Benzoazepine compound-containing pharmaceutical composition

Abstract

To provide a pharmaceutical composition capable of reducing side effects of tolvaptan.SOLUTION: A pharmaceutical composition comprising a compound represented by Formula (1) or a metal salt thereof is provided, wherein it is used such that 4 to 20 mg of the compound represented by Formula (1) or a metal salt thereof is transvascularly administered over a period of 10 minutes or more.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to a pharmaceutical composition containing a benzazepine compound and the like. All the documents described in this specification, including the documents listed as the following prior art documents (patent documents and non-patent documents), are incorporated herein by reference in their entirety of the contents described therein.

Background Art

[0002] Tolvaptan, which is a benzazepine compound, has an antagonistic effect on the vasopressin V2 receptor and is utilized as a diuretic and the like. The structural formula of tolvaptan is shown in the following formula (2).

[0003]

Chemical Formula

[0004] However, since tolvaptan is poorly water-soluble, there are many limitations in terms of dosage form, administration route, etc. Therefore, research and development have been conducted on prodrugs of tolvaptan that are water-soluble. For example, in Patent Document 1, a prodrug of tolvaptan having excellent water-solubility has been proposed.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] However, when tolvaptan and its prodrug are administered, side effects (especially side effects in the skin or subcutaneous tissue), although not severe, may occur, and it has been required to reduce the side effects.

Means for Solving the Problems

[0007] The inventors have found the possibility of reducing side effects by administering a prodrug of a specific tolvaptan at a specific rate, and have further made improvements.

[0008] This disclosure includes, for example, the subject matter described in the following items. Item 1. Formula (1):

[0009]

Chemical formula

[0010] A pharmaceutical composition containing a compound represented by formula (1) or a metal salt thereof, wherein 4 to 20 mg of the compound or its metal salt is used to be administered transvascularly over 10 minutes or more. Item 2. The pharmaceutical composition according to Item 1, wherein the compound represented by formula (1) or a metal salt thereof is used to be administered at a rate of an average of 2 / 3 (mg / min) or less. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein 4 to 20 mg of the compound represented by formula (1) or a metal salt thereof is used to be administered transvascularly over 10 minutes to 4 hours. Item 4. The pharmaceutical composition according to any one of Items 1 to 3 for reducing side effects caused in the skin or subcutaneous tissue by administration of the compound represented by formula (1) or a metal salt thereof. Item 5. The pharmaceutical composition according to Item 4, wherein the side effect caused in the skin or subcutaneous tissue by administration of the compound represented by formula (1) or a metal salt thereof is at least one selected from the group consisting of erythema, hyperhidrosis, and pruritus. Item 6. The pharmaceutical composition according to any one of Items 1 to 5 for the treatment of fluid retention in heart failure (preferably congestive heart failure), fluid retention in cirrhosis, or hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), or autosomal dominant polycystic kidney disease. Item 7. For treatment, it is for a patient who needs to administer 4 to 20 mg of the compound represented by the formula (1) or its metal salt in a single dose, and is the pharmaceutical composition according to any one of items 1 to 6. Item 8. The pharmaceutical composition according to any one of items 1 to 7, which is a lyophilized composition or an aqueous solution composition. Item 9. The pharmaceutical composition according to any one of items 1 to 8, wherein the metal salt is a disodium salt. Item 10. The pharmaceutical composition according to any one of items 1 to 9 is provided in a container (preferably a vial) such that the amount of the compound represented by the formula (1) or its metal salt contained in the pharmaceutical composition is 4 to 20 mg, and is a pharmaceutical preparation.

Advantages of the Invention

[0011] A pharmaceutical composition containing a specific prodrug of tolvaptan and having reduced side effects is provided.

Modes for Carrying Out the Invention

[0012] The present disclosure preferably includes, but is not limited to, pharmaceutical compositions containing a specific prodrug of tolvaptan and used for administration at a specific rate, etc. The present disclosure includes all that is disclosed herein and recognizable by those skilled in the art.

[0013] The pharmaceutical composition included in the present disclosure has the following formula (1):

[0014]

Chemical Formula

[0015] contains a compound represented by the formula or its metal salt, and preferably contains a metal salt of the compound represented by the formula (1). The compound represented by the formula (1) may be referred to as "compound (1)". Further, the pharmaceutical composition containing the compound (1) or its salt may be referred to as "the composition of the present disclosure".

[0016] Compound (1) or its metal salt is a prodrug of a specific tolvaptan contained in the composition of the present disclosure. As the prodrug of the specific tolvaptan, the metal salt of compound (1) is particularly preferred.

[0017] As the metal salt of compound (1), an alkali metal salt, an alkaline earth metal salt or a zinc salt is preferred. More specifically, for example, a sodium salt (1 or 2 sodium salts), a potassium salt (1 or 2 potassium salts), a calcium salt, a magnesium salt, a zinc salt, etc. are preferred. Among them, the 2-sodium salt is particularly preferred. Next, the structural formula of the 2-sodium salt of compound (1) is shown.

[0018]

Chemical formula

[0019] It should be noted that compound (1) or its metal salt can be produced by a known method or a method that can be easily conceived from a known method. For example, it can be produced by the method described in Patent Document 1 (International Publication No. 2007 / 074915) (especially the method described in the examples).

[0020] The composition of the present disclosure is used such that 4 to 20 mg of compound (1) or its metal salt is administered transvascularly over 10 minutes or more. As the transvascular administration, intravenous administration is preferred. Further, since it is used for transvascular administration, as the dosage form of the composition of the present disclosure, for example, an injection, a drip infusion, etc. are preferred. It should be noted that within the range of 4 to 20 mg of the compound (1) or its metal salt, the upper limit or the lower limit may be, for example, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, or 19.5 mg. For example, the range may be about 5 to 19 mg, 6 to 18 mg, 6.5 to 17.5 mg, 7 to 17 mg, 7.5 to 16.5 mg, or 8 to 16 mg.

[0021] In addition, the time taken for transvascular administration is preferably about 10 minutes to 4 hours. In this administration time range, the upper or lower limit can be, for example, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 1 hour 5 minutes, 1 hour 10 minutes, 1 hour 15 minutes, 1 hour 20 minutes, 1 hour 25 minutes, 1 hour 30 minutes, 1 hour 35 minutes, 1 hour 40 minutes, 1 hour 45 minutes, 1 hour 50 minutes, 1 hour 55 minutes, 2 hours, 2 hours 5 minutes, 2 hours 10 minutes, 2 hours 15 minutes, 2 hours 20 minutes, 2 hours 25 minutes, 2 hours 30 minutes, 2 hours 35 minutes, 2 hours 40 minutes, 2 hours 45 minutes, 2 hours 50 minutes, 2 hours 55 minutes, 3 hours, 3 hours 5 minutes, 3 hours 10 minutes, 3 hours 15 minutes, 3 hours 20 minutes, 3 hours 25 minutes, 3 hours 30 minutes, 3 hours 35 minutes, 3 hours 40 minutes, 3 hours 45 minutes, 3 hours 50 minutes, or about 3 hours 55 minutes. For example, the administration time range is more preferably about 15 to 4 hours or about 30 minutes to 4 hours, even more preferably about 30 minutes to 3 hours or about 30 minutes to 2 hours, and even more preferably about 45 minutes to 2 hours or about 45 minutes to 1 hour 30 minutes.

[0022] In addition, the composition of the present disclosure is preferably used such that the compound represented by formula (1) or its metal salt is administered at a rate of 2 / 3 (mg / min) or less on average. That is, it is preferably used so as to be administered at a rate that is 2 / 3 (mg / min) or less and greater than 0 (mg / min). The upper or lower limit of this range can be, for example, an average of 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 (mg / min). For example, the compound represented by formula (1) or its metal salt can be used so as to be administered at a rate of an average of 1 to 0.05 (mg / min), an average of 0.5 to 0.1 (mg / min), or an average of 0.3 to 0.1 (mg / min).

[0023] In addition, the composition of the present disclosure can be preferably used to reduce side effects that occur in the skin or subcutaneous tissue due to administration of the compound represented by formula (1) or its metal salt. By administering a specific prodrug of tolvaptan, which is the compound represented by formula (1) or its metal salt, at the specific rate described above, it is possible to reduce side effects that may occur in the skin or subcutaneous tissue due to administration of tolvaptan or its prodrug.

[0024] Examples of the side effects that occur in the skin or subcutaneous tissue include erythema, hyperhidrosis, and pruritus. According to the composition of the present disclosure, one or more side effects that occur in the skin or subcutaneous tissue can be preferably reduced.

[0025] The composition of the present disclosure can be used for the same uses as tolvaptan, and can be preferably used for the same uses as the known uses of tolvaptan. For example, it can be preferably used as a vasopressin receptor (particularly the V2 receptor) antagonist. More specifically, for example, it can be preferably used for the treatment of fluid retention in heart failure (preferably congestive heart failure), fluid retention in cirrhosis, hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), or the treatment of autosomal dominant polycystic kidney disease. Here, the treatment of autosomal dominant polycystic kidney disease preferably refers to the suppression of renal volume increase and / or the suppression of renal function decline in autosomal dominant polycystic kidney disease.

[0026] Among them, it can be preferably used for the treatment of fluid retention in heart failure where other diuretics such as loop diuretics are ineffective, the treatment of fluid retention in cirrhosis where other diuretics such as loop diuretics are ineffective, or the suppression of the progression of autosomal dominant polycystic kidney disease where the renal volume has already increased and the rate of renal volume increase is rapid.

[0027] In addition, the composition of the present disclosure can be preferably used for patients who need to administer 4 to 20 mg of the compound represented by formula (1) or its metal salt in a single dose for the above treatment. In particular, it can be more preferably used for patients who develop side effects in the skin or subcutaneous tissue when administering such an amount in a single dose. Note that the age of the administration target of the composition of the present disclosure is not particularly limited. For example, it is preferably administered to adults, and more preferably administered to adults so as to satisfy the above conditions.

[0028] The composition of the present disclosure is not particularly limited, but is preferably a lyophilized composition or an aqueous solution composition containing the compound represented by formula (1) or its metal salt.

[0029] The aqueous solution composition can be directly used for transvascular administration and is slowly administered transvascularly over the above-mentioned time (for example, over 10 minutes or more, preferably over 30 minutes or more, more preferably over about 60 minutes). In addition, the aqueous solution composition can be diluted with water (the water may contain other components known in the technical field of transvascular administration, and preferably include physiological saline, glucose injection solution, or various infusion preparations, etc. in this regard) and used for transvascular administration. The administration form of the aqueous solution composition is not particularly limited, but it is also possible to administer it by drip from an infusion bag or vial, and it is also possible to administer it slowly using an injection syringe. Furthermore, when precise administration is desired, it is also possible to administer it at a constant rate over a long time using a device such as an infusion pump or a syringe pump. The lyophilized composition is not particularly limited, but an aqueous solution composition obtained by dissolving (i.e., constituting) it in water (the water may contain other components known in the technical field of transvascular administration, and preferably include physiological saline, glucose injection solution, or various infusion preparations, etc. in this regard) can be used for transvascular administration. In addition, the aqueous solution composition obtained from the lyophilized composition can be further diluted with water (the water may contain other components known in the technical field of transvascular administration, and preferably include physiological saline, glucose injection solution, or various infusion preparations, etc. in this regard) and used for transvascular administration.

[0030] The lyophilized composition or the aqueous solution composition preferably contains a disaccharide.

[0031] As the disaccharide, a disaccharide in which at least one of the two sugars constituting the disaccharide is glucose is preferable. Specifically, sucrose, maltose, trehalose, lactose, etc. are mentioned, and sucrose is particularly preferable. The disaccharide can be used alone or in combination of two or more.

[0032] When the content of the compound (1) or its metal salt is 1 part by mass, the content of the disaccharide is preferably, for example, 0.5 to 70 parts by mass, more preferably 0.8 to 60 parts by mass, and even more preferably 1 to 15 parts by mass.

[0033] In particular, when the composition is a lyophilized composition, the total content of the compound (1) or its metal salt and the disaccharide is preferably 65% by mass or more of the whole composition, and more preferably 66, 67, 68, 69, or 70% by mass or more.

[0034] The lyophilized composition or the aqueous solution composition preferably further contains a buffering agent. As the buffering agent, a phosphate buffering agent and a carbonate buffering agent are preferable. In particular, a phosphate buffering agent is preferable. More specifically, for example, disodium hydrogen phosphate (sodium hydrogen phosphate hydrate) and / or sodium dihydrogen phosphate are preferably mentioned.

[0035] In addition, the lyophilized composition or the aqueous solution composition may contain a pH adjuster as needed. Specific examples of the pH adjuster include hydrochloric acid, acetic acid, phosphoric acid, etc. as acidic pH adjusters, and sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, magnesium hydroxide, etc. as basic pH adjusters.

[0036] ​In addition to these, the lyophilized composition or aqueous solution composition may also contain a pharmaceutically acceptable carrier, particularly components known in the field of lyophilized pharmaceutical preparations, if necessary.

[0037] The composition of the present disclosure (particularly the lyophilized composition or aqueous solution composition) is preferably sterilized, for example, by sterilization. The sterilization method is not particularly limited, and for example, a method of performing aseptic filtration during the preparation of the aqueous solution is exemplified.

[0038] 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, for the lyophilized composition or aqueous solution composition, the compound (1) or its metal salt, disaccharide, and, if necessary, a buffer, pH adjuster, etc. are mixed and dissolved with water to prepare an aqueous solution composition. Further, as described above, the lyophilized composition can be prepared by lyophilizing the aqueous solution composition.

[0039] The present disclosure also includes pharmaceutical preparations containing an appropriate amount of the composition of the present disclosure. As such a pharmaceutical preparation, a pharmaceutical preparation provided in a container such that the amount of the compound represented by formula (1) or its metal salt contained in the composition of the present disclosure is 4 to 20 mg is preferable. The pharmaceutical preparation can be preferably used as a pharmaceutical preparation for single or multiple administrations. In the range of 4 to 20 mg of the compound (1) or its metal salt, the upper limit or lower limit may be, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 mg. For example, the range may be about 5 to 19 mg, 6 to 18 mg, 7 to 17 mg, or 8 to 16 mg. Further, as such a pharmaceutical preparation, particularly a vial filled with a lyophilized composition (preferably a cake-like composition) or an aqueous solution composition in the required amount is preferably exemplified.

[0040] As used herein, the term "comprising" includes "consisting essentially of” and "consisting of."

[0041] In addition, the various characteristics (properties, structures, functions, etc.) described for each of the above-described embodiments may be combined in any manner when specifying the subject matter encompassed by the present disclosure.

Example

[0042] Hereinafter, the subject matter encompassed by the present disclosure will be described more specifically, but the subject matter is not limited to the following examples.

[0043] Production of the metal salt of compound (1) According to the method described in the examples of Patent Document 1 (International Publication No. 2007 / 074915) (particularly Examples 1, 3, and 9), Compound (1) and its disodium salt were prepared. The disodium salt was used as Compound A in the following studies. Specifically, the preparation was carried out as follows. In the description of the following specific preparation method, Compound (1b) corresponds to Compound (1), and the disodium salt of Compound (1b) corresponds to Compound A.

[0044]

Chemical formula

[0045] 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.

[0046] The resulting reaction solution was cooled to -40 °C, and 6 ml of a methylene chloride solution containing 920 mg of metachloroperbenzoic acid was added dropwise to the solution. This mixture was stirred at the same temperature for 30 minutes and further at 0 °C for 30 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The resulting reaction mixture was filtered, 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).

[0047]

Chemical formula

[0048] 5.3 g of compound (1a-1) was dissolved in 100 ml of ethanol. Using 2 g of 5% palladium on carbon as a catalyst, the solution was subjected to catalytic hydrogenation at room temperature and atmospheric pressure for 10 minutes. The catalyst was filtered off from the solution, and the resulting filtrate was concentrated (4.2 g). The resulting residue was crystallized from methanol-water. The crystals were collected by filtration and dried under reduced pressure (phosphorus pentoxide) to obtain 3.5 g (yield 88.5%) of a white powder of compound (1b). The crystals were collected by filtration and dried under reduced pressure (phosphorus pentoxide) to obtain 3.5 g (yield 88.5%) of a white powder of compound (1b).

[0049] Furthermore, 1.0 ml of 1N aqueous 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.

[0050] In addition, according to the method described in the examples of Patent Document 1, the calcium salt, magnesium salt, or zinc salt of compound (1) was also produced.

[0051] Preparation of a lyophilized formulation of compound A According to the composition described in Table 1 below, Compound A, 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 with the composition of Table 1. After the aqueous solution of the composition was aseptically filtered, 5.21 mL was filled into a sterilized glass vial. Further, after freezing at -40°C or lower, the pressure was reduced to vacuum, the shelf temperature was set to -10°C to remove water, and then the shelf temperature was set to 30°C to remove residual moisture, thereby obtaining a sterile lyophilized composition (in a vial) with the composition of Table 2.

[0052] Note that Table 1 shows the amount per 1 mL, and Table 2 shows the amount per vial. Also, the 25 mg formulation contains 26.5 mg of the active ingredient (Compound A) per vial.

[0053]

Table 1

[0054]

Table 2

[0055] To each of the obtained 0 mg formulation and 25 mg formulation, 5 mL of water for injection was added to dissolve the lyophilized composition (lyophilized cake) to obtain an aqueous solution for injection. When 5 mL of water for injection is added to the 25 mg formulation and dissolved, an aqueous solution composition of Table 1 containing 5 mg / mL of the active ingredient (Compound A) (25 mg formulation aqueous solution for injection) is reconstituted to 5.21 mL. Then, according to the composition of Table 3 below, the 25 mg formulation aqueous solution for injection, the 0 mg formulation aqueous solution for injection, and physiological saline (physiological saline solution) were mixed to prepare each administration solution. L is added and dissolved, and an aqueous solution composition of Table 1 containing 5 mg / mL of the active ingredient (Compound A) (25 mg formulation aqueous solution for injection) is reconstituted to 5.21 mL. And, according to the composition of Table 3 below, the 25 mg formulation aqueous solution for injection, the 0 mg formulation aqueous solution for injection, and physiological saline (physiological saline solution) were mixed to prepare each administration solution. And, according to the composition of Table 3 below, the 25 mg formulation aqueous solution for injection, the 0 mg formulation aqueous solution for injection, and physiological saline (physiological saline solution) were mixed to prepare each administration solution.

[0056]

Table 3

[0057] Using a syringe pump, each administration solution obtained was intravenously administered over the administration time described in Table 3. The number of subjects to whom each administration solution was administered was six healthy adult males (aged 20 to 40 years) (N = 6) in each case.

[0058] The number of people who developed side effects (erythema, hyperhidrosis, or pruritus) that could appear in the skin or subcutaneous tissue, observed up to 24 hours after the start of administration, was recorded. The results are shown in Table 4. When an administration solution containing 7.5 mg or 15 mg of Compound A was intravenously administered over 1 minute or 5 minutes, erythema, hyperhidrosis, or pruritus occurred frequently (Table 4: Administration results of administration solutions 3 to 6). On the other hand, when an administration solution containing 7.5 mg or 15 mg of Compound A was slowly administered over 2 hours, no side effects that could appear in the skin or subcutaneous tissue, such as erythema, hyperhidrosis, or pruritus, were observed (Table 4: Administration results of administration solutions 1 to 2). Table 4 also shows the maximum blood concentration (Cmax) of tolvaptan in the subjects to whom each administration solution was administered.

[0059]

Table 4

[0060] Formulation Examples 1 to 35 are shown below. Table 5 shows the amount (mg) per 1 mL, and Table 6 shows the amount (mg) per vial, respectively.

[0061]

Table 5

[0062] TIFF2025081484000012.tif233170

[0063] TIFF2025081484000013.tif233170

[0064]

Table 6

[0065] TIFF2025081484000015.tif233170

[0066] TIFF2025081484000016.tif233170

Claims

[Claim 1] The invention described in the specification.

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