Pharmaceutical preparation stable over long period of time

Abstract

The present invention pertains to a method for producing a DFP-10917 preparation stable over a long period of time.

Description

Long-term Stable Pharmaceutical Formulation

[0001] The present invention relates to a long-term stable pharmaceutical formulation of 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-Pyrimidinone monohydrochloride (hereinafter referred to as "DFP-10917") for use in the treatment of cancer patients such as acute myeloid leukemia (hereinafter referred to as "AML").

[0002] It is known that DFP-10917, when administered intravenously via long-term continuous infusion at a low dose, is triphosphorylated by the action of deoxycytidine kinase (hereinafter referred to as "CDK") in cancer cells, incorporated into DNA strands, induces double-strand breaks of DNA strands in the G2 / M phase of the cancer cell cycle, and induces apoptosis and death of cancer cells (Patent Document 1). In basic experiments using various cancer cells and tumor-bearing animals, it has been confirmed that DFP-10917 is expected to exert anti-cancer effects as a chemotherapeutic agent for solid cancers such as non-small cell lung cancer (hereinafter referred to as "NSCLC"), pancreatic cancer and breast cancer, and hematological cancers such as acute myeloid leukemia (hereinafter referred to as "AML") (Non-Patent Document 1).

[0003] In addition, in a Phase I / II clinical trial of DFP-10917 conducted at MD Anderson Cancer Center in Texas, USA (hereinafter referred to as "MDACC"), complete remission has been observed in approximately half of AML patients with refractory or relapsed (hereinafter referred to as "R / R") standard chemotherapy (Non-Patent Document 2).

[0004] Thereafter, after obtaining approval from the United States Food and Drug Administration (hereinafter referred to as "FDA"), a large-scale Phase III comparative clinical trial targeting R / R AML patients has been conducted at cancer centers and major hospitals (approximately 40 institutions) in the United States.

[0005] WO 2009 / 133963WO 2010 / 131475

[0006] K. Iizuka, et al., "Analysis of the prolonged infusion of DFP-10917, a deoxycytidine analog, as a therapeutic strategy for the treatment of human tumor xenografts in vivo." Int. J. Oncol. 52 (3), 851-860, 2018H. M Kantarjian, et al., "Phase 1 / 2 study of DFP-10917 administered by continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia." Cancer. 125 (10), 1665-1673, 2019

[0007] In the initial stages of DFP-10917 development (Clinical Phase I / II trials), a formulation manufactured by conventional freeze-drying (consisting of amorphous fine powder) was provisionally used. However, this formulation had the problem of not being able to maintain stability over long storage periods. To date, Type I and Type II crystals of DFP-10917 have been invented using small-scale laboratory-level recrystallization methods (Patent Document 2). However, if DFP-10917 is to be commercialized, a formulation that is stable over a storage period of two years or more is required. Therefore, the present invention aims to provide a new means that enables the mass production of a long-term stable DFP-10917 formulation on an industrial scale, based on GMP (Good Manufacturing Practice) standards.

[0008] The present inventors, after diligently studying to solve the above problems, found that when an aqueous solution of DFP-10917 is processed by a conventionally known freeze-drying method, only amorphous powder is produced, and the DFP-10917 is easily decomposed due to the influence of moisture such as mannitol (a type of sugar alcohol) as an excipient, making it impossible to maintain stability over a long period of time. On the other hand, they found that by cooling the aqueous solution of DFP-10917 to about -50°C and freezing it before subjecting it to freeze-drying, then raising the temperature to about -10°C and letting it stand for several hours, and then subjecting it to freeze-drying conditions, a freeze-dried formulation containing type II microcrystals of DFP-10917 can be obtained, and that this freeze-dried formulation containing type II microcrystals can be stored stably for a long period of time under low humidity conditions (for example, in a closed-system vial for injection).

[0009] The present invention is based on these novel findings and encompasses the following inventions: [1] A method for producing a formulation containing type II microcrystals of DFP-10917, comprising: (1) cooling a solution containing DFP-10917 to -30°C to -70°C and freezing it, then allowing it to stand at a shelf temperature of -11°C to -9°C; (2) then cooling it to -30°C to -70°C and freezing it, then freeze-drying it at a shelf temperature of -10°C to -50°C; and (3) then raising the temperature to 20°C to 40°C and drying it. [2] The method for producing [1], wherein the type II microcrystals of DFP-10917 have a characteristic peak in the powder X-ray diffraction signal with a 2θ value of 6.8°. [3] A method for producing [1] or [2], comprising: (1) cooling a solution containing DFP-10917 to -50°C and freezing it, then letting it stand at a shelf temperature of -10°C; (2) then cooling it to -50°C and freezing it, then freeze-drying it at a shelf temperature of -20°C; and (3) then raising the temperature to 30°C and drying it. [4] A method for producing any of [1] to [3], wherein the formulation containing type II microcrystals of DFP-10917 is a freeze-dried formulation. [5] A method for producing any of [1] to [4], wherein the solution containing DFP-10917 further contains mannitol. [6] A formulation containing type II microcrystals of DFP-10917 having a characteristic peak with a 2θ value of 6.8° in the powder X-ray diffraction signal. [7] The formulation of [6], which is a freeze-dried formulation.

[0010] According to the present invention, it is possible to provide a novel means that enables the mass production of DFP-10917 formulations that remain stable over a long period of time on an industrial scale based on GMP (Good Manufacturing Practice) standards.

[0011] Figure 1 shows the conditions for a conventionally known freeze-drying process (shelf temperature setting (°C) and elapsed time (hours)). Figure 2 shows the conditions for a freeze-drying process (shelf temperature setting (°C) and elapsed time (hours)) in an example of the present invention method. Figure 3 shows the powder X-ray diffraction data (top) of a type II microcrystalline formulation of DFP-10917 produced by an example of the present invention method. The arrows indicate the powder X-ray diffraction signal (2θ=6.8) characteristic of type II microcrystals. For reference, the powder X-ray diffraction signal data (bottom) of type I crystals of DFP-10917 is also shown. Figure 4 shows the powder X-ray diffraction data (top) of a type II microcrystalline formulation of DFP-10917 after storage under (1) long-term storage conditions for 6 months, (2) accelerated storage conditions for 6 months, and (3) harsh storage conditions for 1 month, as well as before storage. The arrows indicate the powder X-ray diffraction signal (2θ=6.8) characteristic of type II microcrystals.

[0012] The method for producing a formulation containing type II microcrystals of DFP-10917 according to the present invention (hereinafter sometimes simply referred to as "the present invention method") generally comprises the following steps: (1) a step of cooling a solution containing DFP-10917 to -30°C to -70°C and freezing it, and then letting it stand at a shelf temperature of -11°C to -9°C (step 1); (2) a step of then cooling it to -30°C to -70°C and freezing it, and then freeze-drying it at a shelf temperature of -10°C to -50°C (step 2); and (3) a step of then raising the temperature to 20°C to 40°C and drying it (step 3).

[0013] In the present invention, "DFP-10917" can be manufactured according to conventionally known methods, for example, the method described in WO2010 / 131475, etc. That is, 1-(2'-cyano-2'-deoxy-β-D-arabinofuranosyl)-N ４ - Acetylcytosine (hereinafter also referred to as "compound (2)") and 1-(2'-cyano-2'-deoxy-β-D-arabinofuranosyl)cytosine (hereinafter also referred to as "compound (3)") can be obtained by organic chemical synthesis using these as raw materials. For example, compound (2) can be obtained by de-acetylation and hydrochloric acid addition, and compound (3) can be obtained by hydrochloric acid addition.

[0014] More specifically, examples include a method in which compound (2) is treated with acid to obtain compound (3), and then hydrochloric acid is added to obtain DFP-10917; and a method in which compound (2) is treated with acid using a hydrochloric acid methanol solution and hydrochloric acid is added in a single step to obtain DFP-10917.

[0015] Of these, it is preferable to perform the acid treatment and hydrochloric acid addition in a single step from the viewpoint of improving work efficiency and yield. The conditions for this are preferably to use 1 to 20 mL of a 0.5 to 3% hydrochloric acid methanol solution per 100 mg of compound (2), and to stir at a temperature of about 10 to 40°C (preferably room temperature) for 0.5 to 3 hours (preferably 1 ± 0.25 hours).

[0016] Compounds (2) and (3) can be produced by conventionally known methods, such as those described in Japanese Patent Publication No. 2559917; J. Med. Chem., 34, 2917-2919 (1991); J. Med. Chem., 36, 4183-4189 (1993), etc. Examples of acids used in the acid treatment include inorganic acids such as sulfuric acid and hydrochloric acid; and organic acids such as acetic acid and trifluoroacetic acid. These may be used individually or in combination of two or more.

[0017] In the method of the present invention, a "solution containing DFP-10917" can be obtained by dissolving DFP-10917 in a solvent capable of dissolving DFP-10917 (hereinafter also referred to as the "dissolving solvent"). The dissolving solvent is not particularly limited as long as it can dissolve DFP-10917, but examples include water; alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and ethers such as diethyl ether, diisopropyl ether, and t-butyl methyl ether, but water is preferred. These solvents can be used individually or as a mixture of multiple solvents. The concentration of DFP-10917 in the solution containing DFP-10917 is not particularly limited as long as a lyophilized product can be obtained, but for example, it can be about 0.1 to 5 (W / V)%, preferably 0.2 to 1 (W / V)%, and more preferably 0.4 to 0.5 (W / V)% in the dissolving solution.

[0018] Solutions containing DFP-10917 may further contain, as needed, pharmaceutical additives such as excipients, solubilizers, isotonic agents, and pH adjusters. Examples of such pharmaceutical additives include lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, gum arabic, and mixtures thereof. Examples of lubricants include, but are not limited to, purified talc, stearate, borax, polyethylene glycol, and mixtures thereof; sodium chloride, boric acid, glucose, glycerin, and mixtures thereof; sodium citrate, citric acid, sodium acetate, sodium phosphate, and mixtures thereof.

[0019] The present invention's method includes a step (step 1) to form and mature type II microcrystals of DFP-10917 before subjecting the solution containing DFP-10917 to freeze-drying. In step 1, the solution containing DFP-10917 is first cooled to -30°C to -70°C, preferably -40°C to -60°C, more preferably -50°C and frozen. The solution is held at the above temperature for 0 to 8 hours, then preferably held for 0 hours, i.e., immediately after reaching the above temperature, it is heated to -11°C to -9°C, preferably -10°C, and left to stand at that temperature (shelf temperature) for 1 to 12 hours, preferably 1 to 8 hours, more preferably 3 to 5 hours. This promotes the formation and maturation of type II microcrystals of DFP-10917.

[0020] Next, the process includes freeze-drying the DFP-10917 that has undergone the formation and maturation of the type II microcrystals. This freeze-drying process can be carried out in accordance with conventionally known general freeze-drying conditions and is not particularly limited as long as the DFP-10917 can be freeze-dried. For example, the DFP-10917 is cooled to -30°C to -70°C, preferably -40°C to -60°C, more preferably -50°C, and frozen at that temperature for 1 to 12 hours, preferably 5 to 10 hours, more preferably 7 to 8 hours, and then heated to -10°C to -50°C, preferably -20°C to -30°C, more preferably -20°C, and freeze-dried at that temperature (shelf temperature) for 12 to 72 hours, preferably 24 to 60 hours, more preferably 36 to 48 hours (step 2). Subsequently, the temperature is raised to 20°C to 40°C, preferably 25°C to 35°C, more preferably 30°C, and the final drying is performed at that temperature (shelf temperature) for 1 to 12 hours, preferably 5 to 10 hours, more preferably 7 to 8 hours (step 3), thereby obtaining a freeze-dried solution containing DFP-10917.

[0021] In one embodiment, the method of the present invention preferably includes: (1) a step of cooling a solution containing DFP-10917 to -50°C, raising the temperature to -10°C after reaching that temperature, and letting it stand at that temperature (shelf temperature) for about 3 hours (Step 1); (2) a step of then cooling it to -50°C, freezing it at that temperature for about 7 hours, raising the temperature to -20°C, and freeze-drying it at that temperature (shelf temperature) for about 40 hours (Step 2); and (3) a step of then raising the temperature to 30°C and performing final drying at that temperature (shelf temperature) for about 8 hours (Step 3).

[0022] The freeze-dried product of a solution containing DFP-10917 obtained by the method of the present invention contains type II microcrystals of DFP-10917, or more preferably consists of type II microcrystals of DFP-10917.

[0023] In the present invention, the "Type II microcrystal of DFP-10917" is characterized by having a distinctive peak in the powder X-ray diffraction signal where the value of 2θ is 6.8°.

[0024] The lyophilized solution containing DFP-10917 may, if necessary, further contain a pharmacologically acceptable carrier commonly used in the preparation of pharmaceutical formulations. Various organic or inorganic carrier materials conventionally used as pharmaceutical materials can be used as such carriers. In solid injection formulations, excipients, lubricants, binders, disintegrants, etc., may be added. In liquid injection formulations, diluents, solubilizers, suspending agents, isotonic agents, pH adjusters, buffers, stabilizers, analgesics, etc., may be added. Furthermore, pharmaceutical additives such as preservatives, antioxidants, and colorants may be used as necessary.

[0025] Examples of excipients include lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, gum arabic, and mixtures thereof. Examples of lubricants include refined talc, stearate, borax, polyethylene glycol, and mixtures thereof. Examples of binders include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, potassium phosphate, and mixtures thereof. Examples of disintegrants include dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, and mixtures thereof. Examples of diluents include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures thereof. Examples of stabilizers include sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and mixtures thereof. Examples of isotonic agents include sodium chloride, boric acid, glucose, glycerin, and mixtures thereof. Examples of pH adjusters and buffers include sodium citrate, citric acid, sodium acetate, sodium phosphate, and mixtures thereof. Examples of pain relievers include procaine hydrochloride, lidocaine hydrochloride, and mixtures of these components.

[0026] The lyophilized solution containing DFP-10917 obtained by the method of the present invention can be provided in the form of a solid injection, such as a lyophilized injection or a powder injection, which can be dissolved and used at the time of use.

[0027] The lyophilized solution containing DFP-10917 obtained by the method of the present invention (hereinafter sometimes referred to as "formulation containing type II microcrystals of DFP-10917") has excellent storage stability, as detailed in the following examples, and can be stored stably for a long period of time.

[0028] The formulation containing type II microcrystals of DFP-10917 according to the present invention can be used as an antitumor agent and can be applied to, for example, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, gallbladder and bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, testicular tumors, bone and soft tissue sarcomas, malignant lymphoma, leukemia, cervical cancer, skin cancer, brain tumors, etc. The formulation containing type II microcrystals of DFP-10917 according to the present invention can be administered to patients who have not received cancer treatment, patients who are currently receiving treatment, and patients who have received treatment in the past.

[0029] The formulation containing type II microcrystals of DFP-10917 according to the present invention is administered intravenously, and is administered by dissolving it in a suitable injection solution or infusion solution such as physiological saline.

[0030] The dosage of the formulation containing type II microcrystals of DFP-10917 according to the present invention is not fixed depending on the symptoms of the patient to whom it should be administered. However, since it can efficiently treat cancer while suppressing the occurrence of side effects, it is preferable to repeatedly administer the formulation containing type II microcrystals of DFP-10917 according to the present invention as a series of administration schedules, which constitute one course. Such an administration schedule would be 2.0 to 6.0 mg / m² of DFP-10917 per day, once every two to three weeks. 2 It is preferable to administer the amount by continuous intravenous infusion over 168 to 336 hours, which constitutes one course and is repeated once or multiple times.

[0031] Furthermore, the formulation containing type II microcrystals of DFP-10917 according to the present invention can maintain excellent stability over a long period of time in the administration solution by keeping the administration solution at a low temperature, as detailed in the following examples. When performing the above-mentioned continuous intravenous administration, means that enable the temperature of the administration solution in which the formulation containing type II microcrystals of DFP-10917 is dissolved to be kept low (for example, preferably around 10 to 25°C, more preferably around 15 to 25°C) may be used in combination. Examples of means for keeping the temperature of the administration solution low include, but are not limited to, refrigerators, coolers, and cooler boxes.

[0032] Furthermore, when administering the above-mentioned continuous intravenous infusion, a portable infusion pump may be used, and the patient may be asked to carry the pump, the administration solution containing the formulation of DFP-10917 type II microcrystals, and preferably a means to maintain the temperature of the administration solution at a low temperature (e.g., a cooling pack) for the duration of administration.

[0033] The formulation containing type II microcrystals of DFP-10917 according to the present invention may be used in combination with other antitumor agents and / or radiation. Examples of antitumor agents that can be used in combination include 5-FU, tegafur-uracil preparations, tegafur-gimeracil-oteracil potassium preparations, doxorubicin, epirubicin, irinotecan hydrochloride, etoposide, docetaxel, paclitaxel, cisplatin, carboplatin, oxaliplatin, krestin, lentinan, and picibanil. The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0034] Experiment 1: Preparation of Type II Microcrystalline Formulation of DFP-10917 In an example of the present invention's method, a 5 mL aqueous solution containing 22.8 mg of DFP-10917, 100 mg of D-mannitol (solubilizer), and 17.1 mg of sodium citrate (pH adjuster) was frozen at -50°C as shown in Figure 2, then quickly raised to -10°C, left at that temperature for approximately 3 hours, then cooled and frozen at -50°C for approximately 7 hours, then raised to -20°C and freeze-dried at that temperature for approximately 40 hours, and then raised to 30°C for final drying.

[0035] When the formulation produced according to the example of the present invention was analyzed by powder X-ray diffraction, an X-ray signal characteristic of type II microcrystals (2θ=6.8) was detected (Figure 3), confirming the presence of type II microcrystals. For reference, Figure 3 also shows the X-ray diffraction signal data of type I crystals of DFP-10917, which is stable at room temperature and humidity. The type I crystals of DFP-10917 were produced by recrystallizing DFP-10917 at room temperature and humidity.

[0036] A formulation containing type II microcrystals of DFP-10917, produced by the embodiment of the present invention (hereinafter referred to as "type II microcrystalline formulation of DFP-10917"), was used in the following experiments.

[0037] Experiment 2: Evaluation of the Stability of Type II Microcrystalline Formulation of DFP-10917 The stability of the Type II microcrystalline formulation of DFP-10917 produced in Example 1 was investigated using the following method. Specifically, the stability was evaluated based on the following conditions: (1) stability for 1, 3, and 6 months under long-term storage conditions (25°C, 60% relative humidity (hereinafter referred to as "RH")), (2) stability for 1, 3, and 6 months under accelerated storage conditions (40°C, 75% RH), and (3) stability for 1 month under severe storage conditions (60°C). The evaluation breakdown (properties, pH, moisture content, related substances, and maintenance of crystal form) was evaluated based on the respective standard values.

[0038] (1) Table 1 shows the results of the stability evaluation of the type II microcrystalline formulation of DFP-10917 under long-term storage conditions (25°C, 60%RH).

[0039] In addition, "RT" in the following tables means room temperature, "RRT" means the retention time in high-performance liquid chromatography (hereinafter referred to as "HPLC"), "cytosine" is a substance obtained by elimination of the sugar moiety of DFP-10917, "glical" is a substance obtained by elimination of the nucleobase moiety of DFP-10917, "CNDC" is a substance obtained by steric inversion of the CN group of DFP-10917, "-" means that the substance was not detected, "ND" means that the content was below the detection limit, "pH" means hydrogen ion concentration, "moisture correction" means expressing purity by subtracting the moisture content, and "NT" means that the measurement was not performed, respectively.

[0040] From these results, the stability of the type II microcrystalline preparation of DFP-10917 was confirmed throughout the 6-month storage period.

[0041]

[0042] (2) Table 2 shows the evaluation results of the stability of the type II microcrystalline preparation of DFP-10917 under accelerated storage conditions (40°C, 75%RH). From these results, the stability of the type II microcrystalline preparation of DFP-10917 was confirmed throughout the 6-month storage period.

[0043]

[0044] (3) Table 3 shows the evaluation results of the stability of the type II microcrystalline preparation of DFP-10917 under severe storage conditions (60°C). From these results, the stability of the type II microcrystalline preparation of DFP-10917 was confirmed throughout the 1-month storage period.

[0045]

[0046] In addition, Figure 4 shows the powder X-ray diffraction results of the type II microcrystalline preparation of DFP-10917 after storage under (1) long-term storage conditions for 6 months, (2) accelerated storage conditions for 6 months, and (3) severe storage conditions for 1 month. When stored under any of the conditions, an X-ray diffraction signal (2θ=6.8°) characteristic of type II microcrystals of DFP-10917 was detected in the same manner as before storage, confirming the stability of the preparation.

[0047] Experiment 3: Stability test of type II microcrystalline formulation of DFP-10917 produced on an industrial scale according to GMP standards. A type II microcrystalline formulation of DFP-10917 (20 mg vial) was produced on an industrial scale according to GMP standards as an investigational drug for a large-scale Phase 3 comparative clinical trial of DFP-10917 in patients with R / R AML, using the lyophilization method (Figure 2) according to the example of the present invention. The obtained formulation was then stored at 5°C and subjected to a stability test.

[0048] The results are shown in Table 4. These results confirm the stability of the type II microcrystalline formulation of DFP-10917 produced as an investigational drug throughout a 5-year storage period at 5°C. In Table 4, "compliant" means within specifications, and "EU" refers to the unit of endotoxin.

[0049]

[0050] On the other hand, the formulation (investigational drug) used in the early stages of clinical development (Clinical Phase I / II trial) of DFP-10917 was prepared by preparing a 5 mL aqueous solution containing 22.8 mg of DFP-10917, 100 mg of D-mannitol (solubilizer), and 17.1 mg of sodium citrate (pH adjuster) using the method shown in Figure 1, i.e., by rapidly raising the temperature to -20°C after several hours and performing freeze-drying. The resulting formulation was amorphous and showed no X-ray signal in powder X-ray diffraction. The results of the stability test conducted on this formulation under conditions of 25°C / 60% RH are shown in Table 5 below. After 3 months, the total amount of related substances exceeded the standard value of 2%, reaching 2.06%. Furthermore, although the standard value for individual related substances is 0.5% or less, the cytosine content was 0.71% and the glycoru content was 1.08%, both exceeding the standard values, so the stability test was discontinued after 6 months.

[0051]

[0052] Experiment 4: Stability of DFP-10917 in the administration solution. The type II microcrystalline formulation of DFP-10917, produced in Experiment 3 as an investigational drug, was dissolved in physiological saline in the sterile room of the pharmacy department of each hospital facility to prepare an administration solution for cancer patients. This administration solution was stored at 25°C or 35°C for 10 days and a stability test was performed.

[0053] The results are shown in Table 6. From these results, it was confirmed that the stability of DFP-10917 in the administration solution was unstable when stored at 35°C, but at 25°C, all measured values ​​were within specifications, indicating stability for 10 days.

[0054]

[0055] DFP-10917 in the administration solution should be administered at an appropriate rate (e.g., 6 mg / m²) in conjunction with means to maintain the temperature of the administration solution at 25°C (e.g., a cooling pack). 2 The drug can be administered to cancer patients participating in the clinical trial using a pump that allows for continuous intravenous infusion for two weeks at an infusion rate of ( / day).

Claims

1. A method for producing a formulation containing type II microcrystals of 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-Pyrimidinone monohydrochloride (hereinafter referred to as "DFP-10917"), comprising: (1) a step of cooling a solution containing DFP-10917 to -30°C to -70°C and freezing it, and then allowing it to stand at a shelf temperature of -11°C to -9°C; (2) a step of then cooling it to -30°C to -70°C and freezing it, and then freeze-drying it at a shelf temperature of -10°C to -50°C; and (3) a step of then raising the temperature to 20°C to 40°C and drying it.

2. The manufacturing method according to claim 1, wherein the type II microcrystals of DFP-10917 have a characteristic peak in the powder X-ray diffraction signal where the value of 2θ is 6.8°.

3. A manufacturing method according to claim 1, comprising: (1) cooling a solution containing DFP-10917 to -50°C and freezing it, and then letting it stand at a shelf temperature of -10°C; (2) then cooling it to -50°C and freezing it, and then freeze-drying it at a shelf temperature of -20°C; and (3) then raising the temperature to 30°C and drying it.

4. The manufacturing method according to claim 1, wherein the formulation containing type II microcrystals of DFP-10917 is a lyophilized formulation.

5. The manufacturing method according to claim 1, wherein the solution containing DFP-10917 further contains mannitol.

6. A formulation containing type II microcrystals of DFP-10917, which exhibits a characteristic peak with a 2θ value of 6.8° in the powder X-ray diffraction signal.

7. The formulation according to claim 6, which is a freeze-dried formulation.

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