Indocyanine compound-containing solid pharmaceutical composition

Abstract

Provided is a stable solid pharmaceutical composition containing Pudexacianinium. The solid pharmaceutical composition contains: Pudexacianinium or a pharmaceutically acceptable salt thereof; a buffer; and an excipient, wherein the moisture content in the solid pharmaceutical composition is at most 4 wt%.

Description

Solid pharmaceutical composition containing indocyanine compound

[0001] The present invention relates to a stable solid pharmaceutical composition containing Pudexacianinium.

[0002] Pudexacianinium, also known as TK-1, is a cyclodextrin-conjugated indocyanine green compound (Non-Patent Document 1). This compound is a near-infrared fluorescent dye used in fluorescence imaging. Its structure contains two cyclodextrin molecules, making it highly hydrophilic. This hydrophilicity alters its renal clearance and ureteral visualization, compared with indocyanine green, which accumulates in the liver. Therefore, it has been used, for example, as a ureteral imaging agent (Non-Patent Document 2).

[0003] Regarding indocyanine green, Non-Patent Document 3 is the package insert for "Diagnogreen® Injection 25 mg," a fluorescent angiographic contrast agent trade name of which is "Diagnogreen® Injection 25 mg," containing 25 mg of indocyanine green as a lyophilized product per vial (the accompanying dissolving solution is 10 mL of Japanese Pharmacopoeia water for injection). Non-Patent Document 3 describes that indocyanine green contains 5.0% or less sodium iodide, but does not describe any other pharmaceutical additives. Patent Document 1 discloses an indocyanine green-containing liquid formulation containing 9.3 wt% sucrose and a pH 7 phosphate buffer as an imaging composition for animal administration. Patent Document 1 exemplifies the formulation of the imaging composition as a liquid or powder, and discloses that the powder can be prepared by an appropriate known method, such as freeze-drying or spray-drying. Non-Patent Document 4 discloses an indocyanine green liposome formulation for ureteral imaging containing 9.3 wt% sucrose and a pH 7 PBS.

[0004] Regarding the indocyanine green derivative pudexacianinium or its analogous compounds, Non-Patent Documents 1 and 2 evaluate pudexacianinium as an aqueous solution or a solution in phosphate-buffered saline (PBS) at pH 7.4, but do not disclose pharmaceutical additives. Patent Document 2 also discloses a diagnostic composition that allows separate observation of two or more compounds with significantly different excitation and / or fluorescence wavelengths. The explanation of pharmaceutical additives commonly used in formulations includes examples of excipients such as lactose, starch, sorbitol, D-mannitol, sucrose, etc., and buffers such as phosphates, citrates, and acetates. There is no specific mention of pH in the diagnostic composition, and examples of dosage forms include tablets, powders, fine granules, granules, capsules, syrups, injections, topical preparations, and suppositories.

[0005] WO2016 / 128979 JP2011-173859

[0006] Journal of Biomedical Optics 21(8), 086009 (August 2016) Mol Imaging Biol (2021), published online: 11 May 2021, DOI: 10.1007 / s11307-021-01613-0 Diagnogreen® Injection 25mg Package Insert Nanomedicine: Nanotechnology, Biology and Medicine, Volume 11, Issue 5, July 2015, Pages 1057-1064

[0007] As disclosed in Non-Patent Document 3, indocyanine green has already been marketed as a lyophilized formulation. However, to the present inventors' knowledge, no pharmaceutical additives capable of sufficiently satisfying the storage stability of lyophilized formulations of indocyanine green derivatives, including cyclodextrin-linked cyclic sugar chain indocyanine compounds, including Pudexacianinium, have been investigated. Patent Document 2 lists examples of excipients and buffers as pharmaceutical additives commonly used in formulation, but does not disclose or suggest anything regarding the storage stability of lyophilized formulations containing Pudexacianinium. The stability of pharmaceutical compositions varies depending on the structure, physical properties, etc. of the compound, and therefore a technology for providing a stable solid pharmaceutical composition containing Pudexacianinium or a pharmaceutically acceptable salt thereof is desired. An object of the present invention is to provide a stable solid pharmaceutical composition containing Pudexacianinium or a pharmaceutically acceptable salt thereof.

[0008] The present inventors have found that the appearance of Pudexacianinium analogues is suppressed at a certain water content in the solid pharmaceutical composition of the present invention.

[0009] The present invention relates to the following inventions: [1] A solid pharmaceutical composition comprising Pudexacianinium or a pharmaceutically acceptable salt thereof, a buffer, and an excipient, wherein the water content in the solid pharmaceutical composition is 4% by weight or less. [2] The solid pharmaceutical composition of [1], wherein the pH of the solid pharmaceutical composition when dissolved in water is 6 or more and 7 or less. [3] The solid pharmaceutical composition of [1] or [2], wherein the buffer is selected from the group consisting of citric acid, phosphoric acid, and histidine. [4] The solid pharmaceutical composition of any of [1] to [3], wherein the buffer concentration when dissolved in water is 10 to 50 mmol / L. [5] The solid pharmaceutical composition of any of [1] to [4], wherein the excipient is a sugar and / or a salt. [6] The solid pharmaceutical composition of [5], wherein the sugar is sucrose and / or trehalose. [7] The solid pharmaceutical composition of [6], wherein the concentration of sucrose and / or trehalose when the solid pharmaceutical composition is made into an aqueous solution is 5 to 20 (w / v)%. [8] The solid pharmaceutical composition of [5], wherein the salt is sodium chloride. [9] The solid pharmaceutical composition of any of [1] to [8], wherein the total amount of related substances after one month of storage under stability test conditions of 40°C and 75% relative humidity is 7.5% or less.

[10] The solid pharmaceutical composition of any of [1] to [9], which is a lyophilized preparation.

[11] The solid pharmaceutical composition of any of [1] to [9], wherein the Pudexacianinium or a pharmaceutically acceptable salt thereof is Pudexacianinium chloride.

[12] A method for producing the solid pharmaceutical composition of

[10] , comprising the steps of: (a) preparing a solvent solution containing a solvent, Pudexacianinium or a pharmaceutically acceptable salt thereof, a buffer, and an excipient, and adjusting the pH of the solvent solution; and (b) lyophilizing the pH-adjusted solvent solution to obtain a lyophilized product.

[13] A solid pharmaceutical composition comprising Pudexacianinium or a pharmaceutically acceptable salt thereof, citric acid, and sucrose, wherein the water content in the solid pharmaceutical composition is 4% by weight or less, and the pH of the solid pharmaceutical composition when dissolved in water is 6 or more and 7 or less.

[0010] According to the present invention, a stable solid pharmaceutical composition containing Pudexacianinium can be provided.

[0011] 1 is a graph showing the quantitative values ​​(%) of Pudexacianinium pharmaceutical compositions (lyophilized preparations) with different moisture values ​​after storage at 40°C and 75% RH for 3 months and 6 months. FIG. 2 is a graph showing the moisture values ​​(wt%) of Pudexacianinium pharmaceutical compositions (lyophilized preparations) with different moisture values ​​after storage at 40°C and 75% RH for 1 month, 2 months, and 3 months. FIG. 3 is a graph showing the residual rate (%) of the Pudexacianinium peak of Pudexacianinium pharmaceutical compositions (liquids) with different pH values ​​after storage at 70°C for 1 day. FIG. 4 is a graph showing the residual rate (%) of the Pudexacianinium peak of Pudexacianinium pharmaceutical compositions (liquids, pH 6.5) with different buffers after storage at 70°C for 1 day. FIG. 5 is a graph showing the area ratio (%) of the Pudexacianinium peak of Pudexacianinium pharmaceutical compositions (liquids, pH 6.5) with different buffers after storage at -20°C for 6 months. 1 is a graph showing the total amount (%) of related substances in Pudexacianinium pharmaceutical compositions (lyophilized preparations) with different excipients (stabilizers) after storage at 40°C and 75% RH for one month. 2 is a graph showing the total amount (%) of related substances in Pudexacianinium pharmaceutical compositions (lyophilized preparations) with different drug concentrations and excipient (stabilizer) concentrations after storage at 40°C and 75% RH for one month. 3 is a graph showing the moisture content (wt%) of Pudexacianinium pharmaceutical compositions (lyophilized preparations) with different pH values ​​before storage. 4 is a graph showing the moisture content (wt%) of Pudexacianinium pharmaceutical compositions (lyophilized preparations) with different buffers before storage. 5 is a graph showing the moisture content (wt%) of Pudexacianinium pharmaceutical compositions (lyophilized preparations) with different excipients before storage. 6 is a graph showing the total amount (%) of related substances in lyophilized and liquid Pudexacianinium pharmaceutical compositions after storage at 40°C and 75% RH for three months. 1 is a graph showing the total amount (%) of related substances in Pudexacianinium pharmaceutical compositions (lyophilized preparations) with different pH values ​​after storage at 40°C and 75% RH for 3 months. 2 is a graph showing the total amount (%) of related substances in Pudexacianinium pharmaceutical compositions (lyophilized preparations) with different buffers after storage at 40°C and 75% RH for 3 months.1 is a graph showing the total amount (%) of related substances for Pudexacianinium pharmaceutical compositions (lyophilized formulations) containing different excipients after storage at 40°C and 75% RH for 3 months. 2 is a graph showing the change (mm) in the height of the lyophilized cake from before storage for Pudexacianinium pharmaceutical compositions (lyophilized formulations) containing different pH values ​​after storage at 40°C and 75% RH for 3 months. 3 is a graph showing the change (mm) in the height of the lyophilized cake from before storage for Pudexacianinium pharmaceutical compositions (lyophilized formulations) containing different buffers after storage at 40°C and 75% RH for 3 months. 4 is a graph showing the change (mm) in the height of the lyophilized cake from before storage for Pudexacianinium pharmaceutical compositions (lyophilized formulations) containing different excipients after storage at 40°C and 75% RH for 3 months. 5 is a graph showing the redissolution time (seconds) for Pudexacianinium pharmaceutical compositions (lyophilized formulations) containing different pH values ​​after storage at 40°C and 75% RH for 3 months. 1 is a graph showing the redissolution time (seconds) of Pudexacianinium pharmaceutical compositions (lyophilized formulations) containing different buffers after storage at 40°C and 75% RH for 3 months. 2 is a graph showing the redissolution time (seconds) of Pudexacianinium pharmaceutical compositions (lyophilized formulations) containing different excipients after storage at 40°C and 75% RH for 3 months. 3 is a graph showing the total amount (%) of related substances of Pudexacianinium pharmaceutical compositions (lyophilized formulations) containing different drug concentrations after storage at 40°C and 75% RH for 6 months. 4 is a graph showing the total amount (%) of related substances of Pudexacianinium pharmaceutical compositions (lyophilized formulations) containing different drug concentrations after storage at 40°C and 75% RH for 6 months.

[0012] As used herein, the term "stable" means that the solid pharmaceutical composition has high storage stability. Here, "storage stability" refers to the stability of Pudexacianinium in a solid pharmaceutical composition when the solid pharmaceutical composition is stored in a solid state under certain storage conditions, and can be evaluated by changes in the amount of Pudexacianinium itself, or changes in the total amount of related substances derived from Pudexacianinium or the amount of a specific related substance.

[0013] For example, after storing a solid pharmaceutical composition under specified conditions for a specified period of time, the storage stability can be evaluated by analyzing the change in the amount of Pudexacianinium itself, or the change in the total amount of related substances derived from Pudexacianinium or the amount of a specific related substance, using an analytical means capable of measuring the amount of Pudexacianinium and / or its related substances, such as high performance liquid chromatography (hereinafter sometimes abbreviated as HPLC).

[0014] Typically, storage conditions can be selected from 40°C and 75% relative humidity (hereinafter sometimes abbreviated as %RH), and storage periods can be selected from 1 month, 2 months, 3 months, and 6 months under the above storage conditions.

[0015] In one embodiment, the storage stability can be evaluated as "stable" when the residual percentage of Pudexacianinium after 6 months of storage at 40°C and 75% RH is typically 90% or more, preferably 93% or more. Alternatively, the storage stability can be evaluated as "stable" when the total amount of Pudexacianinium-derived related substances after 3 months of storage at 40°C and 75% RH is typically 7% or less, preferably 5% or less, and more preferably 3% or less.

[0016] The solid pharmaceutical composition of the present invention is a solid preparation having a water content of 4% by weight or less. In another embodiment, it is 3% by weight or less. The lower limit is determined by the drying method used (e.g., lyophilization), and is, for example, 0.5% by weight, or 0.3% by weight in another embodiment. The upper and lower limits can be arbitrarily combined as desired, for example, to a range of 0.3% by weight to 4% by weight.

[0017] The measurement of the water content in a solid pharmaceutical composition is not particularly limited, but can typically be carried out using coulometric titration of the Karl Fischer method or a water content measuring device (Arizona Instrument or AMETEK Brookfield). For example, in the coulometric titration of the Karl Fischer method, Aquamicron AX (Mitsubishi Chemical) is used as the anolyte for water content measurement, Aquamicron CXU (Mitsubishi Chemical) is used as the catholyte, and ultra-dehydrated methanol is used as the sample dissolution solvent. A known amount of ultra-dehydrated methanol is added to a sealed vial, the sample is dispersed by ultrasonic irradiation, and 500 μL of the supernatant after centrifugation is added to a water content measuring device (Mitsubishi Chemical Analytical), and the water content of the sample can be measured.

[0018] In the method using a moisture measuring device (Arizona Instrument or AMETEK Brookfield), the weight of a vial containing a sample is measured, the sample is placed in the moisture measuring device, and the amount of moisture in the sample is measured by heating. After the measurement, the vial is washed and dried, and the weight of the empty vial is measured to calculate the weight of the sample. The moisture value can be calculated by dividing the amount of moisture by the sample weight.

[0019] The solid pharmaceutical composition of the present invention has an aqueous solution having a pH of typically 6 to 7, in another embodiment 5 to 8, and in yet another embodiment 4 to 9. The upper and lower limits can be arbitrarily combined as desired, for example, to obtain a pH of 6 to 8.

[0020] Pudexacianinium used in the solid pharmaceutical composition of the present invention has the following structural formula: It is a compound represented by the formula:

[0021] Pudexacianinium or a pharmaceutically acceptable salt thereof is easily available by the production method described in, for example, Non-Patent Document 1, WO 2011 / 093098, or WO 2021 / 105888, or a production method similar thereto. Pudexacianinium or a pharmaceutically acceptable salt thereof may be in an amorphous form obtained by the production method described in Non-Patent Document 1. Alternatively, it may be in a crystalline form (WO 2021 / 105888).

[0022] Pharmaceutically acceptable salts of pudexacianinium may include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid. A typical pharmaceutically acceptable salt of pudexacianinium is pudexacianinium chloride, which is an acid addition salt with hydrochloric acid.

[0023] Pudexacianinium or a pharmaceutically acceptable salt thereof is a near-infrared fluorescent dye and is useful for near-infrared fluorescent imaging, such as ureter imaging, lymphatic imaging, and cancer imaging.

[0024] The dose of pudexacianinium or a pharmaceutically acceptable salt thereof can be appropriately determined for each individual case, taking into consideration, for example, the organ or tissue to be imaged, the administration route, the age, race, sex of the patient, etc. The dose per adult is typically 0.3 to 24 mg / person, calculated as the free form of pudexacianinium.

[0025] The content of pudexacianinium or a pharmaceutically acceptable salt thereof is typically 0.1 to 7 wt %, 0.05 to 16 wt % in another embodiment, and 0.05 to 28 wt % in still another embodiment, based on the weight of the solid pharmaceutical composition. The upper and lower limits can be arbitrarily combined, as desired, to give, for example, 0.1 to 16 wt %.

[0026] Furthermore, when the solid pharmaceutical composition is made into an aqueous solution, the concentration of Pudexacianinium is typically 0.1 to 8 mg / mL.

[0027] The buffer used in the solid pharmaceutical composition of the present invention is not particularly limited as long as it is a buffer that can set the pH of the solid pharmaceutical composition in an aqueous solution to between 6 and 7. The buffer can typically be selected from the group consisting of citric acid, phosphoric acid, and histidine, and in another embodiment, it is citric acid or phosphoric acid, and in yet another embodiment, it is citric acid.

[0028] The blending ratio of the buffering agent is typically 3 to 15 wt %, 1 to 25 wt % in another embodiment, and 1 to 40 wt % in still another embodiment, based on the weight of the solid pharmaceutical composition. The upper and lower limits can be arbitrarily combined as desired, for example, 3 to 25 wt %.

[0029] Furthermore, when the solid pharmaceutical composition is made into an aqueous solution, the buffer concentration is typically 10 to 50 mmol / L, in another embodiment 5 to 100 mmol / L, and in yet another embodiment 5 to 200 mmol / L. The upper and lower limits can be arbitrarily combined as desired, for example, to obtain a concentration of 10 to 100 mmol / L.

[0030] The excipient used in the solid pharmaceutical composition of the present invention is not particularly limited as long as it is a substance that can maintain or improve the storage stability of the solid pharmaceutical composition when stored in a solid state. The excipient is typically a sugar and / or a salt (i.e., a sugar or a salt, or a combination of a sugar and a salt).

[0031] When sugar is used as the excipient, it is typically sucrose and / or trehalose (ie, sucrose or trehalose, or a combination of sucrose and trehalose), and alternatively sucrose.

[0032] When a sugar is used as the excipient, the sugar concentration (typically the concentration of sucrose and / or trehalose) when the solid pharmaceutical composition is dissolved in water is typically 5 to 20 (w / v)%, in another embodiment 2 to 30 (w / v)%, and in yet another embodiment 2 to 50 (w / v)%. The upper and lower limits can be arbitrarily combined as desired, for example, 5 to 30 (w / v)%. If the excipient concentration is too high, the redissolution time will be long, and if it is too low, stability will decrease, so it is best to select an appropriate concentration.

[0033] When a salt is used as the excipient, it is typically sodium chloride. When a salt is used as the excipient, the salt concentration (typically, sodium chloride concentration) when the solid pharmaceutical composition is made into an aqueous solution is typically 0.9 to 1.8 (w / v)%, in another embodiment 0.5 to 2.7 (w / v)%, and in yet another embodiment 0.5 to 4.5 (w / v)%. The upper and lower limits can be arbitrarily combined as desired, for example, 0.9 to 2.7 (w / v)%, etc.

[0034] The dosage form of the solid pharmaceutical composition of the present invention is not particularly limited as long as it is a solid preparation that can be dissolved when used. Examples of the dosage form include freeze-dried preparations and spray-dried preparations, but freeze-dried preparations are preferred because of their excellent stability.

[0035] The solid pharmaceutical composition of the present invention can be formulated by further using various pharmaceutical additives as desired, as long as the desired effects described herein can be achieved. Such pharmaceutical additives are not particularly limited as long as they are pharmaceutically and pharmacologically acceptable, and examples of such additives include excipients, antioxidants, surfactants, etc. Various pharmaceutical additives can be used in appropriate amounts as long as the desired effects of the present invention can be achieved.

[0036] Examples of excipients include lactose, starch, sorbitol, D-mannitol, and sucrose.

[0037] Examples of antioxidants include methionine, erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and salts thereof, L-ascorbyl palmitate, L-ascorbyl stearate, sodium hydrogen sulfite, sodium sulfite, triamyl gallate, propyl gallate, and chelating agents such as disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.

[0038] Specific examples of surfactants include nonionic surfactants, such as sorbitan fatty acid esters such as sorbitan monocaprylate, sorbitan monolaurate, and sorbitan monopalmitate; glycerin fatty acid esters such as glycerol monocaprylate, glycerol monomyristate, and glycerol monostearate; polyglycerol fatty acid esters such as decaglyceryl monostearate, decaglyceryl distearate, and decaglyceryl monolinoleate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, and polyoxyethylene sorbitan tristearate; polyoxyethylene sorbitol fatty acid esters such as polyoxyethylene sorbitol tetrastearate and polyoxyethylene sorbitol tetraoleate; and polyoxyethylene sorbitol fatty acid esters such as polyoxyethylene glyceryl monostearate. polyethylene glycerin fatty acid esters; polyethylene glycol fatty acid esters such as polyethylene glycol distearate; polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether, and other polyoxyethylene polyoxypropylene alkyl ethers; polyoxyethylene alkylphenyl ethers such as polyoxyethylene nonylphenyl ether; polyoxyethylene hydrogenated castor oils such as polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil; polyoxyethylene beeswax derivatives such as polyoxyethylene sorbitol beeswax; polyoxyethylene lanolin derivatives such as polyoxyethylene lanolin; surfactants having an HLB of 6 to 18, such as polyoxyethylene fatty acid amides, for example, polyoxyethylene octadecane amide; anionic surfactants, for example, C surfactants such as sodium cetyl sulfate, sodium lauryl sulfate, and sodium oleyl sulfate. １０ ~C １８alkyl sulfates having an alkyl group; polyoxyethylene alkyl ether sulfates having an average mole number of added ethylene oxide units of 2 to 4 and an alkyl group having 10 to 18 carbon atoms, such as sodium polyoxyethylene lauryl sulfate; C ８ ~C １８ alkyl salts of sulfosuccinic acid having an alkyl group; natural surfactants such as lecithin and glycerophospholipids; sphingophospholipids such as sphingomyelin; or C １２ ~C １８ Contains sucrose esters of fatty acids.

[0039] Since the solid pharmaceutical composition of the present invention is a solid preparation, it can be used as an injection, for example, for near-infrared fluorescence imaging, by adding an appropriate injection solvent (typically water, particularly sterile water) before use. The amount (e.g., mL) of the injection solvent added to prepare the solid pharmaceutical composition into an injection is typically 0.25 to 1 (vol / wt) times, in another embodiment 0.1 to 1.5 (vol / wt) times, in yet another embodiment 0.1 to 5 (vol / wt) times, and in yet another embodiment 0.1 to 8 (vol / wt) times the weight (e.g., mg) of the solid pharmaceutical composition. The above upper and lower limits can be arbitrarily combined as desired, for example, 0.25 to 1.5 (vol / wt) times.

[0040] The production method of the present invention for a freeze-dried preparation, which is one embodiment of the solid pharmaceutical composition of the present invention, will be described below, but the present invention is not limited thereto.

[0041] The production method of the present invention comprises the steps of: (a) preparing a solvent solution containing a solvent, Pudexacianinium or a pharmaceutically acceptable salt thereof, a buffer, and an excipient, and adjusting the pH of the solvent solution; and (b) lyophilizing the pH-adjusted solvent solution to obtain a lyophilized product. The same explanations as for the solid pharmaceutical composition of the present invention can be applied to the "Pudexacianinium or a pharmaceutically acceptable salt thereof," "buffer," and "excipient" used in the "production method" of the present invention.

[0042] In step (a) of the production method of the present invention, pudexacianinium or a pharmaceutically acceptable salt thereof, a buffer, and an excipient are prepared, along with a solvent capable of dissolving all of these. Examples of the solvent include water. The solvent, pudexacianinium or a pharmaceutically acceptable salt thereof, a buffer, and an excipient are mixed and dissolved by stirring or the like to prepare a solvent solution. The pH of the solvent solution is then adjusted to typically 6 to 7, 5 to 8 in another embodiment, or 4 to 9 in yet another embodiment. The upper and lower limits can be arbitrarily combined, as desired, for example, to 6 to 8.

[0043] In the step (b) of the production method of the present invention, the solvent solution adjusted to a predetermined pH is freeze-dried to obtain a freeze-dried product, which is one embodiment of the solid pharmaceutical composition of the present invention. The freeze-drying can be carried out by a conventional method.

[0044] The present invention will be specifically described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0045] Example 1: Pudexacianinium was dissolved in 20 mmol / L citrate buffer (pH 6.5) containing 10% (w / v) sucrose to a concentration of 1 mg / mL in terms of free form to obtain an aqueous Pudexacianinium solution. The pH of this aqueous solution was confirmed and adjusted as necessary, and the solution was filled into a vial and lyophilized to obtain a Pudexacianinium pharmaceutical composition (lyophilized preparation) with a water content of 1.3%. The pressure was restored with nitrogen, and the vial was sealed with a rubber stopper and then sealed with an aluminum cap.

[0046] [Example 2] The rubber stopper of the pudexacianinium freeze-dried preparation prepared in Example 1 was opened and placed in a thermo-hygrostat at 25°C and 40% RH, and the standing time was adjusted to prepare a pudexacianinium pharmaceutical composition (freeze-dried preparation) with a moisture content of 3.0 wt%.

[0047] Comparative Example 1 A Pudexacianinium pharmaceutical composition (lyophilized preparation) was prepared in the same manner as in Example 2, except that the water content was changed to 4.2% by weight.

[0048] [Test Example 1] Stability Test To evaluate the stability of the pharmaceutical composition (lyophilized preparation), a storage stability test (storage at 40°C, 75% RH for 6 months) was conducted on each sample. The quantitative values ​​of Pudexacianinium before and after storage were evaluated by high performance liquid chromatography (HPLC). The test method was as follows.

[0049] A CAPCELL CORE AQ column (OSAKA SODA) was connected to the HPLC system. 10 mmol / L phosphate buffer (pH 7.3) was connected to the mobile phase A line, and acetonitrile was connected to the mobile phase B line. The flow rate was 1.0 mL / min. The sample was diluted to 0.26 mg / mL with mobile phase A, and 5 μL was injected. The gradient program in Table 1 was applied. Detection was performed at UV 255 nm. The column temperature was set at 45°C, and the sample temperature was set at 5°C.

[0050]

[0051] Regarding the measurement of the quantitative value, the area of ​​the Pudexacianinium peak detected by HPLC was measured by an automatic analysis method, and the quantitative value (%) was calculated by the external standard method. The evaluation results of the quantitative value are shown in Figure 1.

[0052] Test Example 2: Moisture content measurement To evaluate the stability of the pudexacianinium pharmaceutical composition (lyophilized formulation), a storage stability test (storage at 40°C, 75% RH for 6 months) was conducted on each sample. The moisture content of the pudexacianinium pharmaceutical composition (lyophilized formulation) was then measured and evaluated before and after storage. The test method was as follows.

[0053] The moisture content of the lyophilized formulations of Examples 1, 2, and Comparative Example 1 was measured using coulometric titration by the Karl Fischer method. Aquamicron AX (Mitsubishi Chemical) was used as the anolyte for moisture content measurement, Aquamicron CXU (Mitsubishi Chemical) was used as the catholyte, and ultra-dehydrated methanol was used as the sample dissolution solvent. A known amount of ultra-dehydrated methanol was added to a sealed vial, and the lyophilized cake was dispersed by ultrasonic irradiation. 500 μL of the supernatant after centrifugation was added to a moisture analyzer (Mitsubishi Chemical Analytical), and the moisture content of the sample was measured. The moisture content measurement results are shown in Figure 2. Figure 1 shows that in Comparative Example 1, the quantitative value after storage was below 90%, indicating that the lyophilized formulation is stable if its moisture content is 4% or less. On the other hand, Figure 2 shows that there was almost no increase in moisture content during storage, confirming that the moisture content of the lyophilized formulation immediately after production contributes to its stability.

[0054] [Reference Example 1] <pH> Sample Preparation Pudexacianinium was dissolved in 100 mmol / L phosphate buffer (pH 6) to a concentration of 1 mg / mL to prepare the composition of Reference Example 1. The formulation is as shown in Table 2 below.

[0055] [Reference Example 2] <pH> Sample Preparation The composition of Reference Example 2 was prepared in the same manner as in Reference Example 1, except that the pH was set to 7. The formulation is as shown in Table 2 below.

[0056] [Reference Example 3] <pH> Sample Preparation The composition of Reference Example 3 was prepared in the same manner as in Reference Example 1, except that the pH was set to 3. The formulation is as shown in Table 2 below.

[0057] [Reference Example 4] <pH> Sample Preparation The composition of Reference Example 4 was prepared in the same manner as in Reference Example 1, except that the pH was set to 5. The formulation is as shown in Table 2 below.

[0058] [Reference Example 5] <pH> Sample Preparation The composition of Reference Example 5 was prepared in the same manner as in Reference Example 1, except that the pH was set to 8. The formulation is as shown in Table 2 below.

[0059] [Reference Example 6] <pH> Sample Preparation Pudexacianinium was dissolved in 100 mmol / L carbonate buffer (pH 9) to a concentration of 1 mg / mL to prepare the composition of Reference Example 6. The formulation is as shown in Table 2 below.

[0060]

[0061] [Reference Test Example 1] To evaluate the stability of the liquid formulations, a thermal stress test (storage at 70°C for 1 day) was carried out on the compositions described in Reference Examples 1 to 6. The quantitative values ​​of Pudexacianinium before and after the thermal stress test were evaluated by high performance liquid chromatography (HPLC). The analytical conditions were as follows:

[0062] A Meteoric Core C18 BIO column (YMC) was connected to the HPLC system. A 100 mmol / L aqueous ammonium acetate solution was connected to the mobile phase A line, and acetonitrile was connected to the mobile phase B line. The flow rate was 0.3 mL / min. The sample was diluted to 0.1 mg / mL with 50 (v / v)% aqueous methanol, and 50 μL was injected. The gradient program shown in Table 3 was applied. Detection was performed at UV 254 nm. The column temperature was set to 50°C, and the sample temperature was set to 5°C.

[0063]

[0064] The area of ​​the Pudexacianinium peak detected by HPLC was measured by automated analysis, and the quantitative value (mg / mL) was calculated using the external standard method. The quantitative value after storage was divided by the quantitative value before storage to determine the residual rate (%) of the Pudexacianinium peak. The evaluation results of the quantitative values ​​obtained in the Reference Example are shown in Figure 3. These results confirmed that stability was good at pH 6 or pH 7. On the other hand, the quantitative values ​​at pH 3 to 5 and pH 8 to 9 decreased significantly after the thermal stress test, confirming that the optimum pH was around pH 6 to 7.

[0065] Reference Example 7 <Type and Concentration of Buffer> Pudexacianinium was dissolved in 10 to 50 mmol / L phosphate buffer (pH 6.5), 10 to 50 mmol / L citrate buffer (pH 6.5), or 10 to 50 mmol / L histidine buffer (pH 6.5) to a concentration of 1 mg / mL to prepare evaluation samples Nos. A1 to A9. The formulations of the evaluation samples are shown in Table 4 below.

[0066]

[0067] [Reference Test Example 2] <Type and concentration of buffer> To evaluate the stability of the liquid formulation, a thermal stress test (storage at 70°C for 1 day) was conducted. The quantification of Pudexacianinium before and after the thermal stress test was evaluated by high performance liquid chromatography (HPLC). The analytical conditions were the same as those in Reference Test Example 1.

[0068] The area of ​​the Pudexacianinium peak detected by HPLC was measured by automated analysis, and the quantitative value (mg / mL) was calculated using the external standard method. The quantitative value after storage was divided by the quantitative value before storage to determine the residual rate (%) of the Pudexacianinium peak. The evaluation results of the quantitative values ​​obtained in this Reference Example are shown in Figure 4. These results confirmed that phosphate or citrate buffers had good stability at concentrations ranging from 10 to 50 mmol / L. On the other hand, histidine buffers showed inferior stability compared to phosphate or citrate buffers. These results confirmed that the compound was stable in 10 to 50 mmol / L phosphate or citrate buffer formulations at pH 6.5.

[0069] Reference Example 8 Selection of Buffer and Excipient Pudexacianinium was dissolved in 20 mmol / L phosphate buffer (pH 6.5) or 20 mmol / L citrate buffer (pH 6.5) containing 0.9 (w / v)% sodium chloride or 5 (w / v)% glucose as an excipient to a concentration of 4 mg / mL to prepare evaluation samples Nos. B1 to B4. The formulations of the evaluation samples are shown in Table 5 below.

[0070]

[0071] [Reference Test Example 3] <Selection of buffer type and excipient> To evaluate the stability of the liquid formulation, a storage stability test (storage at -20°C for 6 months) was conducted on each sample. The percentage of Pudexacianinium peaks in Pudexacianinium before and after the storage stability test was evaluated by high performance liquid chromatography (HPLC). The analytical conditions were the same as in Reference Test Example 1.

[0072] The area of ​​the Pudexacianinium peak detected by HPLC was measured by automated analysis, and the area ratio (%) of the Pudexacianinium peak to the total peaks detected was calculated to evaluate the quantitative value. The storage stability evaluation results obtained in this Reference Example are shown in Figure 5. A tendency for the quantitative value to decrease over time during storage was observed for the combination of phosphate buffer and sodium chloride. On the other hand, no decrease in the quantitative value was observed during storage for the combinations of phosphate buffer and glucose, or citrate buffer and sodium chloride or glucose. Furthermore, it was suggested that citrate buffer was particularly preferable.

[0073] [Example 3] <Excipient (Stabilizer)> Pudexacianinium was dissolved in 20 mmol / L citrate buffer (pH 6.5) containing 5 (w / v)% glucose, 10 (w / v)% sucrose, 10 (w / v)% trehalose, or 5 (w / v)% mannitol to a concentration of 4 mg / mL, to prepare aqueous solutions of samples for evaluation, Samples C1 to C4. The formulations are shown in Table 6 below. Each aqueous solution of the evaluation sample was filled into a vial and lyophilized to obtain a Pudexacianinium pharmaceutical composition (lyophilized preparation). The vial was restored to pressure with nitrogen, stoppered with a rubber stopper, and then sealed with an aluminum cap.

[0074]

[0075] [Test Example 3] Appearance Evaluation Regarding the appearance of the freeze-dried preparation obtained in this example, when glucose was used as an excipient, shrinkage and porosity of the freeze-dried cake were observed. The other excipients showed good appearance and resolubility.

[0076] Test Example 4: To evaluate the stability of the pharmaceutical compositions (lyophilized preparations), a storage stability test (storage at 40°C and 75% RH for 1 month) was conducted on each sample. The amount of Pudexacianinium related substances before and after storage was evaluated by high performance liquid chromatography (HPLC). The analytical conditions were as follows:

[0077] A Kinetex C18 column (Phenomenex) was connected to the HPLC system. The mobile phase A line was connected to 10 mmol / L phosphate buffer (pH 3.0), and the mobile phase B line was connected to methanol. The flow rate was 1.2 mL / min. The sample was reconstituted with water to a concentration of 4 mg / mL, then diluted to 2 mg / mL with a mobile phase A / methanol mixture (4:1), and 80 μL was injected. The gradient program shown in Table 7 was applied. Detection was performed at UV 250 nm. The column temperature was set to 40°C, and the sample temperature was set to 5°C.

[0078]

[0079] The peak areas of the related substances and Pudexacianinium detected by HPLC were measured by automated analysis, and the amount of each related substance (%) and the Pudexacianinium peak area ratio (%) were calculated. The total amount of related substances was calculated by subtracting the detected Pudexacianinium peak area ratio from 100%. The results of evaluating the storage stability of the lyophilized formulation obtained in this example are shown in Figure 6. The total amount of related substances increased most significantly when mannitol was selected as the excipient. Comprehensive evaluation of these results confirmed that stable lyophilized formulations could be obtained by selecting sucrose or trehalose as the excipient.

[0080] Example 4: Effect of Excipient (Stabilizer) Concentration Sample Preparation Method In this study, to evaluate the effect of excipient type and concentration, Pudexacianinium was dissolved in 20 mmol / L citrate buffer (pH 6.5) containing 10% (w / v) sucrose or 10% (w / v) trehalose to a concentration of 0.45 mg / mL to prepare aqueous samples for evaluation (Samples D1 and D2). Similarly, Pudexacianinium was dissolved in 40 mmol / L citrate buffer (pH 6.5) containing 20% ​​(w / v) sucrose or 20% (w / v) trehalose to a concentration of 0.9 mg / mL to prepare aqueous samples for evaluation (Samples D3 and D4). The formulations of the aqueous samples for evaluation are shown in Table 8 below. Each aqueous sample for evaluation was filled into a vial and lyophilized to obtain a Pudexacianinium pharmaceutical composition (lyophilized formulation). The pressure was restored with nitrogen, the container was sealed with a rubber stopper, and then sealed with an aluminum cap.

[0081]

[0082] [Test Example 5] Stability Evaluation To evaluate the stability of the lyophilized preparations, a storage stability test (storage at 40°C and 75% RH for 1 month) was conducted on each sample. The amount of Pudexacianinium related substances before and after storage was evaluated by high performance liquid chromatography (HPLC). The analytical conditions were as follows:

[0083] The same procedure as in Test Example 4 was repeated except that the sample was redissolved in water to a Pudexacianinium concentration of 0.45 mg / mL, and 80 μL was injected.

[0084] The peak areas of the related substances and Pudexacianinium detected by HPLC were measured by automated analysis, and the amount (%) of each related substance and the Pudexacianinium peak area ratio (%) were calculated. The total amount of related substances was calculated by subtracting the detected Pudexacianinium peak area ratio from 100%.

[0085] The storage stability evaluation results obtained in this example are shown in Figure 7. When sucrose and trehalose were selected as excipients, the increase in related substances after storage was similar in both cases. These results confirmed that stable lyophilized formulations could be obtained using 20-40 mmol / L citrate buffer formulations containing 10-20% (w / v) sucrose or trehalose.

[0086] Example 5: Pudexacianinium was dissolved in 20 mmol / L citrate buffer (pH 6.5) containing 10% (w / v) sucrose to a concentration of 1 mg / mL in terms of free form to obtain an aqueous Pudexacianinium solution. After confirming the pH of this aqueous solution, it was filled into a vial and lyophilized to obtain a Pudexacianinium pharmaceutical composition (lyophilized formulation). The pressure was restored with nitrogen, and the vial was sealed with a rubber stopper and then sealed with an aluminum cap.

[0087] Comparative Example 2 A drug solution prepared in the same manner as in Example 5 was filled into a vial, which was then stoppered with a rubber stopper and then sealed with an aluminum cap.

[0088] Example 6 Evaluation samples Nos. E1 to E6 were prepared in the same manner as in Example 5, except that the buffer solution was a 20 mmol / L phosphate buffer solution (pH 3 to 8) or a carbonate-bicarbonate buffer solution (pH 9). The formulations of the evaluation samples are shown in Table 9.

[0089]

[0090] Example 7 Evaluation samples Nos. F1 to F5 were prepared in the same manner as in Example 5, except that the buffer solution was a 5 to 100 mmol / L citrate buffer solution (pH 6.5) or a 20 mmol / L histidine buffer solution (pH 6.5). The formulations of the evaluation samples are shown in Table 10.

[0091]

[0092] Example 8 Evaluation samples Nos. G1 to G4 were prepared in the same manner as in Example 5, except that the excipient was 5 to 40 (w / v) % sucrose or 10 (w / v) % trehalose. The formulations of the evaluation samples are shown in Table 11.

[0093]

[0094] Test Example 6 The moisture content of the prepared pharmaceutical composition (lyophilized preparation) before storage was measured and evaluated. The test method was the same as in Test Example 2.

[0095] The results of measuring the moisture content before storage obtained in Examples 5 to 8 are shown in FIGS.

[0096] Test Example 7: To evaluate the stability of the pharmaceutical composition (lyophilized formulation) and the liquid formulation, a storage stability test (storage at 40°C, 75% RH for 3 months) was conducted on each sample. The amount of Pudexacianinium related substances before and after storage was evaluated by high performance liquid chromatography (HPLC). The test method was as follows.

[0097] A CAPCELL CORE AQ column (OSAKA SODA) was connected to the HPLC system. The mobile phase A line was connected to 10 mmol / L phosphate buffer (pH 7.3), and the mobile phase B line was connected to acetonitrile. The flow rate was 1.0 mL / min. The sample was diluted to 0.52 mg / mL with mobile phase A, and 20 μL was injected. The gradient program in Table 12 was applied. Detection was performed at UV 255 nm. The column temperature was set to 45°C, and the sample temperature was set to 5°C.

[0098]

[0099] The peak areas of the related substances and Pudexacianinium detected by HPLC were measured by automated analysis, and the amount (%) of each related substance was calculated using the external standard method. The total amount of related substances was calculated as the sum of the amounts of each related substance. The results of evaluating the total amount of related substances in storage stability obtained in Examples 5 to 8 and Comparative Example 2 are shown in Figures 11 to 14.

[0100] Test Example 8: To evaluate the stability of the pharmaceutical compositions (lyophilized preparations), a storage stability test (storage at 40°C and 75% RH for 3 months) was conducted on each sample. The cake height before and after storage was evaluated. The height from the highest point of the lyophilized cake to the bottom of the vial was measured.

[0101] The freeze-dried cake height evaluation results for storage stability obtained in Examples 5 to 8 are shown in FIGS. 15 to 17.

[0102] Test Example 9: To evaluate the stability of the pharmaceutical compositions (lyophilized preparations), a storage stability test (storage at 40°C and 75% RH for 3 months) was conducted on each sample. The redissolution time before and after storage was evaluated. The test method was as follows.

[0103] Water was added to the vial using a syringe and needle, and the time was measured from the time the addition was completed. The vial was inverted once every 5 seconds to mix, and the presence of residual dissolution was checked under fluorescent light. The time when the particles had completely disappeared was recorded as the end point.

[0104] The evaluation results of the redissolution time for storage stability obtained in Examples 5 to 8 are shown in FIGS. 18 to 20.

[0105] FIG. 11 confirmed that freeze-drying treatment significantly improved storage stability. FIG. 8 showed that the moisture content of the freeze-dried formulations before storage was approximately 1% by weight regardless of pH, which was comparable among samples. FIG. 12 showed that after 3 months of storage at 40°C and 75% RH, a significant increase in related substances was observed at pH 3. Meanwhile, at pH 5 to 9, although the amount of related substances increased compared to before storage, stability was good. FIG. 15 showed that no shrinkage of the freeze-dried cakes was observed after storage at any pH. FIG. 18 showed that pH 3 to 8 exhibited good resolubility before and after storage, but pH 9 required time for resolubility from before storage. Because the freeze-dried formulations were redissolved upon use, a pH of approximately 6 to 7 was confirmed as the optimal pH, based on the stability results for the liquid formulations in Reference Examples 1 to 6.

[0106] Figure 9 confirms that the water content increases with increasing citrate buffer concentration. Figure 13 confirms that, although the citrate buffer showed an increase in related substances after storage with increasing concentration, good stability was observed within the 5 to 100 mmol / L concentration range. Histidine buffer showed comparable stability to citrate buffer under storage conditions of 40°C and 75% RH. Figure 16 shows that no shrinkage of the lyophilized cake was observed after storage at any citrate buffer concentration or histidine buffer. Figure 19 confirms that the reconstitution time was extended for the 5 mmol / L citrate buffer after storage and for the histidine buffer formulation before and after storage. On the other hand, the 10 to 100 mmol / L citrate buffer formulation showed good reconstitution both before and after storage. These results confirm that a stable lyophilized formulation can be obtained with a 10 to 100 mmol / L citrate buffer formulation containing 10 (w / v)% sucrose and pH 6.5.

[0107] As shown in Figure 10, moisture content increased significantly with increasing sucrose concentration, and at a sucrose concentration of 40% (w / v), the moisture content before storage was high, approximately 4% by weight. As shown in Figure 14, sucrose concentrations of 5 to 20% (w / v) remained stable in terms of related substances even after storage. On the other hand, the 40% (w / v) sucrose formulation showed a significant increase in the total amount of related substances after storage. This was largely due to the high moisture content before storage. The 10% (w / v) trehalose excipient showed good storage stability in terms of related substances. As shown in Figure 17, the 40% (w / v) sucrose formulation lost its lyophilized cake shape and dissolved during storage. On the other hand, no significant shrinkage of the lyophilized cake was observed before and after storage at sucrose concentrations of 5 to 20% (w / v) and 10% (w / v) trehalose. 20, the reconstitution time correlated with the dissolution of the lyophilized cake, and was significantly extended with the 40 (w / v)% sucrose formulation. The reconstitution time after storage also tended to be extended with the 20 (w / v)% sucrose formulation. These results confirmed that stable lyophilized preparations could be obtained with 20 mmol / L citrate buffer formulations containing 5-10 (w / v)% sucrose or trehalose.

[0108] Example 9 Samples for evaluation, Nos. H1 to H3, were prepared using the same method as in Example 5, except that the pudexacianinium concentrations were 0.1, 0.5, and 8 mg / mL. The formulations of the evaluation samples are shown in Table 13. The moisture content of the resulting pharmaceutical compositions (lyophilized preparations) was 1.2 to 1.4 wt %. The moisture content was measured as in Test Example 10.

[0109]

[0110] Test Example 10 The moisture content of the lyophilized preparation of Example 9 was measured using a moisture measuring device (Arizona Instrument or AMETEK Brookfield). The test method was as follows.

[0111] The weight of the vial containing the freeze-dried cake was measured, and the sample was placed in a moisture analyzer and heated to measure the moisture content of the sample. After measurement, the vial was washed and dried, and the weight of the empty vial was measured to calculate the weight of the freeze-dried cake. The moisture value was calculated by dividing the moisture content by the weight of the freeze-dried cake.

[0112] Test Example 11: To evaluate the stability of the pharmaceutical compositions (lyophilized preparations), a storage stability test (storage at 40°C and 75% RH for 6 months) was conducted on each sample. The amount of Pudexacianinium related substances before and after storage was evaluated by high performance liquid chromatography (HPLC). The test method and analytical conditions were as follows:

[0113] The sample was redissolved in water to a Pudexacianinium concentration of 0.1 to 8 mg / mL, and then a 10 mmol / L phosphate buffer solution (pH 3.0) / methanol mixture (4:1) was added to make the concentration 0.1 mg / mL, and 100 μL of the solution was injected. The procedure was otherwise the same as in Test Example 4.

[0114] The peak areas of the related substances and Pudexacianinium detected by HPLC were measured by automated analysis, and the amount (%) of each related substance and the Pudexacianinium peak area ratio (%) were calculated. The total amount of related substances was calculated by subtracting the detected Pudexacianinium peak area ratio from 100%.

[0115] The storage stability evaluation results obtained in this example are shown in Figure 21. When the pudexacianinium concentration was 0.1 to 8 mg / mL, the increase in related substances during the storage period was small, and the higher the concentration, the more stable the formulation. These results confirmed that a stable lyophilized formulation could be obtained when the pudexacianinium concentration was 0.1 to 8 mg / mL and the formulation was prepared in a 20 mmol / L citrate buffer solution at pH 6.5 containing 10 (w / v)% sucrose.

[0116] Example 10: Samples Nos. I1 and I2 were prepared as evaluation samples in the same manner as in Example 5, except that the pudexacianinium concentrations were 2 and 8 mg / mL. The formulations of the evaluation samples are shown in Table 14. The moisture contents of the resulting pharmaceutical compositions (lyophilized preparations) were 2.5% by weight and 2.2% by weight, respectively. The moisture contents were measured in the same manner as in Test Example 10.

[0117]

[0118] Test Example 12: To evaluate the stability of the pharmaceutical compositions (lyophilized preparations), a storage stability test (storage at 40°C and 75% RH for 6 months) was conducted on each sample. The amount of Pudexacianinium related substances before and after storage was evaluated by high performance liquid chromatography (HPLC). The test method and analytical conditions are as follows:

[0119] The sample was redissolved in water to a Pudexacianinium concentration of 2 or 8 mg / mL, and then diluted and analyzed in the same manner as in Test Example 10.

[0120] The peak areas of the related substances and Pudexacianinium detected by HPLC were measured by automated analysis, and the amount (%) of each related substance and the Pudexacianinium peak area ratio (%) were calculated. The total amount of related substances was calculated by subtracting the detected Pudexacianinium peak area ratio from 100%.

[0121] The storage stability evaluation results obtained in this example are shown in Figure 22. When the pudexacianinium concentration was 2 or 8 mg / mL, the increase in related substances during storage was small and the product was stable. These results confirmed that a stable lyophilized formulation could be obtained at pudexacianinium concentrations of 2 to 8 mg / mL using a 20 mmol / L citrate buffer solution at pH 6.5 containing 10 (w / v)% sucrose.

[0122] [Example 11] A pudexacianinium pharmaceutical composition (lyophilized preparation) with a water content of 1.1 wt% was obtained in the same manner as in Example 5, except that the pudexacianinium concentration was 3 mg / mL. The water content was measured in the same manner as in Test Example 10.

[0123] The solid pharmaceutical composition of the present invention can be used, for example, in the field of near-infrared fluorescence imaging.

Claims

1. A solid pharmaceutical composition comprising Pudexacianinium or a pharmaceutically acceptable salt thereof, a buffer, and an excipient, wherein the water content in the solid pharmaceutical composition is 4% by weight or less.

2. 2. The solid pharmaceutical composition according to claim 1, wherein the solid pharmaceutical composition has a pH of 6 or more and 7 or less when dissolved in water.

3. 3. The solid pharmaceutical composition according to claim 1, wherein the buffering agent is selected from the group consisting of citric acid, phosphate, and histidine.

4. 3. The solid pharmaceutical composition according to claim 1, wherein the concentration of the buffer in an aqueous solution of the solid pharmaceutical composition is 10 to 50 mmol / L.

5. 3. The solid pharmaceutical composition according to claim 1, wherein the excipient is a sugar and / or a salt.

6. 6. The solid pharmaceutical composition according to claim 5, wherein the sugar is sucrose and / or trehalose.

7. 7. The solid pharmaceutical composition according to claim 6, wherein the concentration of sucrose and / or trehalose in the solid pharmaceutical composition when the solid pharmaceutical composition is dissolved in water is 5 to 20 (w / v)%.

8. 6. The solid pharmaceutical composition of claim 5, wherein the salt is sodium chloride.

9. 3. The solid pharmaceutical composition according to claim 1, wherein the total amount of related substances is 7.5% or less after storage for one month under stability test conditions of 40°C and 75% relative humidity.

10. The solid pharmaceutical composition according to claim 1 or 2, which is a freeze-dried formulation.

11. 3. The solid pharmaceutical composition according to claim 1, wherein the pudexacianinium or a pharmaceutically acceptable salt thereof is pudexacianinium chloride.

12. A method for producing the solid pharmaceutical composition of claim 10, comprising: (a) preparing a solvent solution containing a solvent, Pudexacianinium or a pharmaceutically acceptable salt thereof, a buffer, and an excipient, and adjusting the pH of the solvent solution; (b) freeze-drying the pH-adjusted solvent solution to obtain a freeze-dried product; The above method, comprising:

13. A solid pharmaceutical composition comprising Pudexacianinium or a pharmaceutically acceptable salt thereof, citric acid, and sucrose, wherein the water content in the solid pharmaceutical composition is 4% by weight or less, and the pH of the solid pharmaceutical composition when dissolved in water is 6 or more and 7 or less.

Images