Injectable pharmaceutical compositions for use in dialysis patients

Abstract

The present invention aims to provide an injectable pharmaceutical composition containing diferikephalin that can reduce human error and labor associated with dosage preparation in medical settings. [Solution] The present invention relates to an injectable pharmaceutical composition containing diferikephalin or a pharmacoagulably acceptable salt thereof for the treatment of pruritus in dialysis patients, wherein the injectable pharmaceutical composition is designed to reduce human error and labor associated with dosage preparation in medical settings, and the injectable pharmaceutical composition contains diferikephalin or a pharmacoagulably acceptable salt thereof in amounts of 17.5 μg, 25.0 μg, 35.0 μg, or 42.5 μg in free form equivalent, and relates to an injectable pharmaceutical composition for administration to dialysis patients with a dry weight of less than 45 kg, 45 kg or more but less than 65 kg, 65 kg or more but less than 85 kg, or 85 kg or more, respectively.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for dialysis patients containing a pharmaceutical, particularly difelikefarin or a pharmacologically acceptable salt thereof.

Background Art

[0002] The cause of pruritus in dialysis patients has not been fully elucidated and is considered intractable. Multiple factors are involved in the development of pruritus, including skin dryness, accumulation of endogenous substances, overproduction of chemical mediators such as histamine and substance P, etc. Furthermore, changes in immune function and disruption of the opioid balance are also one of the causes. In dialysis patients with pruritus, it is thought that the μ-opioid system that induces itching is dominant over the κ-opioid system that suppresses itching.

[0003] For the treatment of pruritus in dialysis patients, there are topical treatments with moisturizers such as emulsions and creams and steroid agents, topical or oral treatments with antihistamines and anti-allergy drugs, phototherapy using ultraviolet rays with a wide wavelength, etc.

[0004] In Japan, nalflurafine hydrochloride, an oral κ-opioid receptor (KOR) agonist, is used for patients who are not sufficiently effective with existing treatments such as topical treatment and oral treatment.

[0005] Difelikefarin is a novel peptide KOR agonist that has been developed as a drug for improving pruritus overseas (Non-Patent Document 1). It has also been developed in the same way in Japan. The peptide structure of difelikefarin is quite different from KOR agonists of low molecular weight heterocyclic compounds with central nervous system (CNS) action developed so far. Due to its physicochemical properties, its membrane permeability is low and its transfer to the CNS is limited. Therefore, it has high selectivity for the κ-opioid receptor and weak action on other opioid receptors, so it does not easily transfer to the CNS and is expected to be launched early as a drug with excellent safety and tolerance.

Prior Art Documents

[0006] [Patent Document 1] Patent No. 5807140 [Patent Document 2] Patent No. 5244810 [Non-patent literature]

[0007] [Non-Patent Document 1] Steven Fishbane et al., *Kidney International Reports*, 2020, Vol. 5, pp. 600-610. [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] The present invention aims to provide an injectable pharmaceutical composition containing diferikephalin that can reduce human error and labor associated with dosage preparation in medical settings.

[0009] Diferikephalin injection is an injectable drug administered via the dialysis circuit during blood return at the end of dialysis. However, in foreign countries where clinical development is currently advanced, the dosage of diferikephalin injection is to be precisely adjusted in 1 kg increments according to the individual patient's weight in clinical practice (Non-Patent Literature 1). Therefore, there is an unavoidable risk of human error (incident) occurring in some part of the dosage preparation process (for example, the calculation of the dosage based on free-form equivalent concentration, body weight, and dilution, or the actual weighing, depending on the case). Furthermore, even if such errors can be sufficiently prevented by a double or triple checking system, performing such dosage adjustments every time in a clinical setting would involve considerable effort, expense, and difficulty, and as a result, administration that contributes to the patient's treatment may be avoided.

[0010] Therefore, it would be extremely beneficial if a new pharmaceutical formulation could be developed that eliminates the need to precisely adjust the dosage in 1kg increments for each individual patient's weight in medical settings, thereby reducing human error associated with dosage preparation and alleviating the workload involved.

[0011] However, there are several challenges to overcome in providing a diferikepharin pharmaceutical formulation suitable for clinical practice. First, the number of pharmaceutical formulations (number of strengths) provided to medical facilities must be acceptable to the medical field. Furthermore, there is no knowledge whatsoever regarding the potential of novel pharmaceutical formulations that do not strictly adjust the dosage in 1 kg increments according to the patient's weight, making it difficult to predict efficacy and safety. Therefore, it was even unclear whether such novel pharmaceutical formulations could be provided at all. In other words, the novel pharmaceutical formulation must be effective and safe for pruritus in dialysis patients, depending on its usage and dosage, and the impact on efficacy and safety between strengths must not differ significantly. [Means for solving the problem]

[0012] The inventors first conceived that if the number of strengths of diferikephalin injectable formulations could be limited to around 3 to 4 strengths, it would be particularly suitable for clinical application in Japan. Through careful analysis of interview results with medical institutions in Japan, with this injectable formulation in mind, they found that in the field of dialysis, a single-use pharmaceutical formulation with a maximum of 3 to 4 strengths is desirable. Therefore, after diligently studying pharmaceutical formulations that could achieve this number of strengths, they surprisingly discovered that a dosage and administration method combining specific dry weight classes with a prescribed amount of diferikephalin was effective and safe for treating pruritus in dialysis patients, and that there was no significant difference in effectiveness and safety among the different dry weight classes. This led to the completion of the present invention.

[0013] To solve the aforementioned problems, the present invention has, in one embodiment, the following configuration.

[0014] That is, an injectable pharmaceutical composition containing diferikephalin or a pharmacoagulably acceptable salt thereof for the treatment of pruritus in dialysis patients, The aforementioned injectable pharmaceutical composition is an injectable pharmaceutical composition that reduces human error and labor associated with dosage preparation in medical settings. The aforementioned injectable pharmaceutical composition contains 17.5 μg, 25.0 μg, 35.0 μg, or 42.5 μg of diferikephalin or a pharmacoposly acceptable salt thereof in terms of free form of diferikephalin, and is an injectable pharmaceutical composition for administration to dialysis patients with a dry weight of less than 45 kg, 45 kg or more but less than 65 kg, 65 kg or more but less than 85 kg, or 85 kg or more, respectively. The aforementioned injectable pharmaceutical composition is sealed in a pre-filled syringe in a unit dose intended for single-dose use. A pharmaceutical composition for injection. [Effects of the Invention]

[0015] The present invention provides an injectable pharmaceutical composition that reduces human error and labor associated with dosage preparation in medical settings. [Brief explanation of the drawing]

[0016] [Figure 1] This graph shows the change in NRS score (NRS Score) in hemodialysis patients. The vertical axis shows the change in NRS score (Adjusted Mean ± SE) at 8 weeks of treatment for Group A (A), Group B (B), Group C (C), and Placebo (Placebo). [Figure 2] This graph shows the change in NRS score for each dry weight category. The vertical axis shows the change in NRS score (Mean ± SD) for Group B (B) for each dry weight (DW) category at 4 weeks of treatment. [Figure 3] This graph shows the change in NRS score for each dry weight category. The vertical axis shows the change in NRS score (Mean ± SD) for each dry weight (DW) category in group C (C) at 4 weeks of treatment.

Mode for Carrying Out the Invention

[0017] Hereinafter, embodiments of the present invention will be described in more detail.

[0018] In the present invention, each term has the following meaning unless otherwise specified.

[0019] Difelikefalin (INN) is a compound represented by the following formula.

[0020]

Chemical formula

[0021] In the present invention, difelikefalin can be converted into its pharmacologically acceptable salts according to conventional methods as necessary. Examples of such salts of difelikefalin include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid. Preferably, difelikefalin acetate (JAN) is included.

[0022] In the present invention, "pharmacologically acceptable salts of difelikefalin" also include solvates with solvents acceptable as pharmaceuticals such as water and ethanol.

[0023] Difelikefalin of the present invention can be produced by known methods. For example, it can also be produced by the methods described in Patent Documents 1 and 2 or methods analogous thereto.

[0024] One embodiment of the injectable pharmaceutical composition of the present invention is an injectable preparation, preferably a single-use injectable preparation that can reduce human error associated with dosage preparation in a medical setting and reduce labor during administration. Examples of such injectable preparations include an injectable preparation in which the entirety of the pre-filled drug solution is used up, and an injectable preparation in which the entirety of the filled drug solution is drawn up with a syringe and then used up completely. Examples of forms of injectable preparations that can be used in this way include pre-filled syringe preparations, vial preparations, ampoule preparations, etc.

[0025] The injectable pharmaceutical composition of the present invention can be provided as an injectable preparation in multiple strengths with different concentrations of diferikephalin, while maintaining a constant amount of drug solution filled in a vial or pre-filled syringe. In one embodiment, the composition can also be provided as an injectable preparation in multiple strengths with different drug solution volumes, while maintaining a constant concentration of diferikephalin. The amount of drug solution filled is not particularly limited as long as it is the amount of drug solution that can be filled into the injectable preparation, but is preferably in the range of 0.3 mL to 2.5 mL. The amount of diferikephalin enclosed is 17.5 μg, 25.0 μg, 35.0 μg, or 42.5 μg in free form equivalent, and is intended for administration to dialysis patients with a dry weight of less than 45 kg, 45 kg to less than 65 kg, 65 kg to less than 85 kg, or 85 kg or more, respectively.

[0026] The injectable pharmaceutical composition of the present invention is prepared using diferikephalin or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable carrier. The injectable pharmaceutical composition of the present invention can also be prepared by appropriately mixing, diluting, or dissolving with a pharmaceutically acceptable carrier using a pharmaceutically known method. Examples of such pharmaceutically acceptable carriers include sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, glucose, and propylene glycol as isotonic agents. Sodium chloride and potassium chloride are preferred. Examples of buffering agents include acetic acid, tartaric acid, lactic acid, citric acid, boric acid, phosphoric acid, carbonic acid, and their salts. More specifically, examples include acetic acid and sodium acetate, citric acid and trisodium citrate, sodium bicarbonate and sodium carbonate, sodium dihydrogen phosphate and disodium hydrogen phosphate. Acetic acid and sodium acetate, sodium bicarbonate and sodium carbonate are preferred. Examples of preservatives include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, and borax. Parahydroxybenzoic acid esters and benzalkonium chloride are preferred. Examples of thickeners include hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, and polyethylene glycol. Hydroxyethylcellulose and hydroxypropylcellulose are preferred. Examples of stabilizers include sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, and dibutylhydroxytoluene. Sodium citrate and ascorbic acid are preferred. Examples of pH adjusters include hydrochloric acid, sodium hydroxide, phosphoric acid, and acetic acid. Hydrochloric acid and sodium hydroxide are preferred.

[0027] The solvent used in the injectable pharmaceutical composition of the present invention is not particularly limited as long as it is suitable for use in injection, and is preferably an aqueous solvent, such as water for injection or physiological saline.

[0028] The pH of the injectable pharmaceutical composition of the present invention is not particularly limited, but for example, it is preferably 5.0 or less, and more preferably in the range of 4.0 to 5.0.

[0029] The injectable pharmaceutical composition of the present invention is usually provided as an injectable preparation having multiple strengths with different diferikephalin content. In one aspect of the present invention, it is provided to medical institutions as an injectable preparation having multiple strengths, each pre-filled with a specified amount of diferikephalin according to the patient's dry weight classification. The number of strengths is not particularly limited as long as it is an acceptable number in a medical setting, but is preferably 4 or less, and more preferably 3 or less. The number of strengths is usually the same as the number of the patient's dry weight classifications, but if it is possible to substitute a high-content injectable preparation with a combination of low-content strengths, it may also be provided as an injectable preparation with fewer strengths than the number of the patient's dry weight classifications.

[0030] The term "dry weight" is a target weight after fluid removal, set as an indicator for treatment planning tailored to each individual patient's condition in hemodialysis treatment. The Japanese Society for Dialysis Therapy defines it as "a weight in which the body fluid volume is appropriate, excessive blood pressure drops do not occur during dialysis, and the burden on the cardiovascular system is minimal in the long term." In other words, it is a weight that does not involve excessive fluid retention. Dry weight is usually determined by a physician and is set, for example, to be as close as possible to the weight of a patient with normal renal function after urination. Therefore, dry weight can also mean the lowest weight that can be safely achieved after hemodialysis without exhibiting symptoms of blood pressure drop associated with excessive fluid removal, such as seizures.

[0031] Dry weight can be set according to commonly used indicators. These indicators include, for example, the absence of a significant drop in blood pressure during dialysis, the blood pressure at the end of dialysis not being higher than the blood pressure at the start of dialysis, the absence of peripheral edema, the absence of pleural effusion or pulmonary congestion on chest X-ray, and a cardiothoracic ratio of 50% or less (53% or less for women).

[0032] The injectable pharmaceutical composition of the present invention is used to administer a specified amount of diferikephalin based on the patient's dry weight classification. This avoids the complex administration method of adjusting the dosage in 1 kg increments of body weight at each administration, thereby reducing human error and labor associated with dosage preparation in medical settings. In the present invention, the specified amount of diferikephalin based on the patient's dry weight classification may be, for example, 17.5 μg for adults with a dry weight of less than 45 kg, 25.0 μg for adults with a dry weight of 45 kg or more but less than 65 kg, 35.0 μg for adults with a dry weight of 65 kg or more but less than 85 kg, and 42.5 μg for adults with a dry weight of 85 kg or more.

[0033] In another embodiment, patients with a dry weight of 85 kg or more may be those with a dry weight of 85 kg or more but less than 100 kg, 85 kg or more but less than 105 kg, 85 kg or more but less than 110 kg, or 85 kg or more but less than 115 kg.

[0034] When the injectable pharmaceutical composition of the present invention is applied to dialysis patients, for example, it can be used by injecting it into the venous side of the dialysis circuit three times a week during blood return at the end of dialysis. If administration through the dialysis circuit is not possible due to problems with the dialysis circuit, it can also be administered by intravenous injection. If a fourth dialysis session is performed on an ad-hoc basis, it can also be administered four times a week.

[0035] The injectable pharmaceutical composition of the present invention is useful for the treatment of pruritus. In the present invention, pruritus is not limited to any disease accompanied by itching, but examples include the improvement of pruritus in hemodialysis patients and peritoneal dialysis patients. Since the injectable pharmaceutical composition of the present invention is a KOR agonist, it can also be used for the treatment of mood swings, improvement of depressive symptoms, postoperative pain, osteoarthritis, and sleep disorders associated with dialysis.

[0036] In the present invention, the therapeutic effect of pruritus can also be evaluated using evaluation methods known to those skilled in the art, which score the degree of itching felt by the subject. Examples include the Numerical Rating Scale (NRS), Visual Analogue Scale (VAS), Shiratori's severity criteria, Skindex-10, Skindex-16, 5-D Itch Scale, and Patient Global Impression of Change (PGIC).

[0037] The NRS (Numerical Rating Scale), arguably the most representative index, evaluates the most intense itchiness experienced during a day on an integer scale from 0 to 10, with 0 representing "no itchiness" and 10 representing "the most intense itchiness possible." Generally, an NRS score of 1 to less than 4 indicates mild itchiness, 4 to less than 7 indicates moderate itchiness, and 7 or higher indicates severe itchiness. The VAS (Visual Analog Scale) uses a 100mm line, with the left end representing "no itchiness" and the right end representing "the most intense itchiness possible." A mark is placed at the position representing the most intense itchiness experienced during the day, and the length from the left end of the line is measured for evaluation. While NRS and VAS evaluations show correlation, the NRS is a simpler evaluation method. The NRS score for itchiness is widely used in clinical trials as a method for evaluating pruritus.

[0038] Shiratori's severity criteria use a scale of 0 to 4, ranging from "no symptoms" to "intense itching," with subjects themselves assessing and evaluating their symptoms during the day and at night. Shiratori's severity criteria are widely used in dermatology in Japan to assess the degree of itching, and they use the impact on daily life as the criterion for determining severity.

[0039] The Skindex-16 uses a score from 0 to 6, ranging from "never bothered" to "always bothered." The Skindex-16 is used to assess quality of life related to skin diseases.

[0040] The 5-D Itch Scale assesses five components of itching: duration, severity, tendency, adverse effects, and distribution.

[0041] PGIC evaluates the overall symptoms of itching on a 7-point scale: "Greatly improved," "Improved," "Slightly improved," "No change," "Slightly worsened," "Worsened," and "Severely worsened."

[0042] The effectiveness of a drug against itching can also be confirmed by evaluating the change in score using the evaluation method described above. Specifically, by comparing the degree of itching before drug administration (baseline) with the degree of itching after drug administration, if the degree of itching improves, it can be evaluated as having been reduced. In the present invention, from the perspective of improving the patient's quality of life (QOL), it is preferable that the effectiveness against itching be recognized not only by an improvement in the NRS or VAS score, but also by an improvement in the QOL score (Shiratori severity criteria, Skindex-16, 5-D Itch Scale, PGIC).

[0043] In the present invention, it is preferable that the efficacy and safety of the injectable pharmaceutical composition of the present invention do not differ significantly between each dry weight class. Specifically, it is preferable that an improvement in pruritus is observed in all dry weight classes, or that there is no significant fluctuation in the pre-dialysis trough value (plasma drug concentration immediately before administration (plasma diferikephalin (unchanged) concentration)), or both conditions are met. The plasma concentration of diferikephalin can be measured by general methods, but for example, it can be measured by LC-MS / MS.

[0044] One embodiment of the injectable pharmaceutical composition of the present invention includes (a) the injectable pharmaceutical composition of the present invention; and (b) a kit including one or more labels or accompanying documents attached to or accompanying a container. In the present invention, "including accompanying documents" includes not only cases where instructions are enclosed, but also cases where means of making the information contained in the accompanying documents available are clearly indicated. When means of making the information contained in the accompanying documents available are clearly indicated, there are no limitations as long as the contents can be confirmed, but for example, means of making the information available via an electronic communication line. Specifically, this includes cases where a QR code (registered trademark) or URL is included in a commercially available pharmaceutical preparation. [Examples]

[0045] The present invention will be described in more detail below based on examples, but the present invention is not limited thereto. In the examples, the amount of diferikephalin refers to the amount administered as diferikephalin acetate in its free form (free form equivalent). Example 1 Clinical trial (double-blind, parallel-group comparative trial) targeting hemodialysis patients with pruritus. 1. Test Method (1) Method of administration In this study, 247 patients were divided into four groups: Group A (61 patients), Group B (61 patients), Group C (62 patients), and Placebo (63 patients). Each group received their respective investigational drug three times a week for eight weeks, administered via infusion into the venous side of the dialysis circuit during blood return at the end of dialysis. The study period consisted of a pre-observation period (two weeks before transitioning to the treatment period), a treatment period (eight weeks), and a post-observation period (two weeks after the end of the treatment period). No investigational drugs were administered during the pre-observation and post-observation periods. (2) Investigational drug Group A: Injectable solution prepared by dissolving diferikephalin at a concentration of 0.025 mg / mL in 0.04 M isotonic buffered acetic acid solution (pH 4.5). Group B: Injectable solution prepared by dissolving diferikephalin at a concentration of 0.05 mg / mL in 0.04 M isotonic buffered acetic acid solution (pH 4.5). Group C: Injectable solution prepared by dissolving diferikephalin at a concentration of 0.1 mg / mL in 0.04 M isotonic buffered acetic acid solution (pH 4.5). Placebo group: 0.04 M isotonic buffered acetic acid solution (pH 4.5) (3) Dosage The dosage of the investigational drug and the amount of diferikephalin administered to each treatment group were determined according to the table below, based on each patient's dry weight category on the day of administration.

[0046] [Table 1]

[0047] 2. Evaluation items regarding efficacy and safety Effectiveness was evaluated based on the following subjective symptoms related to itching. For each score below, week 0 of the treatment period was used as the baseline, and the difference from the baseline was defined as the change. (1) NRS score The most intense itchiness experienced during the day was rated on an integer scale from 0 to 10, with 0 representing "no itchiness" and 10 representing "the most intense itchiness imaginable." (2) Itch score based on Shiratori's severity criteria Once a day, the degree of itching from the time of waking up the day before the evaluation until the time of waking up on the day of the evaluation (including during sleep) was assessed on a scale of 0 to 4, ranging from "no symptoms" to "intense itching," evaluating both daytime and nighttime symptoms. (3) Skindex-16 score At the beginning of each week (before administration of the investigational drug), patients were assessed on the frequency of itching during the past week. A score from 0 to 6 was used, ranging from "never bothered" to "always bothered." (4) 5-D Itch Scale Score At the beginning of each week, during each patient's visit (before administration of the investigational drug), they reviewed their itching experience over the past two weeks and assessed the five components of their itching: duration, severity, tendency, adverse effects, and distribution. (5) PGIC score At the beginning of each week, patients evaluated their overall itching symptoms compared to the previous observation period on a 7-point scale: "much better," "better," "slightly better," "no change," "slightly worse," "worse," and "much worse."

[0048] For the analysis, a mixed-effects model for repeated measures (MMRM) was used for the mean NRS score and the itch score based on Shiratori's severity criteria. Specifically, for the mean NRS score, the change in score was used as the dependent variable, the group, observation time, and interaction between the group and observation time as fixed effects, the mean baseline score, whether or not prior medication for itch was used, and the presence or absence of specific signs or symptoms observed during the pre-observation period as covariates, and the subject as a random effect. Similarly, for the itch score based on Shiratori's severity criteria, the change in score was used as the dependent variable, the group, observation time, and interaction between the group and observation time as fixed effects, the mean baseline score as a covariate, and the subject as a random effect.

[0049] Regarding safety, we evaluated the number of adverse events and side effects, the number of cases, and the incidence rate. 3.Results (1) Figure 1 shows the change in NRS score at 8 weeks of treatment.

[0050] At 8 weeks of treatment, the change in NRS score was -2.86 in the placebo group, compared to -2.97 in group A, -3.65 in group B, and -3.64 in group C. Groups B and C showed significant improvement compared to the placebo group (MMRM, P<0.05). (2) Figures 2 and 3 show the changes in NRS scores for each dry weight category in groups B and C, specifically the changes at week 4 of the treatment period, when efficacy was maximized. As shown in Figures 2 and 3, improvements in NRS scores were observed in all dry weight categories in both groups B and C. (3) At 8 weeks of treatment, the change in itching score based on Shiratori's severity criteria (the change being the higher of the daytime or nighttime scores) was -1.00 for the placebo group, -1.14 for group A, -1.31 for group B, and -1.31 for group C. Groups B and C showed significant improvement compared to the placebo group (MMRM, P<0.05). (4) At 8 weeks of treatment, the change in the Skindex-16 overall score was -24.04 in the placebo group, -24.25 in group A, -27.79 in group B, and -22.69 in group C, showing an improvement trend in group B. (5) At 8 weeks of treatment, the change in the total 5-D Itch Scale score was -5.8 in the placebo group, compared to -6.6 in group A, -6.5 in group B, and -6.8 in group C. An improvement trend was observed at doses of group A or higher. (6) The percentage of subjects whose PGIC at the final evaluation of the treatment period was "improved" or "greatly improved" was 24.2% and 17.7% in the placebo group, compared to 34.4% and 19.7% in group A, 28.8% and 37.3% in group B, and 38.3% and 31.7% in group C. Groups B and C showed significantly greater improvement compared to placebo (two-sample Wilcoxon test, P<0.01). (7) The incidence of adverse events during the treatment period increased in a dose-dependent manner: 66.7% in the placebo group, 72.1% in group A, 77.0% in group B, and 85.5% in group C. The incidence in group C was significantly higher than in the placebo group (Fisher's exact test, P<0.05).

[0051] The incidence of adverse events during treatment increased in a dose-dependent manner: 11.1% in the placebo group, 14.8% in group A, 14.8% in group B, and 27.4% in group C. The incidence in group C was significantly higher than in the placebo group (Fisher's exact test, P<0.05).

[0052] Based on these results, significant improvement in pruritus in hemodialysis patients was demonstrated in groups B and C. On the other hand, no significant improvement was shown in group A. Furthermore, there was no significant difference in the incidence of adverse events and side effects during treatment in group B compared to the placebo group, confirming that group B is a dose with excellent safety and tolerability. 4. Evaluation items related to pharmacokinetics (1) Measurement method: In groups B and C, "Plasma drug concentration: Plasma diferikephalin (unchanged) concentration" was measured by LC-MS / MS. (2) Results: The geometric mean values ​​of predialysis trough values ​​(predialysis plasma diferikephalin concentration) at week 7 in the dry weight categories of Group B (less than 45 kg (4 cases), 45 kg to less than 65 kg (32 cases), 65 kg to less than 85 kg (15 cases), 85 kg or more (1 case)) were 0.5903 ng / mL, 0.5826 ng / mL, 0.5275 ng / mL, and 0.7480 ng / mL, respectively. In Group C (less than 45 kg (3 cases), 45 kg to less than 65 kg (32 cases), 65 kg to less than 85 kg (15 cases), 85 kg or more (2 cases)), the geometric mean values ​​of predialysis trough values ​​(predialysis plasma diferikephalin concentration) at week 7, according to dry weight categories, were 0.9306 ng / mL, 0.9700 ng / mL, 1.0671 ng / mL, and 1.0396 ng / mL, respectively.

[0053] Based on these results, no significant differences were observed in the range of variation in plasma diferikephalin concentration within each dry weight group of Group B. Similar results were observed in Group C.

[0054] The results from the examples showed that Group B demonstrated efficacy and safety for pruritus in hemodialysis patients of various body weights without requiring dose adjustments based on individual patient weight in 1 kg increments. Therefore, it has been demonstrated that the injectable pharmaceutical composition of the present invention can reduce human error and labor associated with dosage preparation in medical settings. [Industrial applicability]

[0055] The injectable pharmaceutical composition of the present invention is extremely useful as a pharmaceutical for use in dialysis patients.

Claims

[Claim 1] A pharmaceutical composition for injection containing diferikephalin or a pharmacopositically acceptable salt thereof for the treatment of pruritus in dialysis patients, The aforementioned injectable pharmaceutical composition is an injectable pharmaceutical composition that reduces human error and labor associated with dosage preparation in medical settings. The aforementioned injectable pharmaceutical composition contains 17.5 μg, 25.0 μg, 35.0 μg, or 42.5 μg of diferikephalin or a pharmacoposly acceptable salt thereof in terms of free form of diferikephalin, and is an injectable pharmaceutical composition for administration to dialysis patients with a dry weight of less than 45 kg, 45 kg or more but less than 65 kg, 65 kg or more but less than 85 kg, or 85 kg or more, respectively. The aforementioned injectable pharmaceutical composition is sealed in a pre-filled syringe in a unit dose intended for single-dose use. A pharmaceutical composition for injection.

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