Benzoazepine compound-containing freeze-dried composition

Abstract

To provide a formulation that stably contains a tolvaptan prodrug.SOLUTION: The invention provides a freeze-dried composition containing a compound represented by Formula (1) in the figure or a metal salt thereof and a disaccharide.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to a lyophilized composition containing a benzoazepine compound, etc. All of the documents described in this specification, including the documents listed below as prior art documents (patent documents and non-patent documents), are incorporated herein by reference in their entirety. [Background technology]

[0002] Tolvaptan, a benzoazepine compound, has a vasopressin V2 receptor antagonistic effect and is used as a diuretic, etc. The structural formula of tolvaptan is shown below in formula (2).

[0003] [ka]

[0004] However, since tolvaptan is poorly soluble in water, there are many limitations in terms of dosage form and administration route. Since tolvaptan can be administered to patients who have difficulty in oral administration (difficulty in swallowing, unconsciousness) and is expected to have a faster onset of drug effects than tablets, there has been a demand for an injectable formulation of tolvaptan to be used by intravascular administration, but since tolvaptan is poorly soluble in water, its development has been difficult. Therefore, research and development has been conducted on water-soluble prodrugs of tolvaptan. For example, Patent Document 1 proposes a prodrug of tolvaptan with excellent water solubility. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2007 / 074915 Summary of the Invention [Problem to be solved by the invention]

[0006] However, since the prodrug of tolvaptan is unstable and easily reverts to tolvaptan, the present inventors attempted to develop a formulation that stably contains a prodrug of tolvaptan. [Means for solving the problem]

[0007] The present inventors have investigated the stability of a tolvaptan prodrug and found that when the prodrug was dissolved in water and sterilized by high-pressure steam in the formulation process for preparing an aqueous solution formulation such as an injection, the prodrug decomposed to produce poorly water-soluble tolvaptan, causing the formulation to become cloudy or to produce insoluble fine particles. Furthermore, when the aqueous solution formulation was stored for a long period of time, the prodrug decomposed to produce tolvaptan, causing the precipitation of insoluble foreign matter or the production of insoluble fine particles.

[0008] Therefore, the present inventors further investigated the stability of the tolvaptan prodrug, The present inventors found that a composition containing a specific tolvaptan prodrug and a disaccharide could stably contain the prodrug, and further improved the composition.

[0009] The present disclosure includes, for example, the subject matter described in the following sections: Section 1. Formula (1):

[0010] [ka]

[0011] or a metal salt thereof, and a disaccharide. Section 2. The freeze-dried composition of claim 1 , wherein the metal salt is a disodium salt. Section 3. Item 3. The freeze-dried composition according to item 1 or 2, wherein the disaccharide is at least one selected from the group consisting of sucrose, maltose, lactose, and trehalose. Section 4. 4. The freeze-dried composition according to claim 1, comprising 0.5 to 70 parts by mass of a disaccharide per 1 part by mass of the compound represented by formula (1) or a metal salt thereof. Section 5. 5. The freeze-dried composition according to any one of items 1 to 4, wherein the total amount of the compound represented by formula (1) or a metal salt thereof, and the disaccharide is 65% by mass or more of the total composition. Section 6. Item 6. The freeze-dried composition according to any one of Items 1 to 5, further comprising a buffering agent. Section 7. Item 7. The freeze-dried composition according to item 6, wherein the buffer is a phosphate buffer. Section 8. The freeze-dried composition according to any one of Items 1 to 7, which is dissolved in water (preferably physiological saline or glucose injection solution) to form an aqueous solution composition having a pH of 7.5 to 9 and is used by intravascular administration. Section 9. Formula (1):

[0012] [ka]

[0013] or a metal salt thereof, and a disaccharide. Section 10. Item 10. The aqueous solution composition according to item 9, wherein the metal salt is a disodium salt. Section 11. Item 11. The aqueous solution composition according to item 9 or 10, wherein the disaccharide is at least one selected from the group consisting of sucrose, maltose, lactose, and trehalose. Section 12. Item 12. The aqueous solution composition according to any one of items 9 to 11, comprising 0.5 to 70 parts by mass of a disaccharide per part by mass of the compound represented by formula (1) or a metal salt thereof. Section 13. Item 13. The aqueous solution composition according to any one of Items 9 to 12, wherein the disaccharide is contained in an amount of 1 to 8 (w / v) %. Item 14. The aqueous solution composition according to any one of items 9 to 13, further comprising a buffer. Section 15. Item 15. The aqueous solution composition according to item 14, wherein the buffer is a phosphate buffer. Section 16. Item 16. The aqueous solution composition according to any one of Items 9 to 15, which is for intravascular administration. Section 17. Item 17. The aqueous solution composition according to any one of Items 9 to 16, which is for preparing the freeze-dried composition according to any one of Items 1 to 8. Section 18. Item 17. The freeze-dried composition according to any one of Items 1 to 8, which is for preparing an aqueous solution composition according to any one of Items 9 to 16. Section 19. Item 19. The composition according to any one of items 1 to 18, which is sterilized. Section 20. 20. The composition according to any one of items 1 to 19, which is a pharmaceutical composition. Effect of the Invention

[0014] The present invention provides a preparation (preferably an aqueous injection) that stably contains a specific tolvaptan prodrug. Since the aqueous injection is administered via the blood vessel, the formation of insoluble foreign matter or insoluble fine particles in the solution in a number greater than or equal to the number specified in the pharmacopoeia of each country is not permitted. The preparation that stably contains the tolvaptan prodrug is particularly suitable as an aqueous injection because it is unlikely to form insoluble foreign matter or insoluble fine particles in a number greater than or equal to the number specified in the pharmacopoeia even when stored for a long period of time. [Brief description of the drawings]

[0015] [Figure 1] The results of examining the stability of a 0.1 (w / v) % aqueous solution of compound (1) after high-pressure steam sterilization (121° C., 20 minutes) are shown. [Diagram 2] The stability of a freeze-dried composition of Compound (1) was examined by changing the pH of the aqueous solution during preparation, and the results are shown below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present disclosure preferably encompasses freeze-dried compositions or aqueous solution compositions containing a specific tolvaptan prodrug, but is not limited thereto, and the present disclosure encompasses all that are disclosed herein and that would be recognized by a person of ordinary skill in the art.

[0017] The lyophilized compositions and aqueous solution compositions encompassed by the present disclosure include a compound represented by the following formula (1):

[0018] [ka]

[0019] The composition contains a compound represented by the formula (1) or a metal salt thereof, and a disaccharide. Preferably, the composition contains a metal salt of a compound represented by the formula (1) and a disaccharide. The compound represented by the formula (1) may be referred to as "compound (1)". The freeze-dried composition and the aqueous solution composition containing compound (1) or a salt thereof and a disaccharide may be referred to as "the freeze-dried composition of the present disclosure" and "the aqueous solution composition of the present disclosure", respectively. These may be collectively referred to as "the composition of the present disclosure". The freeze-dried composition of the present disclosure can be preferably prepared by freeze-drying the aqueous solution composition of the present disclosure. The aqueous solution composition of the present disclosure can be preferably prepared by reconstituting the freeze-dried composition of the present disclosure with water. The freeze-dried composition of the present disclosure is preferably a cake-like composition.

[0020] Compound (1) or a metal salt thereof is a specific prodrug of tolvaptan contained in the freeze-dried composition or aqueous solution composition of the present disclosure. As the specific prodrug of tolvaptan, a metal salt of compound (1) is particularly preferred.

[0021] The metal salt of compound (1) is preferably an alkali metal salt, an alkaline earth metal salt, or a zinc salt, and more specifically, for example, a sodium salt (monosodium or disodium salt), a potassium salt (monosodium or dipotassium salt), a calcium salt, a magnesium salt, a zinc salt, etc. are preferable. Among them, a disodium salt is particularly preferable. The structural formula of the disodium salt of compound (1) is shown below.

[0022] [ka]

[0023] Compound (1) or a metal salt thereof can be produced by a known method or a method that can be easily derived from a known method, for example, by the method described in Patent Document 1 (WO 2007 / 074915) (particularly the method described in the Examples).

[0024] The disaccharide is preferably a disaccharide in which at least one of the two sugars constituting the disaccharide is glucose, and specific examples thereof include sucrose, maltose, trehalose, lactose, cellobiose, etc., with sucrose, maltose, trehalose, and lactose being preferred, sucrose and trehalose being more preferred, and sucrose being particularly preferred. The disaccharide may be used alone or in combination of two or more kinds.

[0025] The content of the disaccharide is preferably about 0.5 to 70 parts by mass when the content of the compound (1) or a metal salt thereof is taken as 1 part by mass. The upper or lower limit of the range is, for example, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69 parts by mass. For example, when the content of compound (1) or a metal salt thereof is 1 part by mass, it may be about 0.8 to 60 parts by mass, and considering foaming when the freeze-dried composition of the present disclosure is reconstituted with water, about 1 to 15 parts by mass is less likely to foam and is preferable.

[0026] In particular, when the composition is a freeze-dried composition, the total content of compound (1) or a metal salt thereof and the disaccharide is preferably 65% ​​by mass or more of the total composition, and more preferably 66, 67, 68, 69, or 70% by mass or more.

[0027] In particular, when the composition is an aqueous solution composition, the disaccharide is preferably contained at 1 to 8 (w / v)%. The upper or lower limit of the range may be, for example, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, or 7.5 (w / v)%. For example, in consideration of foaming when the freeze-dried composition of the present disclosure is reconstituted with water, a disaccharide content of 1 to 3 (w / v)% is more preferable since it is less likely to foam.

[0028] The composition of the present disclosure preferably further comprises a buffering agent. As the phosphate buffer, a phosphate buffer and a carbonate buffer are preferred, and a phosphate buffer is particularly preferred. More specifically, for example, disodium hydrogen phosphate (sodium hydrogen phosphate) and / or sodium dihydrogen phosphate are preferred. The concentration of the phosphate buffer in the aqueous solution composition is is not particularly limited as long as it is within a range in which the buffer capacity is exhibited, but is preferably, for example, about 5 to 100 mM. The upper or lower limit of the range may be, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 mM. For example, it is more preferably about 10 to 80 mM, even more preferably about 15 to 50 mM, and even more preferably about 20 to 40 mM.

[0029] The composition of the present disclosure may contain a pH adjuster as necessary. Specific examples of pH adjusters include acidic pH adjusters such as hydrochloric acid, acetic acid, and phosphoric acid, and basic pH adjusters such as sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, and magnesium hydroxide. Since the pH of the aqueous solution composition of the present disclosure is 7.5 to 9, it is particularly preferable to use a basic pH adjuster, and sodium hydroxide is particularly preferable. The upper or lower limit of the pH range of the aqueous solution composition of the present disclosure may be, for example, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, or 8.9. For example, the pH of the aqueous solution composition of the present disclosure is preferably about 8 to 9, and is most preferably about pH 8.5.

[0030] In addition to the above, the composition of the present disclosure may contain pharma- ceutically acceptable carriers, particularly components known in the field of lyophilized pharmaceutical preparations, as necessary.

[0031] The composition of the present disclosure can be preferably used, for example, as a pharmaceutical composition. In particular, it can be preferably used as a vasopressin receptor (particularly V2 receptor) antagonist. More specifically, the pharmaceutical composition can be preferably used, for example, for the treatment of congestive heart failure, liver cirrhosis, and hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), and for the suppression of renal volume increase and renal function decline in autosomal dominant polycystic kidney disease.

[0032] The administration form of the composition of the present disclosure is not particularly limited, but is preferably administered via blood vessels, and more preferably administered intravenously. The aqueous solution composition can be directly administered via blood vessels. The freeze-dried composition can be dissolved in water (i.e., reconstituted) and then administered via blood vessels. The water in which the freeze-dried composition is dissolved may contain other components known in the art. For example, the water is more preferably physiological saline or glucose injection solution.

[0033] The dosage form of the composition of the present disclosure is not particularly limited, and it can be used in the form of, for example, injections, drip infusions, and the like.

[0034] As described above, the aqueous solution composition of the present disclosure can be directly administered via blood vessels, and can also be subjected to a freeze-drying process to prepare a freeze-dried composition of the present disclosure. In other words, the aqueous solution composition of the present disclosure is also useful for preparing the freeze-dried composition of the present disclosure.

[0035] The lyophilized composition of the present disclosure can be preferably prepared into an aqueous solution composition of the present disclosure by adding water to dissolve (i.e., reconstitute) the lyophilized composition of the present disclosure. That is, the lyophilized composition of the present disclosure can be prepared from the aqueous solution composition of the present disclosure, and is also useful for (re)preparing the aqueous solution composition of the present disclosure.

[0036] In the case of an injection, the composition of the present disclosure is preferably sterilized and made aseptic. The sterilization method is not particularly limited, and a preferred example is a method in which an aqueous solution is prepared and then subjected to aseptic filtration.

[0037] The composition of the present disclosure can be prepared based on known methods, for example, methods for preparing lyophilized pharmaceutical preparations. More specifically, for example, compound (1) or a metal salt thereof, a disaccharide, and, if necessary, a buffer, a pH adjuster, and the like, can be mixed and dissolved in water to prepare an aqueous solution composition. As described above, the freeze-dried composition can be prepared by freeze-drying the aqueous solution composition.

[0038] It should be noted that in this specification, the term "comprising" encompasses "consisting essentially of" and "consisting of."

[0039] Furthermore, the various characteristics (properties, structures, functions, etc.) described in each of the above-mentioned embodiments may be combined in any manner to specify the subject matter encompassed by the present disclosure. EXAMPLES

[0040] The subject matter encompassed by the present disclosure will now be described in more detail, but the subject matter is not limited to the following examples.

[0041] Preparation of metal salts of compound (1) Compound (1) and its disodium salt were prepared according to the method described in the Examples (particularly Examples 1, 3, and 9) of Patent Document 1 (WO 2007 / 074915). The disodium salt was used as Compound A in the following study. Specifically, the preparation was carried out as follows. In the following description of the specific preparation method, Compound (1b) corresponds to Compound (1), and the disodium salt of Compound (1b) corresponds to Compound A.

[0042] [ka]

[0043] 1.0 g of tolvaptan and 460 mg of 1H-tetrazole were dissolved in 30 ml of methylene chloride, and 1.2 g of dibenzyldiisopropylphosphoramidite was added dropwise to the solution with stirring at room temperature, followed by stirring at the same temperature for 2 hours.

[0044] The resulting reaction solution was cooled to -40°C, and 920 mg of methachloroperbenzoic acid was added to the solution. 6 ml of methylene solution was added dropwise. This mixture was stirred at the same temperature for 30 minutes and then at 0°C for another 30 minutes. The reaction mixture was washed with an aqueous solution of sodium thiosulfate and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (elution solvent: n-hexane:ethyl acetate=1:1) to obtain 1.5 g (yield 97.2%) of an amorphous form of compound (1a-1).

[0045] [ka]

[0046] 5.3 g of compound (1a-1) was dissolved in 100 ml of ethanol. Using 2 g of 5% palladium carbon as a catalyst, the solution was catalytically reduced at room temperature and normal pressure for 10 minutes. The catalyst was filtered off from the solution, and the obtained filtrate was concentrated (4.2 g). The obtained residue was crystallized from methanol-water. The crystals were collected by filtration and dried under reduced pressure (diphosphorus pentoxide), to obtain 3.5 g (yield 88.5%) of white powder of compound (1b).

[0047] Further, 1.0 ml of 1N sodium hydroxide solution was added to a methanol solution (2 ml) of 276 mg (0.52 mmol) of compound (1b) under ice cooling, and the resulting mixture was stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from acetone-water to obtain 221 mg of the disodium salt of compound (1b) as a white powder.

[0048] In addition, calcium salt, magnesium salt, and zinc salt of compound (1) were also produced according to the method described in the examples of Patent Document 1. When the solid-state stability of the above metal salts was examined, the stability of the disodium salt (i.e., compound A), calcium salt, magnesium salt, and zinc salt was significantly improved compared to compound (1). Furthermore, when the solubility in water was examined, the disodium salt (i.e., compound A) was significantly superior to compound (1), calcium salt, magnesium salt, and zinc salt as shown in the table below, and was suitable as an ingredient for an aqueous injection preparation.

[0049] [Table 1]

[0050] Stability of the phosphate ester bond of compound (1) during high-pressure steam sterilization A 0.1 (w / v)% aqueous solution of compound (1) was prepared, and the stability was examined after high-pressure steam sterilization (121°C, 20 minutes). The aqueous solution was prepared using 100 mM sodium phosphate buffer or 100 mM Tris buffer. In addition, the pH of the aqueous solution using each buffer was adjusted using sodium hydroxide to prepare solutions with different pH values. After the treatment, the purity of compound (1) and the amount of tolvaptan produced were measured by HPLC area percentage method.

[0051] The results are shown in Figure 1. The results show that the phosphate ester bond of compound (1) is hydrolyzed to tolvaptan by high-pressure steam sterilization, which precipitates. It was also found that the hydrolysis was effectively suppressed when a sodium phosphate buffer solution with a pH of 7.5 or higher was used, and the stability of the phosphate ester bond of compound (1) was high.

[0052] Study on stability of freeze-dried formulation of compound (1) 1 Using 20 mM disodium hydrogen phosphate buffer, an aqueous solution (pH 7, 7.5, 8, 8.5, or 9) containing 0.1 (w / v)% compound (1), 4 (w / v)% mannitol, and an appropriate amount of sodium hydroxide was prepared.

[0053] The aqueous solution was filled into a 2 mL glass vial, frozen to below -40°C, and then evacuated to a vacuum. The water was removed and the composition was freeze-dried to obtain a freeze-dried composition. This was stored at 40°C for 3 months or at 60°C for 1 month, and then reconstituted with the same amount of water as the amount removed by freeze-drying to return it to an aqueous solution. The amount (%) of total decomposition products or tolvaptan produced in the resulting aqueous solution was measured by the area percentage method of HPLC.

[0054] The results are shown in Figure 2. In the freeze-dried compositions prepared from solutions with a pH higher than 8, compound (1) was relatively stable even when stored at 60°C. However, when mannitol was added, the freeze-dried compositions prepared from high pH solutions were not stable even when stored at 60°C for one month. However, the stabilization effect of tolvaptan was insufficient, since it produced 1.45% tolvaptan at pH 8.5 and 0.9% at pH 9.

[0055] Stability study of freeze-dried formulation of compound (1) 2 Freeze-dried compositions were prepared in the same manner as in "Study 1 on the stability of freeze-dried preparations of compound (1)" above, except that NaCl, sorbitol, sucrose, maltose, trehalose, or lactose was used as an additive other than mannitol. However, the pH of the aqueous solution before preparation of the freeze-dried composition was adjusted to 8.5. However, for lactose, the pH of the aqueous solution before preparation of the freeze-dried composition was adjusted to 9.0 using 24 mM sodium bicarbonate buffer.

[0056] The obtained freeze-dried compositions were stored at 60°C for one month, and the amount of tolvaptan produced was measured by the area percentage method of HPLC to examine the stability of compound (1) in each composition. The results are shown in Table 2. The results show that the amount of tolvaptan produced was significantly suppressed when a disaccharide (sucrose, maltose, trehalose, or lactose) was added, compared with sodium chloride and mannitol. The suppression was particularly notable in sucrose, maltose, and lactose. In addition, the aqueous solutions before preparation of the freeze-dried compositions were stored at 60°C for one week, and the stability of compound (1) in each composition was examined. The results are shown in Table 3. As a result, the amount of tolvaptan produced (%) increased when maltose and lactose were used.

[0057] From the above, it was found that the use of a disaccharide in the preparation of a freeze-dried composition (i.e., the preparation of an aqueous solution composition for preparing a freeze-dried composition) significantly increases the stability of the tolvaptan prodrug (compound (1)) in the freeze-dried composition, and further, when sucrose is used, the stability of the tolvaptan prodrug (compound (1)) is significantly increased even in the state of an aqueous solution composition that is not freeze-dried. Thus, it was found that the stabilizing effect of adding sucrose is extremely significant in the freeze-dried product and in the aqueous solution state.

[0058] [Table 2]

[0059] [Table 3]

[0060] Stability study of lyophilized formulation of Compound A 1 Except for using compound A, the content of which was 0.541 (w / v)%, and the sucrose content was 7.5 (w / v)%, the same procedure as in "Study 2 on the stability of freeze-dried preparations of compound (1)" was followed to prepare aqueous solutions of pH 7.5, 8, 8.5, or 9, which were freeze-dried to obtain freeze-dried compositions, which were then stored at 60°C for one month. The amount of tolvaptan produced (%) was then measured by the HPLC area percentage method. The results were 0.22% for pH 7.5, 0.10% for pH 8, 0.07% for pH 8.5, and below the detection limit for pH 9, indicating that all of the compositions had good stability.

[0061] Stability study of lyophilized formulation of Compound A 2 An aqueous solution of pH 8.5 was prepared in the same manner as in "Study on the stability of a freeze-dried formulation of Compound A 1" above, except that potassium phosphate was used as a buffer instead of sodium phosphate. A freeze-dried composition was then prepared and the stability of Compound A in the freeze-dried composition was examined (stored at 60°C for 1 month). The amount of tolvaptan produced (%) was 0.07%, the same as when sodium phosphate was used.

[0062] In addition, an aqueous solution with a pH of 8.0 was prepared in the same manner as in "Study 1 on the stability of freeze-dried preparations of Compound A" above, using the aqueous solution with a sucrose content of 1%, 2%, 4%, or 7.5%, and a freeze-dried composition was prepared to study the stability of Compound A in the freeze-dried composition (stored at 60°C for 1 month). The amount of tolvaptan produced (%) was 0.25% for the 1% sucrose content, 0.12% for the 2% sucrose content, 0.08% for the 4% sucrose content, and 0.10% for the 7.5% sucrose content. From this, it was found that the stability of Compound A was good in all of the compositions studied, and that the stability was particularly good when the sucrose content in the aqueous solution exceeded 1%. In addition, when the freeze-dried composition with a sucrose content of 4% and 7.5% was reconstituted with water and returned to an aqueous solution, foaming and slight cloudiness were observed, so it was necessary to leave it to stand until it was degassed and returned to transparency. No foaming or cloudiness is observed, although this does not cause any problems during administration. From this viewpoint, it was considered preferable that the sucrose content in the aqueous solution be less than 4%.

[0063] In addition to the aqueous solution with a sodium phosphate concentration of 20 mM and pH 8.5, aqueous solutions with 10 mM or 50 mM were also prepared in the same manner as in the above "Study on the stability of freeze-dried preparations of Compound A 1", and freeze-dried compositions were prepared. After storing the freeze-dried compositions (storage at 60°C for 1 month or storage at 40°C for 3 months), the pH was examined when the compositions were reconstituted with water. The results are shown in the table below.

[0064] [Table 4]

[0065] The results show that there was no significant change in pH compared to before and after storage.

[0066] In addition, the stability of Compound A in the freeze-dried composition was examined (storage at 60°C for 1 month), and the amount of tolvaptan produced (%) was 0.07% at 10 mM, 0.07% at 20 mM, and below the detection limit at 50 mM. All of the compositions had good stability.

[0067] Prescription Example 1 The following table shows an example of a formulation using Compound A. Compound A, refined white sugar (sucrose), sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate were dissolved in water for injection, and the pH was adjusted to 8.5 with sodium hydroxide to prepare an aqueous solution having the composition shown in Table 5. The aqueous solution having the composition shown in Table 5 was sterile filtered, and then 5.21 mL of Preparation Solution Example 1 and 20.66 mL of Preparation Solution Example 2 were filled into a sterilized vial. Furthermore, after freezing to -40°C or lower, the pressure was reduced to a vacuum, the shelf temperature was set to -10°C to remove moisture, and then the shelf temperature was set to 30°C to remove residual moisture, thereby obtaining a sterile freeze-dried composition having the composition shown in Table 6. The stability of Compound A after storing the freeze-dried composition of Preparation Example 1 at 40°C and 75% RH (relative humidity) for 6 months or at 25°C and 60% RH for 36 months was examined. The amount of tolvaptan produced, as measured by the HPLC area percentage method, was below the detection limit, and the composition was extremely stable even after long-term storage. Formulation Example 1 was reconstituted by adding 5 mL of water for injection, and Formulation Example 2 was reconstituted by adding 20 mL of water for injection, to obtain Formulation Solution Example 1 and Formulation Solution Example 2 shown in Table 5, which have insoluble foreign matter and insoluble fine particles within the range specified in the Japanese Pharmacopoeia even after long-term storage.

[0068] [Table 5]

[0069] [Table 6]

[0070] Prescription Example 2 The following table shows a formulation example of a preparation using Compound A. Compound A, refined white sugar (sucrose), sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate were dissolved in water for injection, and the pH was adjusted to 8.5 with sodium hydroxide to prepare an aqueous solution having the composition shown in Table 7. The aqueous solution having the composition shown in Table 7 was sterile filtered, and then filled into a sterilized vial at 2.63 mL to 2.64 mL. Furthermore, after freezing to -40°C or lower, the pressure was reduced to a vacuum, the shelf temperature was set to -20°C to remove moisture, and then the shelf temperature was set to 30°C to remove residual moisture, thereby obtaining a sterile freeze-dried composition having the composition shown in Table 8. The stability of Compound A after storing the freeze-dried compositions of Formulation Examples 3, 4, 5, and 6 in Table 5 at 40°C and 75% RH for 6 months or at 25°C and 60% RH for 18 months was examined. The amount of tolvaptan produced was below the detection limit in all cases, and the composition was extremely stable even after long-term storage. By adding 2.5 mL of water for injection to the lyophilized composition in Table 7 and reconstituting it, insoluble foreign matter and insoluble substances were not observed even after long-term storage. The formulation solutions shown in Table 7, Examples 3, 4, 5, and 6, were obtained, each of which had soluble fine particles within the range specified by the Japanese Pharmacopoeia.

[0071] [Table 7]

[0072] [Table 8]

[0073] Prescription Example 3 The following table shows an example of a formulation using Compound A. Compound A, refined white sugar (sucrose), sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate were dissolved in water for injection, and the pH was adjusted to 8.5 with sodium hydroxide to prepare an aqueous solution having the composition shown in Table 9. The aqueous solution having the composition shown in Table 9 was sterile filtered and filled into a vial in an amount of 2 mL. The solution was then frozen to below -40°C, depressurized to a vacuum, and the shelf temperature was set to -20°C to remove moisture, and then the shelf temperature was set to 30°C to remove residual moisture, thereby obtaining a lyophilized composition having the composition shown in Table 10. The stability of Compound A was examined after the lyophilized compositions of Formulation Examples 7, 8, and 9 in Table 10 were stored at 50°C for 4 weeks, and the amount of tolvaptan produced was 1.2% in Formulation Example 7 (Comparative Example), and below the detection limit in Formulation Examples 8 and 9. The lyophilized compositions of Table 10 stored at 50°C for 4 weeks were reconstituted by adding 2 mL of water for injection. As a result, in the case of Formulation Example 7 (Comparative Example), the amount of insoluble fine particles exceeded the amount specified by the Japanese Pharmacopoeia, but in the cases of Formulation Examples 8 and 9, the amount was within the range specified by the Japanese Pharmacopoeia. Therefore, the effect of adding sucrose on the formation of tolvaptan and the amount of insoluble fine particles was reconfirmed.

[0074] [Table 9]

[0075] [Table 10]

[0076] Prescription Example 4 The following table shows an example of a formulation using compound A. Compound A, refined white sugar (sucrose), sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate were dissolved in water for injection, and the pH was adjusted to 8.5 with sodium hydroxide to prepare an aqueous solution having the composition shown in Table 11. The aqueous solution having the composition shown in Table 11 was sterile filtered and filled into a vial in an amount of 2 mL. The composition was then frozen to -40°C or lower, depressurized under vacuum, and the shelf temperature was set to -20°C to remove moisture, and then the shelf temperature was set to 30°C to remove residual moisture, thereby obtaining a lyophilized composition having the composition shown in Table 12. The stability of compound A was examined after storing the lyophilized compositions of formulation examples 10, 11, 12, and 13 in Table 12 at 50°C for 4 weeks, and the amount of tolvaptan produced was below the detection limit in all formulation examples. When 2 mL of water for injection was added to the lyophilized composition of Table 9 after storing at 50°C for 4 weeks and reconstituted, no insoluble foreign matter or insoluble fine particles were observed. A formulation solution was obtained whose contents were within the range specified in the Japanese Pharmacopoeia.

[0077] [Table 11]

[0078] [Table 12]

[0079] Prescription Example 5 The following table shows an example of a formulation using compound A. Compound A, refined white sugar (sucrose), sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate were dissolved in water for injection, and the pH was adjusted to 8.5 with sodium hydroxide to prepare an aqueous solution having the composition shown in Table 13. The aqueous solution having the composition shown in Table 13 was sterile filtered and filled into a vial in an amount of 2 mL. The composition was then frozen to below -40°C, depressurized to a vacuum, and the shelf temperature was set to -20°C to remove moisture, and the shelf temperature was set to 30°C to remove residual moisture, thereby obtaining a lyophilized composition having the composition shown in Table 14. The stability of compound A was examined after storing the lyophilized compositions of formulation examples 14, 15, 16, and 17 in Table 14 at 50°C for 4 weeks, and the amount of tolvaptan produced was below the detection limit in all formulation examples. When 2 mL of water for injection was added to the lyophilized composition of Table 14 after storing at 50°C for 4 weeks and reconstituted, no insoluble foreign matter or insoluble fine particles were observed. A formulation solution within the range specified by the Japanese Pharmacopoeia was obtained.

[0080] [Table 13]

[0081] [Table 14]

[0082] Prescription Example 6 The following table shows an example of a formulation using compound A. Compound A, refined white sugar (sucrose), sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate were dissolved in water for injection, and the pH was adjusted to 8.5 with sodium hydroxide to prepare an aqueous solution having the composition shown in Table 15. The aqueous solution having the composition shown in Table 15 was sterile filtered and filled into a vial at 2.04 mL. The solution was then frozen to below -40°C, and the pressure was reduced to a vacuum, the shelf temperature was lowered to -20°C to remove moisture, and the shelf temperature was then lowered to 30°C to remove remaining moisture, to obtain a freeze-dried composition having the composition shown in Table 16. The freeze-dried composition shown in Table 16 was added to 50 mL of a vial. Compound A was dissolved in physiological saline or glucose injection to prepare an infusion injection of compound A.

[0083] [Table 15]

[0084] [Table 16]

[0085] Prescription Example 7 The following table shows an example of a formulation using compound A. Compound A, refined white sugar (sucrose), sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate were dissolved in water for injection, and the pH was adjusted to 8.5 with sodium hydroxide or phosphoric acid to prepare an aqueous solution having the composition shown in Table 17. The aqueous solution having the composition shown in Table 17 was sterile filtered and filled into a vial in an amount of 2.14 mL. Furthermore, after freezing to below -40°C, the pressure was reduced to a vacuum, the shelf temperature was set to -10°C to remove moisture, and then the shelf temperature was set to 40°C to remove remaining moisture, thereby obtaining a lyophilized composition having the composition shown in Table 18. The lyophilized composition shown in Table 18 was dissolved in 50 mL of physiological saline or glucose injection to prepare an infusion solution of compound A.

[0086] [Table 17]

[0087] [Table 18]

Claims

[Claim 1] Formula (1): 【Chemistry 1】 or a metal salt thereof, and a disaccharide.

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