 7.5) and osmolarity (about 290 mOsm / kg), as well as the past safety record of intravitreal injections.

[0004] On the other hand, the volume of the vitreous is limited to about 4 mL, and injecting a large volume of the administration solution into the vitreous may damage the intraocular tissue and increase the intraocular pressure. Therefore, the administration volume needs to be as small as possible (about 100 μL or less), and the required dose of the drug needs to be contained in this small volume of the administration solution.

[0005] When preparing an administration solution containing KUS121, the solubility of KUS121 in water (at 25°C) is relatively high, about 2.8 mg / mL, while the solubility of KUS121 in PBS buffer is very low, due to the ionic effect of the high concentration of inorganic ions in the buffer. In order to dissolve a given amount of KUS121 in PBS buffer and administer it to the vitreous, the amount of PBS buffer needs to be significantly increased relative to the amount of KUS121. However, as described above, when administered to the vitreous, it is necessary to minimize the amount of injection solution, and increasing the amount of PBS buffer is inappropriate.

[0006] Furthermore, since the osmotic pressure of normal PBS buffer is approximately the same as that in the vitreous body (about 290 mOsm / kg), considering the extremely low solubility of KUS121 in PBS buffer as described above, it is not appropriate to reduce the concentration of PBS buffer because such dilution will reduce the osmotic pressure.

[0007] Even if an attempt is made to increase solubility by adding a dissolution aid as another means of improving solubility, it is extremely difficult to select an appropriate dissolution aid because the site of administration is the vitreous body, which is a fragile area. Further, even if KUS121 is dissolved in a PBS buffer by warming before administration, it is not practical to perform a series of operations in an actual medical environment, such as quickly dissolving it by warming, cooling it to an appropriate temperature, and then injecting it into the vitreous body of the eye. Alternatively, even if a dissolving solution other than the PBS buffer is to be considered, it is not easy to consider such another solution in consideration of the osmotic pressure matching the fluid in the vitreous body, safety, etc.

[0008] Prior art

[0009] (Patent References)

[0010] [Patent Document 1] WO2012 / 014994 Summary of the invention

[0011] (Technical Issues)

[0012] The object of the present invention is to prepare an injection formulation containing KUS121 for direct injection into the vitreous body, wherein KUS121 is dissolved in a PBS buffer solution and adjusted to a predetermined concentration, the dissolved state can be maintained for a certain period of time, and the pH and osmotic pressure of the application solution are adjusted to the same level as in the vitreous body.

[0013] (Solution to the problem)

[0014] The maximum dose of KUS121 applied to the vitreous of the eye is 50 μg / eye, and the volume of liquid that can be applied to the vitreous is preferably about 100 μL or less. Further, in preliminary experiments, it was found that the soluble concentration of KUS121 in normal PBS buffer solution was 0.01 mg / mL or less at room temperature. In view of these premises and the above-mentioned problems, the inventors have extensively studied the design of KUS121 injection formulations in normal PBS buffer, which can be applied to the vitreous, wherein about 50 μg of KUS121 is dissolved in normal PBS buffer (about 100 μL), that is, the concentration is set to 0.5 mg / mL, and the formulation of the osmotic pressure in the vitreous is matched. Therefore, the inventors have conducted the following experiments, and then have found the following matters: that is, the inventors first prepared 1 mL of 0.1 mg / mL KUS121 aqueous solution by dissolving KUS121 in water for injection, and then adding a PBS buffer solution having about twice the normal concentration to the KUS121 solution, wherein the PBS concentration is 1 / 5 of the normal concentration. Then, the prepared KUS121 aqueous solution was lyophilized, and 200 μL (0.2 mL) of water for injection [200 μL (0.2 mL) corresponds to 1 / 5 of the volume before lyophilization] was added to the lyophilized product. Therefore, the lyophilized formulation containing KUS121 is completely dissolved even if the drug concentration is 5 times higher than the concentration before lyophilization and the drug concentration is more than 50 times higher than its solubility. Further, it was also found that the dissolved state remained stable for more than 24 hours. Based on the new discovery, the present invention has been completed. One of the administration solutions of the present invention is an administration solution in which 50 μg of KUS121 is dissolved in 100 μL of PBS buffer at a maximum dose and adjusted to the pH and osmotic pressure in the vitreous.

[0015] The present invention includes the following embodiments.

[0016] (Item 1) A lyophilized drug product prepared by the following steps: (i) dissolving sodium 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonate dihydrate (hereinafter abbreviated as "KUS121") in water for injection or a PBS buffer solution more diluted than usual, (ii) adding a PBS buffer solution more concentrated than usual to the solution while maintaining the dissolved state of the solution, and (iii) lyophilizing the obtained solution,

[0017] It is characterized in that when the lyophilized product is dissolved in water for injection before administration, the solution remains in a solution state, wherein the concentration of KUS121 is 0.100 to 0.625 mg / mL (preferably 0.125 to 0.5 mg / mL), and the concentration of PBS is a normal PBS concentration.

[0018] (Item 2) The lyophilized drug product according to Item 1, wherein the more concentrated PBS buffer than usual has a concentration 2 to 10 times higher than the normal PBS concentration.

[0019] (Item 3) The lyophilized pharmaceutical product according to Item 1 or 2, wherein before the (iii) lyophilization step, the PBS concentration of the solution is 1 / 5 to 1 / 1 (preferably 1 / 5 to 1 / 2) of the normal PBS concentration.

[0020] (Item 4) The freeze-dried pharmaceutical product according to any one of Items 1 to 3, wherein the volume of water for injection added to the freeze-dried product is 1 / 5 to 1 / 1 (preferably 1 / 5 to 1 / 2) of the volume of the solution before the freeze-drying step (iii).

[0021] (Item 5) The lyophilized pharmaceutical product according to any one of Items 1 to 4, wherein the osmotic pressure of a solution prepared by dissolving the lyophilized product in water for injection is 230 to 360 mOsm / kg.

[0022] (Item 6) The freeze-dried pharmaceutical product according to any one of Items 1 to 5, wherein the pH of a solution prepared by dissolving the freeze-dried product in water for injection is 6.8 to 8.2.

[0023] (Item 7) The lyophilized drug product according to any one of Items 1 to 4, wherein the normal PBS concentration is a concentration of a PBS buffer having an osmotic pressure of 230 to 360 mOsm / kg and a pH of 6.8 to 8.2.

[0024] (Item 8) A lyophilized drug product prepared by the following steps: (i) dissolving KUS121 in water for injection, (ii) adding a PBS buffer having a concentration equivalent to 2 to 10 times (preferably about twice) higher than the normal PBS concentration to the KUS121 solution, whereby the PBS concentration is 1 / 5 to 1 / 2 (preferably about 1 / 5) of the normal concentration, while maintaining the dissolved state of the solution, and (iii) lyophilizing the obtained solution,

[0025] It is characterized in that when the lyophilized product is dissolved in water for injection with a volume of 1 / 5 to 1 / 2 (preferably about 1 / 5) of the solution before the (iii) lyophilization step before administration, the solution remains in a solution state, wherein the concentration of KUS121 is 0.100 to 0.625 mg / mL (preferably 0.125 to 0.5 mg / mL), and the concentration of PBS is a normal PBS concentration.

[0026] (Item 9) The lyophilized drug product according to any one of Items 1 to 8, wherein a KUS solution comprising a PBS buffer is dispensed into each vial prior to the (iii) lyophilization step, wherein the amount of KUS121 is 20 to 125 μg (preferably 25 to 100 μg) per vial, and the drug product is stored in the vial in a lyophilized state.

[0027] (Item 10) A vial containing a lyophilized drug product containing KUS121 for intravitreal injection, wherein the lyophilized drug product comprises 20 μg to 125 μg (preferably 25-100 μg) of KUS121 and a PBS buffer dry component, wherein the PBS buffer dry component corresponds to 0.1 mL to 0.4 mL (preferably 0.2 mL) of a normal PBS buffer solution excluding water.

[0028] (Item 11) A method for preparing a lyophilized drug product, which can be dissolved in water for injection to prepare a PBS buffer solution containing 0.100 to 0.625 mg / mL (preferably 0.125 to 0.5 mg / mL) of KUS121, wherein the PBS concentration is a normal PBS concentration, the method comprising:

[0029] Dissolve KUS121 in water for injection or in a more dilute PBS buffer solution than usual.

[0030] adding a more concentrated PBS buffer than usual to the solution while maintaining the solution in a dissolved state, and

[0031] The obtained solution was lyophilized.

[0032] (Item 12) The method according to Item 11, wherein the normal PBS concentration is a concentration of a PBS buffer having an osmotic pressure of 230 to 360 mOsm / kg and a pH of 6.8 to 8.2.

[0033] (Item 13)

[0034] The method according to item 11 or 12, wherein the more concentrated PBS buffer than usual has a concentration corresponding to 2 to 10 times higher than the concentration of normal PBS.

[0035] (Item 14) The method according to any one of Items 11 to 13, wherein the PBS concentration of the solution before the (iii) freeze-drying step is 1 / 5 to 1 / 1 (preferably 1 / 5 to 1 / 2) of the normal PBS concentration.

[0036] (Item 15) The method according to any one of Items 11 to 14, wherein the volume of water for injection added to the freeze-dried product is 1 / 5 to 1 / 1 (preferably 1 / 5 to 1 / 2) of the volume of the solution before the freeze-drying step (iii).

[0037] (Item 16) The method according to any one of Items 11 to 14, wherein the PBS buffer solution containing KUS121 can be prepared by dissolving the lyophilized drug product in 200 μL of water for injection per vial.

[0038] (Item 17) The method according to any one of Items 11 to 16, wherein the concentration of KUS121 in the solution before the lyophilization step is 0.020 to 0.125 mg / mL (preferably 0.025 to 0.1 mg / mL).

[0039] (Item 18) The lyophilized drug product according to any one of Items 1 to 9, the vial according to Item 10, or the method according to any one of Items 11 to 17, wherein the [Na + ]、[K + ]、[Cl - ] and [PO4 3- ] are 100 to 200mmol / L, 0 to 6.5mmol / L, 90 to 180mmol / L and 6 to 14mmol / L respectively.

[0040] (Effects of the Invention)

[0041] In the present invention, once KUS121 is completely dissolved in water for injection having high solubility for KUS121, a PBS buffer solution having a concentration higher than the usual concentration is added to the solution while maintaining the dissolved state to prepare a PBS solution having a concentration equivalent to about 5 times the concentration of a usual PBS solution diluted. Therefore, the dissolved state of the solution obtained above is more stable than the dissolved state obtained by dissolving KUS121 in a supersaturated state in a PBS buffer solution having a normal concentration, and there is almost no problem of precipitation of KUS121 during operations such as sterile filtration before lyophilization.

[0042] In the present invention, although the same concentration of KUS121 is not dissolved in PBS buffer, a solution obtained by dissolving a lyophilized drug product in water for injection can be smoothly prepared, and although considered to be in a supersaturated state, its dissolved state is very stable and suitable as the administration preparation of the present invention. DETAILED DESCRIPTION

[0043] The active ingredient KUS121 of the present invention is sodium 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonate dihydrate (hereinafter abbreviated as "KUS121"). However, in the pharmaceutical product of the present invention, KUS121 is once dissolved in a PBS buffer solution and then lyophilized, so it does not necessarily exist as a dihydrate or sodium salt in the pharmaceutical product. Therefore, it may be in an anhydrous form, and may be a salt with other cations such as potassium salt, calcium salt and magnesium salt, and is in a salt-free state, so the definition of KUS121 includes these analogs.

[0044] Generally, KUS121 exists stably as a dihydrate, but in the present invention, its concentration is calculated based on the anhydrous form.

[0045] In the present invention, "PBS buffer solution more concentrated than usual" means that it is more concentrated than the normal PBS concentration, and in particular, there is no limitation, as long as when it is added to the KUS121 solution, it maintains its dissolved state once dissolved before lyophilization, and the PBS concentration in the solution prepared by adding water for injection after lyophilization can be adjusted to the normal PBS concentration. "PBS buffer solution more concentrated than usual" is, for example, 2 to 10 times, preferably 2 to 5 times, more preferably 2 to 3 times, and even more preferably about 2 times the normal PBS concentration.

[0046] In the present invention, "a PBS buffer solution more dilute than usual" is not particularly limited as long as it is more dilute than the usual PBS concentration. Since "a PBS buffer solution more dilute than usual" is written in parallel with "water for injection", such as "water for injection or a PBS buffer solution more dilute than usual", the lower limit of "a PBS buffer solution more dilute than usual" is intended to be water for injection, that is, the PBS concentration is 0. Regarding "water for injection or a PBS buffer solution more dilute than usual", water for injection is preferably used. In addition, considering the sterile filtration before lyophilization, the water for injection here can be purified water.

[0047] This state in which KUS121 is dissolved before lyophilization does not necessarily mean that it is dissolved in a normal state, but includes a case in which it is dissolved in a supersaturated state.

[0048] The "volume of water for injection added to the lyophilized product" is not particularly limited as long as the PBS concentration in the solution dissolved by the addition of water for injection becomes the normal PBS concentration. For example, if the PBS concentration of the solution before lyophilization is 1 / 5 of the normal concentration; by adding water for injection in a volume of 1 / 5 of the volume of the solution before lyophilization, the PBS concentration of the administered solution will become the normal PBS concentration. The "volume of water for injection added to the lyophilized product" is, for example, 1 / 5 to 1 / 1, preferably 1 / 5 to 1 / 2, and more preferably about 1 / 5.

[0049] In the present invention, the amount of KUS121 administered to the vitreous body is 12.5 μg / eye, 25 μg / eye, or 50 μg / eye, or 12.5 μg to 50 μg / eye at a time. Alternatively, these doses can be appropriately reduced according to the patient's condition.

[0050] In the pharmaceutical product of the present invention, for example, a lyophilized preparation containing 0.025 to 0.1 mg of KUS121 is dissolved in 200 μL of water for injection, and 100 μL of the solution is injected into the vitreous body, whereby KUS121 can be administered in an amount of 12.5 to 50 μg / eye.

[0051] When dissolved in water for injection, the pH of the solution is 6.8 to 8.2, preferably 7.0 to 8.0, more preferably 7.2 to 7.8.

[0052] When dissolved in water for injection, the osmotic pressure of the solution is 230 to 360 mOsm / kg, preferably 250 to 330 mOsm / kg.

[0053] In the present invention, "phosphate buffered saline (PBS buffer)" is not particularly limited as long as it is a PBS buffer having a commonly prepared composition or a commercially available PBS buffer and it contains Na + , K + , H + , Cl - PO4 3- OH - ions, some do not contain K + , some containing Ca 2+ and Mg 2+ , and the pH is adjusted to 7.2 to 7.4. Examples of common PBS buffers have compositions as shown in the following table. Also, some materials have multiple different hydrates, but the following table shows the amounts calculated based on the anhydrous form, and the type of hydrate is not important.

[0054]

[0055] In the present invention, "PBS concentration" is an index using the concentration of the above-mentioned normal PBS buffer as a standard. For example, if it is 1 / 5 of the normal concentration, it means that the above-mentioned ion concentration is diluted by 1 / 5, and if it is 2 times, it means that the above-mentioned ion concentration is concentrated by 2 times.

[0056] In the present invention, the term "normal PBS concentration" refers to the concentration in a commonly prepared PBS buffer or a commercially available PBS buffer, and includes, for example, a PBS buffer having a composition shown in the above table. In particular, in the present invention, the purpose of setting the PBS concentration of the application solution to the "normal PBS concentration" is to set a PBS concentration that matches the pH (about 7.5) and osmotic pressure (about 290 mOsm / kg) in the vitreous body, and as long as the specific pH and osmotic pressure shown in the above paragraphs are met, the "normal PBS concentration" in the present invention ranges up to (up to) a concentration that includes certain variations in the normal PBS concentration.

[0057] The method for preparing the drug product of the present invention is (i) KUS121 is completely dissolved in water for injection or in a PBS buffer solution that is more dilute than usual, (ii) a more concentrated PBS buffer solution than usual is added to the solution while maintaining the dissolved state of the solution, (iii) the solution is aseptically filtered, and (iv) the filtrate is freeze-dried. The method is not particularly limited, as long as 0.100 to 0.625 mg / mL (preferably 0.125 to 0.5 mg / mL) of KUS121 PBS buffer solution can be prepared by dissolving the lyophilized preparation in water for injection, and the PBS concentration of the dissolved solution is about the normal PBS concentration. In this case, the osmotic pressure is comparable to the osmotic pressure of a normal PBS solution, that is, the osmotic pressure in the vitreous body.

[0058] Example

[0059] Example 1

[0060] 16.00 g of sodium chloride, 2.29 g (anhydrous basis) of disodium hydrogen phosphate, 0.400 g of potassium dihydrogen phosphate, and 0.400 g of potassium chloride were added to a stainless steel cup. The mixture was dissolved in water for injection and the total amount was made to 1000 g, thereby preparing a PBS buffer solution having a concentration twice that of normal PBS.

[0061] 0.0486 g (anhydrous basis: 0.0450 g) of KUS121 was added to another stainless steel cup and dissolved in 405 mL of water for injection. 45 mL of the above-prepared 2x PBS buffer was slowly added to the solution and mixed to prepare the final KUS121 formulation for lyophilization.

[0062] The final KUS121 formulation was sterile filtered, but about 100 mL of the initial flow was discarded. After 1 mL of the sterile filtrate was filled into a vial and it was half-sealed with a rubber stopper, the vial was transferred to a lyophilizer and lyophilized to obtain a lyophilized formulation.

[0063] Example 2

[0064] 1600 g of water for injection, 32.06 g of sodium chloride, 4.59 g (anhydrous) of disodium hydrogen phosphate, 0.80 g of potassium dihydrogen phosphate and 0.80 g of potassium phosphate were added to a 5 L beaker. The mixture was dissolved in water for injection and the total amount was made to 2000 g, thereby preparing a PBS buffer solution having a concentration twice that of normal PBS.

[0065] 0.484 g (anhydrous basis: 0.449 g) of KUS121 was added to a 5 L glass container and dissolved in water for injection, the total amount being 2250 g.

[0066] The KUS121 solution prepared above was transferred to a 10L disposable bag and mixed with 877g of the 2xPBS buffer prepared above and an appropriate amount of water for injection. Further, water for injection was added thereto to make the total amount 8770g, which was used as the final KUS121 preparation for lyophilization.

[0067] The final KUS121 formulation was sterile filtered, but about 700 mL of the initial flow was discarded. After 1 mL of the sterile filtrate was filled into a vial and it was half-sealed with a rubber stopper, the vial was transferred to a lyophilizer and lyophilized to obtain a lyophilized formulation.

[0068] Example 3 (Dissolution of lyophilized preparation)

[0069] 200 μL of water for injection was added to the vial containing the above-prepared lyophilized formulation using a syringe equipped with a needle, wherein each vial of the lyophilized formulation contained KUS121 (0.1 mg), sodium chloride (1.6 mg), disodium hydrogen phosphate (0.229 mg), potassium dihydrogen phosphate (0.04 mg) and potassium chloride (0.04 mg). The mixture was mixed and the time until dissolution was measured with a stopwatch. The dissolution time was less than 90 seconds.

[0070] Example 4 (Stability of dissolved liquid preparation)

[0071] 200 μ L of water for injection was added to the vial containing the above-prepared lyophilized preparation using a syringe equipped with a needle, wherein each vial of the lyophilized preparation contained KUS121 (0.1 mg or 0.05 mg), sodium chloride (1.6 mg), disodium hydrogen phosphate (0.229 mg), potassium dihydrogen phosphate (0.04 mg) and potassium chloride (0.04 mg), and the mixture was dissolved to prepare a PBS buffer solution (0.5 mg / mL or 0.25 mg / mL, PBS concentration of 1 / 1) of KUS121. At the moment of dissolution, after 3 hours, 6 hours, 12 hours and 24 hours, the appearance of the solution at room temperature, the content of KUS121 and related substances in the solution, the presence of insoluble foreign substances and the color of the solution were measured. In two types of dissolving preparations with different concentrations of KUS121, the dissolved state was maintained until 24 hours later, and no changes were observed in any measurement.

[0072] On the other hand, the following preparation has the same composition as above but without lyophilized solution.KUS121 (0.5mg) is dissolved in water for injection (0.9mL), and in this KUS121 solution, slowly add 10 times the PBS buffer (0.1mL) of normal concentration, the every 0.1mL of this PBS buffer comprises sodium chloride (8.00mg), disodium hydrogen phosphate (1.15mg), potassium dihydrogen phosphate (0.2mg) and potassium chloride (0.2mg), thus prepares the PBS solution (0.5mg / mL, PBS concentration 1 / 1) that KUS121 keeps dissolved state.When this solution is stored at room temperature, the solid of KUS121 precipitates in 3 hours.

[0073] Comparing the appearance of two solutions having the same composition of 0.5 mg / mL as described above, the solution remained dissolved for 24 hours by lyophilization, while the solution not lyophilized resulted in solid precipitation within 3 hours.

[0074] Example 5 (Solubility of KUS121 in PBS buffer)

[0075] A PBS buffer solution containing 1.6 mg of sodium chloride, 0.229 mg of disodium hydrogen phosphate, 0.04 mg of potassium dihydrogen phosphate and 0.04 mg of potassium chloride per mL of solution was prepared, and the temperature of the PBS buffer solution was adjusted to 5°C, 25°C, 40°C, 50°C and 60°C. KUS121 was added little by little to each solution at different temperatures and stirred. From the time when some undissolved material appeared, after stirring for a sufficient time, the solution was filtered. As a result of using HPLC to quantify the filtrate, the solubility of KUS121 at each temperature was as follows (detection limit: about 1 μg / mL, quantitative limit: 5 μg / mL). 5°C: below the detection limit, 25°C: below the detection limit, 40°C: 7 μg / mL, 50°C: 47 μg / mL, 60°C: 132 μg / mL.

Claims

1. A lyophilized drug product prepared by the steps of: (i) dissolving sodium 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonate dihydrate (hereinafter abbreviated as "KUS121") in water for injection or in a PBS buffer solution more diluted than usual, (ii) adding a PBS buffer solution more concentrated than usual to the solution while maintaining the dissolved state of the solution, and (iii) lyophilizing the obtained solution, Features: When the lyophilized product is dissolved in water for injection before administration, the solution maintains a solution state in which the concentration of KUS121 is 0.100 to 0.625 mg / mL and the concentration of PBS is a normal PBS concentration.

2. The lyophilized drug product according to claim 1, wherein the concentration of the more concentrated PBS buffer than usual is 2 to 10 times the concentration of normal PBS.

3. The lyophilized pharmaceutical product according to claim 1 or 2, wherein the PBS concentration of the solution before the (iii) lyophilization step is 1 / 5 to 1 / 1 (preferably 1 / 5 to 1 / 2) of the normal PBS concentration.

4. The lyophilized pharmaceutical product according to any one of claims 1 to 3, wherein the volume of water for injection added to the lyophilized product is 1 / 5 to 1 / 1 (preferably 1 / 5 to 1 / 2) of the volume of the solution before the (iii) lyophilization step.

5. The lyophilized pharmaceutical product according to any one of claims 1 to 4, wherein the osmotic pressure of a solution prepared by dissolving the lyophilized product in water for injection is 230 to 360 mOsm / kg.

6. The lyophilized pharmaceutical product according to any one of claims 1 to 5, wherein the pH of a solution prepared by dissolving the lyophilized product in water for injection is 6.8 to 8.

2.

7. The lyophilized pharmaceutical product according to any one of claims 1 to 4, wherein the normal PBS concentration is a concentration of a PBS buffer having an osmotic pressure of 230 to 360 mOsm / kg and a pH of 6.8 to 8.

2.

8. A lyophilized drug product prepared by the following steps: (i) dissolving KUS121 in water for injection, (ii) adding a PBS buffer having a concentration of 2 to 10 times the normal PBS concentration to the KUS121 solution, whereby the PBS concentration is 1 / 5 to 1 / 2 of the normal concentration, while maintaining the dissolved state of the solution, and (iii) lyophilizing the obtained solution, Features: When the lyophilized product is dissolved in water for injection accounting for 1 / 5 to 1 / 2 of the volume of the solution before the (iii) lyophilization step before administration, the solution remains in a solution state, wherein the concentration of KUS121 is 0.100 to 0.625 mg / mL and the concentration of PBS is a normal PBS concentration.

9. The lyophilized drug product according to any one of claims 1 to 8, wherein before the (iii) lyophilization step, a KUS solution comprising PBS buffer is dispensed into each vial, wherein the amount of KUS121 is 20 to 125 μg per vial, and the drug product is stored in the vial in a lyophilized state.

10. A vial containing a lyophilized drug product containing KUS121 for intravitreal injection, wherein: The lyophilized drug product comprises 20 μg to 125 μg of KUS121 and a PBS buffer dry component corresponding to 0.1 mL to 0.4 mL of a normal PBS buffer solution excluding water.

11. A method for preparing a lyophilized drug product that can be dissolved in water for injection to prepare a PBS buffer solution containing 0.100 to 0.625 mg / mL of KUS121, wherein the PBS concentration is a normal PBS concentration, the method comprising: Dissolve KUS121 in water for injection or in a more dilute PBS buffer solution than usual. adding a more concentrated PBS buffer than usual to the solution while maintaining the solution in a dissolved state, and The obtained solution was lyophilized.

12. The method according to claim 11, wherein the normal PBS concentration is a concentration of a PBS buffer having an osmotic pressure of 230 to 360 mOsm / kg and a pH of 6.8 to 8.

2.

13. The method according to claim 11 or 12, wherein the concentration of the more concentrated PBS buffer than usual is 2 to 10 times the concentration of normal PBS.

14. The method according to any one of claims 11 to 13, wherein the PBS concentration of the solution before the (iii) lyophilization step is 1 / 5 to 1 / 1 of the normal PBS concentration.

15. The method according to any one of claims 11 to 14, wherein the volume of water for injection added to the lyophilized product is 1 / 5 to 1 / 1 of the volume of the solution before the (iii) lyophilization step.

16. The method according to any one of claims 11 to 14, wherein: PBS buffer solution containing KUS121 can be prepared by dissolving the lyophilized drug product in 200 μL of water for injection per vial.

17. The method according to any one of claims 11 to 16, wherein the concentration of KUS121 in the solution before the lyophilization step is 0.020 to 0.125 mg / mL.

18. The lyophilized drug product according to any one of claims 1 to 9, wherein the [Na + ]、[K + ]、[Cl - ] and [PO4 3- ] are 100 to 200mmol / L, 0 to 6.5mmol / L, 90 to 180mmol / L and 6 to 14mmol / L respectively.

19. The vial according to claim 10, wherein the [Na + ]、[K + ]、[Cl - ] and [PO4 3- ] are 100 to 200mmol / L, 0 to 6.5mmol / L, 90 to 180mmol / L and 6 to 14mmol / L respectively.

20. The method according to any one of claims 11 to 17, wherein the [Na + ]、[K + ]、[Cl - ] and [PO4 3- ] are 100 to 200mmol / L, 0 to 6.5mmol / L, 90 to 180mmol / L and 6 to 14mmol / L respectively.

Images