A preparation containing isabconazole or its prodrug as the active ingredient, with a single dose equivalent to 100-400 mg of isabconazole.

Abstract

It has excellent safety, and the single dose is equivalent to 100-400 units of isubuconazole. A preparation containing isabconazole or its prodrug as an active ingredient in mg. To provide. [Solution] To administer orally or intravenously to individuals with a specific background (e.g., Japanese people) and.

Description

Technical Field

[0001] The present invention relates to a preparation or the like containing isavuconazole or a prodrug thereof as an active ingredient, wherein the dose per administration is 100 to 400 mg in terms of isavuconazole.

Background Art

[0002] Infections caused by fungi localized on the body surface are called superficial mycosis, while a state in which fungi enter deep into the body such as the lungs, liver, kidneys, brain, etc. and cause infection is called deep mycosis. Deep mycosis is, for example, an infectious disease that may occur in patients with reduced immunity such as after receiving an organ transplant.

[0003] The main deep mycosis experienced in Japan is aspergillosis, candidiasis, and then, although the frequency drops considerably, cryptococcosis, mucormycosis, etc. (Non-Patent Document 1). Various pathologies in deep mycosis are "inflammation" itself, and are "manifestations" of a defensive reaction to protect the body from biological damage caused by fungi that act as proinflammatory stimulating factors (Non-Patent Document 1).

[0004] Invasive aspergillosis (IA) is reported to be the most frequent deep mycosis in the blood area, particularly in chemotherapy for acute leukemia and hematopoietic stem cell transplantation (Non-Patent Document 2). In addition, for chronic pulmonary aspergillosis (CPA), simple pulmonary aspergilloma (SPA) and chronic progressive pulmonary aspergillosis (CPPA) ​It has also been reported that onary aspergillosis exists (Non-Patent Document 1).

[0005] Antifungal drugs that can be used to treat deep-seated fungal infections include, for example, amphotericin B (AMP). HB), amphotericin B liposome formulation (L-AMB), miconazole (MCZ), Fluconazole (FLCZ), Fosfluconazole (F-FLCZ), Voriconazole ( VRCZ), itraconazole (ITCZ), micafungin (MCFG), etc. are well known. (Non-patent document 1)

[0006] Overseas, the novel azole isabuconazole has been shown to treat invasive aspergillosis (IA). It has been reported to be effective against deep-seated fungal infections, including (Non-Patent Literature 2) For example, voriconazole (VRCZ) was used in patients with invasive aspergillosis (IA). In an overseas Phase III trial compared with voriconazole, isabconazole showed superior efficacy compared to voriconazole. It demonstrated non-inferiority to zole (VRCZ) (Non-Patent Literature 3). In addition, in overseas Phase III trials... The efficacy of isabconazole in patients with mucormycosis was investigated using an international registry database. Based on evaluations using a Matched-Case Control study, isabconazole was found to be amphoteric. It has been confirmed to exhibit efficacy not significantly different from that of tericin B (Non-Patent Literature 4).

[0007] In the two previous overseas Phase III trials, isabconazole was found to be a prodrug. Buconazonium sulfate, 3 times a day for 2 days, equivalent to 2 units of isabconazole. The patient was initially given 00 mg, and then 200 mg (equivalent to isabconazole) once daily. This has been reported (Non-Patent Documents 3-4).

[0008] By the way, there are differences in the pharmacokinetics, etc. of drugs between Japanese and foreigners, and it is sometimes difficult to conclude that the recommended dose set based on the clinical trial results in foreigners is the recommended dose for Japanese (Non-Patent Document 7). Therefore, when administering to Japanese, it is necessary to set a dose suitable for Japanese. It is difficult to conclude that the recommended dose set based on the clinical trial results in foreigners is the recommended dose for Japanese (Non-Patent Document 7). Therefore, when administering to Japanese, it is necessary to set a dose suitable for Japanese. in some cases (Non-Patent Document 7). Therefore, when administering to Japanese, it is necessary to set a dose suitable for Japanese. For administration to Japanese, it is necessary to set a dose suitable for Japanese.

Prior Art Documents

Patent Documents

[0009] [[ID=十七]] [[ID=十八]] [[ID=十九]]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0010] [[ID=三十五]] [[ID=三十六]] [[ID=三十七]]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Summary of the Invention

Problems to be Solved by the Invention

[0011] The problem of the present invention is to provide a preparation containing isavuconazole or its prodrug as an active ingredient, which has excellent safety and a dose per administration of 10 0 to 400 mg in terms of isavuconazole.

Means for Solving the Problems

[0012] One aspect of the present invention is a preparation for intravenous administration containing isavuconazole or its prodrug as an active ingredient, and the dose per administration is 100 to 400 mg in terms of isavuconazole, and it is a preparation for intravenous administration for intravenous administration to a person with a specific background.

[0013] One aspect of the present invention is an oral preparation containing isavuconazole or its prodrug as an active ingredient, and the dose per administration is 100 to 400 mg in terms of isavuconazole, and it is an oral preparation for administration to a person with a specific background.

[0014] That is, the present invention relates to the following inventions, etc.

[0015] [1] A preparation for intravenous administration containing isavuconazole or its prodrug as an active ingredient, where the dose per administration is 100 to 400 mg in terms of isavuconazole, and it is a preparation for intravenous administration for intravenous administration to a person with a specific background.

[0016] [2] A preparation for intravenous administration containing isavuconazole or its prodrug as an active ingredient ​​​​​The dosage per dose is 100-400 mg in terms of isabconazole, and Intravenous administration to individuals with a specific background over a period of more than one hour A preparation for administration.

[0017] [3] Oral formulations containing isabconazole or its prodrug as an active ingredient The dosage per dose is 100-400 mg in terms of isabconazole, and An oral formulation for administration to individuals with a specific background.

[0018] [4] The prodrug of isabuconazole is isabuconazonium sulfate, as described in [1]. A preparation described in any of the following [3].

[0019] [5] A preparation described in any of the above [1] to [4], in which a person with a specific background is Japanese. .

[0020] [6] The single dose is 200 mg in terms of isubuconazole equivalent, as described in [1]~ A preparation described in any of [5].

[0021] [7] The dose per administration is 100 mg in terms of isubuconazole equivalent, as described in [1]~ A preparation described in any of [5].

[0022] [8] The single dose is 400 mg in terms of isubuconazole equivalent, as described in [1]~ A preparation described in any of [5].

[0023] [9] A preparation according to any of the above [1] to [8] for the treatment of mycoses. [Modes for carrying out the invention]

[0024] 1. Active ingredients In this invention, isabconazole means the compound represented by the following formula (I) ( Patent Document 1).

[0025] [ka]

[0026] Isavuconazole is also known as Isavuconazole or i-subconazole. It is also said that the CAS number for isabconazole is 241479-67-4. Therefore, a preparation containing isabconazonium sulfate, which is a prodrug of isabconazole, It is in clinical use (Non-Patent Document 5). Isabuconazonium sulfate is represented by the following formula (II). It is a compound that is hydrolyzed in the body. Isabuconazonium sulfate is hydrolyzed in the body. It could become a zole.

[0027] [ka]

[0028] Isabuconazole or its prodrugs can be manufactured or prepared by methods known in themselves (patent) Reference 1, Non-Patent Document 5, etc.). As a prodrug of isabconazole, isabconazonium Sulfates are a preferred example.

[0029] 2. Formulation (2-1) Route of administration The formulation of the present invention has one characteristic feature in that its route of administration is either oral or intravenous. When administering the formulation of the present invention intravenously, it is preferable to adopt a form that allows for continuous administration. For example, a solution containing the formulation of the present invention, placed in a bottle or bag and suspended, is administered intravenously. The method of administering small amounts at a time through a needle (intravenous drip) is adopted. preferable.

[0030] (2-2) Dosage The frequency of administration of the formulation of the present invention can be determined by a physician or other healthcare professional. For example, the active ingredient, the disease state, and The frequency of administration should be adjusted as appropriate depending on the progression of the disability, the patient's age, weight, underlying disease, etiology, etc. It is possible to reduce the dosage. For example, when using the formulation of the present invention, once a day or once a day Preferred methods of administration include administering the drug multiple times, for example, once or three times a day.

[0031] (2-3) Dosage The formulation of the present invention has a single dose of the active ingredient that is equivalent to isabuconazole. The point is that the dosage is 100mg to 400mg (for example, 100mg, 200mg, 400mg). It has one characteristic. In the present invention, the preferred dose per single dose of the active ingredient is As an equivalent amount of isabuconazole, 200 mg can be cited. The active ingredient is When using subconazonium sulfate, 200 mg in isabuconazole equivalent is isabuconazole This is equivalent to 372.6 mg of nazonium sulfate. It is sometimes stated that it is equivalent to mg.

[0032] (2-4) Dosage Form The dosage form of the formulation of the present invention is not particularly limited, but examples include tablets, capsules, granules, and powders. Examples include oral liquid preparations, syrups, and injections. The formulation of the present invention is for oral administration. When formulated, capsules are a preferred dosage form, and the present invention When the drug is prepared for intravenous administration, an injectable formulation is a preferred dosage form.

[0033] If the formulation of the present invention is an injectable preparation, it may be an injectable preparation that has been pre-liquidated, and may be frozen. It may also be an injectable preparation that redissolves a dried preparation.

[0034] (2-5) Additives The additives in the formulation of the present invention are not particularly limited and include excipients, binders, disintegrants, and lubricants suitable for the dosage form. Various pharmaceutical additives, such as methods, can be mixed as needed to form a pharmaceutical preparation.

[0035] When the formulation of the present invention is made into a capsule, for example, Isabucona, which is being used clinically overseas. Zonium sulfate preparations can be used as a reference (CRESEMBA® registered trademark; unpatented). Reference 5). Specifically, using conventional methods, the active ingredient and additive (magnesium citrate) Mixing (crystalline cellulose, talc, light anhydrous silicic acid, stearic acid) and then... The capsule formulation of the present invention is manufactured by filling a capsule base material, which has promellose as its main component, with this capsule. It is possible.

[0036] Even when the formulation of the present invention is made into a lyophilized formulation, it is also used in clinical applications overseas. Um-sulfate preparations can be used as a reference (CRESEMBA® registered trademark; non-patent document). 5) Specifically, mannitol and sulfuric acid as a pH adjuster are combined with the active ingredient of the present invention. The freeze-dried formulation of the present invention can be manufactured using conventional methods.

[0037] (2-6) Target for administration One characteristic of the formulation of the present invention is that it is administered to individuals with a specific background. As a target group, the most typical example is the Japanese.

[0038] Japanese people are those who have lived in Japan since ancient times and whose origins, ancestors, and lineage are rooted in the Japanese archipelago. This refers to a person, generally a person with Japanese nationality. Gender and age are irrelevant, but the person must be an adult. This is preferable. For an adult male, the ideal height is around 165-175 cm and the weight is 55-7 kg. It is preferable that the weight be around 0 kg, and for adult women, this would be approximately 153-163 cm in height. Ideally, the weight should be around 50-60 kg.

[0039] 2. Pharmacokinetics The pharmacokinetics exhibited by the formulation of the present invention are not particularly limited, but the absolute biological properties of the oral formulation are... The utilization rate (%) is preferably around 70-100%.

[0040] Pharmacokinetic parameters can be easily estimated by methods known to those skilled in the art. . As a pharmacokinetic parameter, AUC (Area Under the Drug Concentration-Time Curve) is used. (er the Curve), C max (Maximum blood concentration; Maximum drug co (incentration in plasma), T max (Time to reach maximum blood concentration;), T 1 / 2 (Examples include the half-life of the substance in the blood; biological half-life) It is possible.

[0041] When calculating pharmacokinetic parameters, it is preferable to ensure a sufficient number of measurement time points. For example, when calculating pharmacokinetic parameters in a single dose, on the first day of administration... In this case, before administration, and 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, and 4 hours after administration. 5 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 96 hours, 120 hours, 2 Blood samples were collected at 40 and 480 hours, and the isabconazole concentration in the plasma was measured. Furthermore, analytical methods that do not depend on pharmacokinetic models, namely NCA (Non-Compartmental Analysis), are used. It can be calculated by (tal Analysis).

[0042] 3.Safety (3-1) Evaluation of adverse events, side effects, and safety Generally speaking, this refers to all undesirable or unintended illnesses or other adverse events that occur in a person who has been administered a drug. The signs of adverse events (AEs) can be referred to as adverse events. Adverse events that occur after administration are specifically referred to as TEAEs (Treatment-emergent adverse events). It is sometimes referred to as a verse event.

[0043] Adverse events that cannot be ruled out as having a causal relationship with the drug can be called side effects. Here, "cannot deny a causal relationship" means that a reasonable possibility of a causal relationship can be recognized. This also includes situations where a reasonable possibility of a causal relationship cannot be ruled out.

[0044] Adverse events can be classified into "serious adverse events" and "non-serious adverse events." The severity of the elephant's condition can be classified into "mild," "moderate," and "severe." Such classifications are, for example, In clinical trials, the principal investigator and co-investigators may follow the customary practices of the field in question. It is possible.

[0045] Adverse events, in terms of their changes over time, are categorized by their outcome, for example, recovery. / resolved), recovering / resolving, not recovered ( (not recovered / not resolved), recovered but with lingering effects (r (recovered / resolved with sequelae), deceased, unknown, It can also be classified.

[0046] There are no particular restrictions on the method used to compare the safety of one drug with another; for example, Focusing on adverse events, we compared their frequency, severity, causal relationship, outcome, and / or degree. It is also possible to compare them. Alternatively, it is possible to compare all or part of adverse events or all or part of side effects. The two drugs can also be compared in terms of the likelihood of discontinuing administration due to adverse events. Adverse events can be measured by clinical laboratory values ​​and biologics. This may include abnormalities in tart signs.

[0047] Adverse events are not particularly limited and can be broadly categorized by organ system (System Organ Class). It can also be classified by SOC). Examples of organ-specific classifications related to adverse events are as follows: It is possible.

[0048] 1) Infectious diseases and parasitic diseases 2) Gastrointestinal disorders 3) Musculoskeletal and connective tissue disorders 4) Disorders, poisoning, and complications of treatment 5) General and systemic disorders and the condition of the administration site 6) Skin and subcutaneous tissue disorders 7) Neurological disorders 8) Respiratory, thoracic, and mediastinal disorders 9) Eye disorders 10) Metabolic and nutritional disorders 11) Clinical Laboratory Tests 12) Benign, malignant, and unspecified neoplasms (including cysts and polyps) 13) Ear and labyrinth disorders 14) Cardiac disorders 15) Vascular disorders

[0049] When administering the formulation of the present invention to the target population of the present invention, from the viewpoint of the overall frequency of adverse events, Oral administration is preferred as the route of administration.

[0050] (3-2) Safety related to liver function As mentioned above, isabconazonium sulfate preparations are already being used clinically overseas (CRE SEMBA (registered trademark); Non-Patent Literature 5). Non-Patent Literature 5 states that liver side effects are overseas It has been reported that this was observed in clinical trials (5.1 Hepatic Adv (See the Drug Reactions section). In that section, liver side effects are listed, for example, , ALT (alanine aminotransferase; sometimes called GPT), AST (Aspartate aminotransferase; sometimes referred to as GOT), ALP ( Elevated liver function-related clinical test values ​​such as alkaline phosphatase and total bilirubin. That is how it is perceived.

[0051] Therefore, preparations containing isabconazole or its prodrug as an active ingredient are used in human There is considered to be significant clinical value in improving the safety of liver function when administering this drug.

[0052] ALT is one of the enzymes produced by liver cells, and if there is some abnormality in the liver, the liver cells... It is said that when it breaks down too much, it releases an enzyme into the bloodstream.

[0053] AST is one of the enzymes produced by liver cells, and if the level of AST in the blood is high, the liver It is said that this can help determine the extent of damage to the heart.

[0054] ALP is an enzyme that breaks down phosphate compounds, and its levels can be affected by cholestasis and impaired liver function. It is known that ALP in bile can reflux and enter the bloodstream.

[0055] Total bilirubin is the sum of indirect bilirubin before processing in the liver and direct bilirubin after processing. It is a compound that, due to liver damage, is not excreted from the liver and is released into the bloodstream, causing the skin to turn yellow due to its pigment content. Jaundice may occur.

[0056] Others include γ-GTP (γ-glutamyltransferase) and LDH (lactose derivative). Drogenase, total protein, and albumin are typical clinical test indicators for liver function tests. It is known as.

[0057] Based on the above, a manufacturing product containing isabconazole or its prodrug as an active ingredient ALT, AST, ALP, total bilirubin, γ-GTP, L obtained by administering the agent to humans. Changes in clinical test values ​​of DH, total protein, and albumin (8 types in total) indicate whether the drug affects liver function. It is possible to infer whether or not it will have an impact.

[0058] When administering the formulation of the present invention to the target population of the present invention, the frequency of adverse events related to liver function is From this perspective, intravenous administration is preferred as the route of administration.

[0059] (3-3) Safety regarding administration site reactions As described above, the formulation of the present invention can be administered intravenously to humans, and can be administered by continuous intravenous infusion. It may be administered. Generally, intravenously administered drugs or fluids may be affected by the movement of the catheter tip, etc. This can lead to leakage into surrounding tissues outside the blood vessels, potentially causing tissue inflammation and necrosis. (Non-patent document 6). Such a condition is called extravasation (EV) or This is sometimes called extravasation at the injection site, for example, when an anticancer drug is administered intravenously, 0. Extravasation has been reported to occur in approximately 1-4% of cases (Non-patent Literature). 6).

[0060] When administering the formulation of the present invention intravenously to the target of the present invention, injection site reactions (including extravasation) may occur. From the perspective of reducing the frequency of adverse events related to ) intravenous administration more than 1 hour later This is preferable. "More than one hour" means, for example, more than one hour and one minute, more than one hour and two minutes, You can list 1 hour 30 minutes or more, 2 hours or more, and 3 hours or more, and among them, 2 hours or more. It is preferable that... It is known that there is a relationship between the administration rate of the formulation and the administration site reaction. Surprisingly, when administering the formulation of the present invention, the administration rate can be slowed down. This can suppress injection site reactions. There is no particular upper limit to the administration time, For example, it could be 5 hours, 4 hours, 3 hours, or 2 hours and 30 minutes.

[0061] When the formulation of the present invention is administered by continuous intravenous infusion, The total amount is preferably 150 mg, containing 200 mg of isabconazole or its prodrug. A 350 mL, more preferably 200-300 mL, and even more preferably 250 mL formulation is prepared. The total amount preferably contains 100 mg of isabconazole or its prodrug, and is preferably 150 mg. A 350 mL, more preferably 200-300 mL, and even more preferably 250 mL formulation is prepared. or The total amount is preferably 400 mg, containing 400 mg of isabconazole or its prodrug. A formulation in a volume of 600 mL, more preferably 450-550 mL, and even more preferably 495 mL, It is preferable to administer the drug over the aforementioned administration time.

[0062] 4. Pharmaceutical preparations and administration methods The formulation of the present invention can also be used, for example, as a pharmaceutical formulation for the treatment of fungal infections. Furthermore, fungal infections can be treated by administering the formulation of the present invention to patients with fungal infections. When administering the formulation of the present invention for the purpose of treating fungal infections, the route of administration, frequency of administration, dosage, and administration rate are important. The decision regarding elephants can be made in accordance with the above-mentioned details.

[0063] Examples of mycoses in one aspect of the present invention include deep-seated mycoses. Examples include aspergillosis, candidiasis, cryptococcosis, or mucormycosis. Specifically, aspergillosis can be invasive aspergillosis or chronic pulmonary aspergillosis. Aspergillosis is cited as an example. Furthermore, as a chronic pulmonary aspergillosis, simple pulmonary aspergillosis is also mentioned. SPA (simple pulmonary aspergilloma) or chronic progressive pulmonary aspergillosis ( CPPA (chronic progressive pulmonary aspergillosis) is an example. [Examples]

[0064] The present invention will be described in more detail below with reference to examples. However, the present invention also applies to the following examples. This invention is not restrictive and can be implemented in any form without departing from the spirit of the present invention. It is possible to do so.

[0065] [Example 1] Preparation of the formulation (1) Preparation of oral capsule formulations (for 100, 200, or 400 mg doses) Three types of orally administered capsule formulations were prepared for use in the test of Example 2. Specifically, According to Table 1 below, the active ingredients and additives are mixed using conventional methods and then encapsulated. By filling a base material, an oral capsule formulation (for 100 mg administration) was prepared. The capsule substrate was manufactured using conventional methods as shown in Table 2 below. Oral capsule formulation (for 200 mg dose) is an oral capsule formulation (for 100 mg dose) Two formulations were used for administration. The oral capsule formulation (for 400 mg administration) is an oral capsule. Four formulations (for 100 mg administration) were prepared.

[0066] [Table 1]

[0067] [Table 2]

[0068] (2) Preparation of lyophilized preparations for intravenous administration (for 100, 200, and 400 mg doses) Three types of lyophilized intravenous formulations were prepared for use in the test of Example 2. Specifically, According to Table 3 below, use conventional methods to prepare a lyophilized preparation for intravenous administration (for 200 mg dose). The following was prepared: A lyophilized preparation for intravenous administration (for 400 mg administration) Two formulations (for 200 mg administration) were prepared. The lyophilized preparation for intravenous administration (for 100 mg administration) was prepared intravenously. The formulation used was half the amount of the lyophilized preparation for intravenous administration (for 200 mg dose). At that time, lyophilized preparation for intravenous administration (for 100 mg administration), and lyophilized preparation for intravenous administration ( (For 200 mg administration) Dissolve so that the total volume becomes 250 mL, and prepare as a lyophilized preparation for intravenous administration. The (400mg dose) was dissolved to a total volume of 495mL.

[0069] [Table 3]

[0070] [Example 2] Clinical trial involving Japanese subjects (1) Test method (1-1) Test method for single-dose studies The test formulations included an oral capsule formulation (for 100 mg dose) and an oral capsule. A formulation (for 200 mg administration) or an oral capsule formulation (for 400 mg administration), or The placebo formulation (control formulation) corresponding to these was used in healthy Japanese adult males (hereinafter referred to as Japanese It was administered orally to subjects (sometimes referred to as test subjects).

[0071] The test formulations were a lyophilized preparation for intravenous administration (for 100 mg dose), and a lyophilized preparation for intravenous administration. A preparation (for 200 mg administration) or a lyophilized preparation for intravenous administration (for 400 mg administration), or The corresponding placebo formulations (control formulations) were dissolved immediately before use and administered to Japanese subjects. In contrast, the solution obtained by dissolving was administered intravenously.

[0072] In this study, three cohorts were established based on the amount of active ingredient per dose. Each cohort was divided into two groups based on the route of administration. In addition, the group of investigational agents was divided according to the route of administration within each cohort. A control group was established, with 8 Japanese subjects in the test group and 2 in the control group. The Japanese subjects were randomly assigned to participate in the study, and the main study was conducted under double-blind conditions. Participants were kept fasting for one hour before and after oral administration. A summary of each cohort is shown in Table 4 below.

[0073] [Table 4]

[0074] (1-2) Test methods for repeated dose studies The investigational formulation was an orally administered capsule (200 mg dose) administered to Japanese subjects. The drug was then administered orally for 16 days. On the first day of administration and the following day, it was administered three times a day. The drug was administered every 8 hours, and once daily from the 3rd to the 16th day of administration. .

[0075] As the test preparation, a lyophilized preparation for intravenous administration (for 200 mg dose) was dissolved immediately before use in Japan. For human subjects, administration began three times a day, every eight hours, on the day of administration initiation and the following day. From day 3 to day 16, the drug was administered once a day.

[0076] In other words, in this study, one cohort was established and divided into two groups based on the route of administration. Then, a group of test formulations was established according to each route of administration, and eight Japanese subjects were assigned to each test formulation group. After randomization, the study was conducted in an open-label manner. Participants were kept fasting for one hour before and after oral administration. Table 5 below shows an overview of the topic.

[0077] [Table 5]

[0078] (1-3) Japanese subjects in both studies Japanese subjects were healthy Japanese adult males who were 20 years of age or older at the time of consenting to the clinical trial. Furthermore, the subjects were required to be under 45 years of age. In addition, Japanese subjects were excluded according to the following exclusion criteria (1)~(2 The examination was conducted on the condition that the applicant did not fall under any of the categories in 0).

[0079] Exclusion Criteria (1): Clinically abnormal as judged by the clinical trial physician or other relevant personnel. Exclusion Criterion (2): AST, ALT, and γ-GTP levels exceed the upper limit of the normal range. Exclusion Criterion (3): QTcF is less than 360 msec Exclusion criterion (4): Weight is less than 50.0 kg Exclusion Criterion (5): BMI is less than 18.5 or 25.0 or higher. Exclusion criteria (6): Positive result on HBs antigen, HCV antibody, HIV antigen / antibody, or syphilis qualitative test. sex Exclusion Criteria (7): Being judged to have a history of alcohol or drug dependence. Exclusion criteria (8): Having a history of diseases that make the kidneys, liver, heart, brain, etc. unsuitable. Exclusion criterion (9): History of hypersensitivity to azole compounds Exclusion Criteria (10): Having a history of or presenting with drug allergies. Exclusion criteria (11): History of QT shortening syndrome Exclusion Criterion (12): Failure to maintain abstinence from smoking during hospitalization. Exclusion Criterion (13): The patient has a history of using medications that may affect the evaluation within the four weeks prior to administration. ru Exclusion criteria (14): The patient received hospitalization or surgery within 12 weeks prior to administration. Exclusion criteria (15): The patient has received other medications within 16 weeks prior to administration, or the patient is a patient of the same medical group as the patient. Observation was not completed by the desired time. Exclusion criteria (16): The person has made a prescribed blood donation within the specified period prior to administration. Exclusion Criterion (17): The subject's female partner is unwilling to use medically appropriate contraception. Exclusion criteria (18): Grapefruit and St. John's wort were consumed within 7 days prior to the start of administration. Those who ingested sow or food and beverages containing it Exclusion Criteria (19): Having a history of mental illness Exclusion Criteria (20): The clinical trial physician or other relevant personnel determined the patient to be unsuitable.

[0080] (1-4) Evaluation etc. in both tests In both studies, pharmacokinetic and safety evaluations were conducted.

[0081] In pharmacokinetic studies, the plasma concentration of isabconazole is observed over time, and a model is used. In a non-compartmental model, AUC (drug concentration-time curve) is used. Area Under the Curve), C max (Maximum blood concentration; Ma ximum drug concentration in plasma), T max ( Time to reach maximum blood concentration;), T 1 / 2 (Biological half-life; blood concentration half-life) Pharmacokinetic parameters such as life were estimated. Plasma was collected in a single-dose study. The days are the day of administration start, day 2, day 3, day 4, day 5, day 7, day 11, day 15, and day 1 The days used for plasma collection were the 9th and 21st days. In the repeated-dose study, the plasma collection dates were 2 days from the start of administration. The days considered were all days up to day 0, and days 22, 26, 30, 34, and 36. The isabconazole concentration in plasma was measured using a validated LC-MS / MS method. It was done.

[0082] Regarding safety, the clinical trial physician will examine the Japanese subjects over time, and will monitor their subjective symptoms and objective findings. This was confirmed and evaluated. In the single-dose study, the consultation days were the day of administration, day 2, day 3, and day 4. The administration was performed on days 5, 7, 11, 15, 19, and 21. The consultation days in the trial were all day from the start of administration until day 20, and on days 22, 26, and 30. The test was performed on day 1, day 34, and day 36. However, for Japanese subjects who discontinued the study, the test was performed on day 36. Safety was also evaluated during stopping.

[0083] In the evaluation of pharmacokinetics and safety, or in addition, observation of body weight, observation of vital signs, 1 A two-lead electrocardiogram was obtained, and clinical tests (blood, biochemistry, urine) were performed. On the day of the clinical tests, administration began. The dates were the first day, the second day, the fourth day, the seventh day, the fifteenth day, and the twentieth day. However, the exam was cancelled. For the Japanese subjects who participated, safety was also evaluated at the time of discontinuation.

[0084] Clinical blood test items include red blood cell count, hemoglobin, hematocrit, white blood cell count, and white blood The results were globule fractionation and platelet count.

[0085] The clinical laboratory (biochemistry) items are AST, ALT, LDH, ALP, γ-GTP, CK, and total Bilirubin, direct bilirubin, total protein, albumin, triglycerides, blood glucose, urea nitrogen, creatine cynin, uric acid, total cholesterol, calcium, inorganic phosphorus, sodium, potassium, chloride It was magnesium.

[0086] The clinical urine test items include protein (qualitative), glucose (qualitative), occult blood (qualitative), and urobilinogen. (Qualitative) The result was pH.

[0087] (2) Test results (2-1) Background of Japanese subjects As shown in Table 6 below, there were no significant differences in the subject characteristics among the groups of test formulations.

[0088] [Table 6]

[0089] As shown in Table 7 below, the test drug groups (here, two test drug groups are listed as representative examples) There were no significant differences in the subject characteristics between the group receiving the drug and the control group. [Table 7]

[0090] (2-2) Pharmacokinetics As shown in the table below, the absolute bioavailability of orally administered formulations is approximately 80-100%. Yes, there is no significant difference in bioavailability between oral and intravenous administration, or only a slight difference between oral and intravenous administration. The results showed that [this option] was superior.

[0091] [Table 8]

[0092] (2-3) Safety of formulations administered orally at a dose of 200 mg of the active ingredient per dose. The type of administered preparation is "investigation preparation," and the amount of active ingredient per single dose is Isabuco In each of the six groups, where the dose was either "200 mg" or "400 mg" in terms of nazole equivalent, the formulation was administered. The number of cases that later showed any adverse events was divided by the total number of cases in that group (8 cases), and multiplied by 100. The obtained values ​​were calculated as the "Adverse Event Incidence Rate (%)". The results are shown in Table 9 below. [Table 9]

[0093] These results indicate that the amount of active ingredient per single dose in Japanese subjects was replaced with isabconazole. In an administration mode in which 200-400 mg of the active ingredient is administered, in particular, 200 mg The inventors believe that oral administration suggests excellent overall safety.

[0094] (2-4) Safety of formulations administered intravenously at a dose of 200 mg of the active ingredient per dose. As mentioned above, ALT, AST, ALP, total bilirubin, γ-GTP, LDH, total protein, This study examines how changes in clinical test values ​​of albumin (8 types in total) affect liver function. We considered that.

[0095] The type of administered preparation is "investigation preparation," and the amount of active ingredient per single dose is Isabuco In each of the six groups, which contain either "200 mg" or "400 mg" of nasol equivalent, the above eight types The number of cases in which at least one clinical laboratory indicator of the same category deviates from the normal range is added to the total number of cases in that group (8 For example, divide by and multiply by 100 to obtain the value, which is then used as the "incidence rate of adverse events related to liver function (%)". The calculation was performed. The results are shown in Table 10 below.

[0096] [Table 10]

[0097] These results indicate that the amount of active ingredient per single dose in Japanese subjects was replaced with isabconazole. In an administration mode in which 200-400 mg of the active ingredient is administered, in particular, 200 mg The inventors believe that intravenous administration suggests excellent liver safety. ru.

[0098] As mentioned above, the amount of active ingredient per dose for Japanese subjects was replaced with isabconazole. In administration methods involving the administration of 200-400 mg of the active ingredient, oral administration and intravenous administration are used. The results showed no significant difference in bioavailability between the two methods, or that intravenous administration was slightly superior. This was the case. Taking these pharmacokinetic results into consideration, the combination of "200 mg" and "intravenous administration" is... This result, which suggests particularly excellent safety in terms of liver function, is extremely surprising and groundbreaking. The inventor considers this to be a remarkable achievement.

[0099] (2-5) The amount of active ingredient per single dose is 200-400 mg, and the time exceeding 1 hour is... Safety of formulations administered intravenously As described above, the formulation of the present invention can be administered intravenously to humans, and can be administered by continuous intravenous infusion. While this is possible, generally speaking, intravenously injected drugs may leak into the surrounding tissues outside the blood vessels. This can lead to tissue inflammation and necrosis. Thus, intravenous drug administration In such cases, suppressing extravasation has significant clinical value.

[0100] The type of administered preparation is "investigation preparation," and the amount of active ingredient per dose is isabconazole. The equivalent dose is "200 mg" or "400 mg" in 100ml increments, and the "route of administration is intravenous." In each of the three groups, the number of cases in which an adverse event of extravasation at the administration site occurred was compared to the total number of cases in that group. The value obtained by dividing by 8 cases and multiplying by 100 is the "incidence rate of adverse events due to extravasation at the administration site (%)". The calculation was performed using the formula "[...]". The results are shown in Table 11 below.

[0101] [Table 11]

[0102] As mentioned above, the amount of active ingredient per dose for Japanese subjects was replaced with isabconazole. In an administration method in which 200 or 400 mg of the active ingredient is administered intravenously, increasing the amount of the active ingredient In response, exposure to the drug increased. Generally, adverse events occur when the amount of exposure to the active ingredient increases. The higher the value, the higher the incidence tends to be. Therefore, the results of Cohorts 2 and 3 are relevant. When considering factors that influence the relationship, the frequency of adverse events caused by exposure to the active ingredient is... A significant decline is unlikely.

[0103] Therefore, the above results indicate that the amount of active ingredient per dose for Japanese subjects is determined by Isabuco In an administration method in which 200-400 mg of the active ingredient (in terms of nazole equivalent) is administered intravenously, The duration of administration (the time the injection site is in the administration state) This result suggests that the frequency of site reactions (including extravasation) is affected. The inventors believe this is reasonable.

[0104] In other words, the table above shows the time exceeding approximately 1 hour in the same administration method (more specifically) For example, by administering it intravenously over a period of more than 1 hour and 2 minutes, or more than 2 hours. This suggests that it can remarkably suppress the incidence of administration site reactions (including extravasation). The inventor believes that this is the case.

[0105] [Example 1] Clinical trials conducted overseas targeting foreigners (1) Test method (1-1) Test method for single oral administration study The test formulations included an oral capsule formulation (for 100 mg dose) and an oral capsule. Formulation (for 200 mg administration), oral capsule formulation (for 400 mg administration), or placebo The formulation was administered to healthy foreign adult males (hereinafter sometimes referred to as foreign subjects) via The drugs were administered orally, and their safety and pharmacokinetics were examined. The excipients used in these formulations are as shown in the examples. It was substantially identical to the additive used in the oral formulation in [the relevant context].

[0106] (1-2) Test method for single intravenous administration study The test formulations included a lyophilized preparation for intravenous administration (50 mg dose) and a lyophilized preparation for intravenous administration. Drug (for 100 mg administration), lyophilized preparation for intravenous administration (for 200 mg administration), or placebo. Each agent was dissolved immediately before use, and the resulting solution was administered intravenously to foreign subjects. The administration time was 1 hour. The additives used in these formulations were the same as those used in the example. It was substantially identical to the additives used in the dried formulation.

[0107] (2) Test results (2-1) Results of the single oral dose study [Table 12]

[0108] [Table 13]

[0109] (2-2) Results of the single intravenous administration study [Table 14]

[0110] [Table 15]

[0111] [Table 16]

[0112] Based on the results of the above-mentioned examples and reference cases, compared to administration to foreigners, administration to Japanese people In such cases, even if the dosage and administration remain the same, a higher level of safety is expected to be achieved. Generally speaking, Japanese people are smaller in stature than Westerners, so the relative dosage required is higher (in other words) Therefore, since the exposure level will be high, safety is expected to decrease, It is surprising that this method results in greater safety. Also, the administration rate of the formulation It is also remarkable that delaying the administration can suppress site reactions. [Industrial applicability]

[0113] The formulation of the present invention is a formulation with excellent safety. The present invention is extremely useful in the pharmaceutical industry. be.

Claims

1. An intravenous preparation containing isabconazole or its prodrug as the active ingredient. That is, the single dose is equivalent to 200 mg of isabconazole, and for Japanese people A formulation for intravenous administration.

2. An intravenous preparation containing isabconazole or its prodrug as the active ingredient. That is, the single dose is equivalent to 200 mg of isabconazole, and for Japanese people An intravenous formulation intended for administration over a period exceeding one hour.

3. An oral formulation containing isabconazole or its prodrug as an active ingredient. The dosage per dose is 200 mg in terms of isabconazole equivalent, and the dosage for Japanese people is... An orally administered preparation for administration.

4. Claims 1-3, the prodrug of isabuconazole isabuconazonium sulfate. A preparation described in any one of the items.

5. A formulation according to any one of claims 1 to 3 for treating fungal infections.

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