Injectable pharmaceutical composition for dialysis patients

Abstract

An object of the present invention is to provide an injectable pharmaceutical composition containing difelikefalin that can reduce human errors and labor involved in dosage preparation in medical settings. [Solution] The present invention relates to an injectable pharmaceutical composition containing difelikefalin or a pharmacologically acceptable salt thereof for treating pruritus in dialysis patients, which is an injectable pharmaceutical composition that reduces human error and labor involved in dosage preparation in medical settings, and which contains difelikefalin or a pharmacologically acceptable salt thereof in an amount of 17.5 μg, 25.0 μg, 35.0 μg, or 42.5 μg, calculated as the free form of difelikefalin, and is intended to be administered 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 containing a medicine, particularly difelikefalin or a pharmacologically acceptable salt thereof, which is administered to dialysis patients. [Background technology]

[0002] The causes of pruritus in dialysis patients are not fully understood, and it is considered intractable. Multiple factors contribute to the onset of pruritus, including dry skin, accumulation of endogenous substances, and overproduction of chemical mediators such as histamine and substance P. Furthermore, changes in immune function and disruption of opioid balance are also contributing factors, and it is thought that in dialysis patients with pruritus, the μ-opioid system, which induces itch, is dominant over the κ-opioid system, which suppresses itch.

[0003] Treatments for pruritus in dialysis patients include topical treatment with moisturizers such as lotions and creams or steroids, topical or oral treatment with antihistamines or antiallergic drugs, and phototherapy using broad-wavelength ultraviolet light.

[0004] In Japan, nalfurafine hydrochloride, an oral kappa opioid receptor (KOR) agonist, is used for patients for whom existing treatments such as topical and oral medications are insufficient.

[0005] Difelikefalin is a novel peptide-based KOR agonist that is being developed overseas as a drug for treating pruritus (Non-Patent Document 1). It is also being developed in Japan. The peptide structure of difelikefalin is significantly different from the KOR agonists, which are small-molecule heterocyclic compounds that act on the central nervous system (CNS) and have been developed to date. Its physicochemical properties result in low membrane permeability, limiting its penetration into the CNS. Therefore, because it has high selectivity for the κ-opioid receptor and weak activity on other opioid receptors, it does not readily penetrate the CNS, and its early commercial launch is anticipated as a drug with excellent safety and tolerability. [Prior art documents] [Patent 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. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide an injectable pharmaceutical composition containing difelikefalin that can reduce human errors and labor involved in dosage preparation in medical settings.

[0009] Difelikefalin injection is administered through the dialysis circuit during blood return at the end of dialysis. However, in foreign countries where clinical development is currently advanced, the dose of difelikefalin injection is strictly adjusted in 1 kg increments based on the weight of each individual patient in clinical settings (Non-Patent Document 1). Therefore, there is an unavoidable risk of human error (incident) during any part of the dose preparation process (e.g., the calculation of the dose based on the free form concentration, body weight, and dilution level, or the actual measurement, depending on the case). Furthermore, even if such errors can be adequately prevented by a double- or triple-check system, preparing the dose in this way every time in clinical settings requires significant effort, expense, and difficulty, which may result in patients being discouraged from administering the drug to contribute to patient treatment.

[0010] Therefore, it would be extremely beneficial to develop a new pharmaceutical formulation that would eliminate the need to strictly adjust the dosage in 1 kg increments for each patient's weight in clinical settings, reduce human errors associated with dosage adjustment in clinical settings, and reduce the labor required.

[0011] However, there are various challenges to overcome before a difelikefalin pharmaceutical formulation suitable for clinical use can be provided. First, the number of pharmaceutical formulations (standards) provided to medical settings must be acceptable for the medical field. Furthermore, there is no knowledge regarding the feasibility of new pharmaceutical formulations that do not strictly adjust the dosage in 1 kg increments based on the patient's weight, making it difficult to predict their efficacy and safety. Therefore, it was unclear whether such a new pharmaceutical formulation could even be provided. Specifically, the new pharmaceutical formulation must be effective and safe for pruritus in dialysis patients, depending on the dosage and administration method, and the effects on efficacy and safety must not differ significantly between the different standards. [Means for solving the problem]

[0012] The present inventors first conceived the idea that if the number of standards for an injectable difelikefalin formulation could be reduced to approximately 3-4, it would be particularly suitable for clinical application in Japan. After conducting thorough interviews with Japanese medical institutions with this injectable formulation in mind, they learned that in the field of dialysis, a single-use pharmaceutical formulation with a maximum of 3-4 standards would be desirable. As a result of extensive research into pharmaceutical formulations that could achieve this number of standards, they surprisingly discovered that a dosage regimen combining a specific dry weight category and a specified amount of difelikefalin was effective and safe against pruritus in dialysis patients, and that no significant differences in efficacy or safety were observed between the dry weight categories. This discovery led to the completion of the present invention.

[0013] In order to solve the above problems, one aspect of the present invention has the following configuration.

[0014] That is, an injectable pharmaceutical composition containing difelikefalin or a pharmacologically acceptable salt thereof for treating pruritus in dialysis patients, The injectable pharmaceutical composition is an injectable pharmaceutical composition for reducing human errors and labor involved in dose preparation in medical settings, the injectable pharmaceutical composition contains difelikefalin or a pharmacologically acceptable salt thereof in an amount of 17.5 μg, 25.0 μg, 35.0 μg, or 42.5 μg, calculated as the free form of difelikefalin, and is intended to be administered to a dialysis patient 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 injectable pharmaceutical composition is packaged in a pre-filled syringe in a unit dose for single administration. Injectable pharmaceutical composition. [Effects of the Invention]

[0015] The present invention provides an injectable pharmaceutical composition that reduces human errors and labor involved in dose preparation in medical settings. [Brief explanation of the drawings]

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

[0021] In the present invention, difelikephalin can be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Examples of such difelikephalin salts 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. Difelikephalin acetate (JAN) is preferred.

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

[0023] Difelikefalin of the present invention can be produced by known methods, for example, by the methods described in Patent Documents 1 and 2 or methods based thereon.

[0024] One embodiment of the injectable pharmaceutical composition of the present invention is an injection, preferably a disposable injection, which can reduce human error and labor involved in dosage preparation in medical settings during administration.Such injections include, for example, injections in which the pre-filled medicinal solution is used up completely, and injections in which the filled medicinal solution is used up completely after being sucked up completely with a syringe.Examples of the form of injections that can be used in this way include, for example, pre-filled syringe preparations, vial preparations, and ampule preparations.

[0025] The injectable pharmaceutical composition of the present invention can be provided as multiple standard injections containing a constant amount of difelikephalin in a vial or prefilled syringe, but with different difelikephalin concentrations. In one embodiment, the injectable composition can be provided as multiple standard injections containing a constant difelikephalin concentration, but with different difelikephalin concentrations. The amount of difelikephalin to be filled is not particularly limited as long as it is an amount that can be filled into an injection, but is preferably in the range of 0.3 mL to 2.5 mL. The amount of difelikephalin encapsulated is 17.5 μg, 25.0 μg, 35.0 μg, or 42.5 μg, calculated as free form, 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 difelikefalin or a pharmacologically acceptable salt thereof as the 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 known pharmaceutical techniques. Examples of such pharmaceutically acceptable carriers include isotonicity agents such as sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, glucose, and propylene glycol. Preferred are sodium chloride and potassium chloride. Buffers include acetic acid, tartaric acid, lactic acid, citric acid, boric acid, phosphoric acid, carbonic acid, and salts thereof. More specifically, acetic acid and sodium acetate, citric acid and trisodium citrate, sodium bicarbonate and sodium carbonate, sodium dihydrogen phosphate and disodium hydrogen phosphate, etc. Preferred are acetic acid and sodium acetate, sodium bicarbonate and sodium carbonate. Examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, and borax. Preferred examples include parahydroxybenzoates and benzalkonium chloride. Examples of thickeners include hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene glycol. Preferred examples include hydroxyethyl cellulose and hydroxypropyl cellulose. Examples of stabilizers include sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, and dibutylhydroxytoluene. Preferred examples include sodium citrate and ascorbic acid. Examples of pH adjusters include hydrochloric acid, sodium hydroxide, phosphoric acid, and acetic acid. Preferred examples include hydrochloric acid and sodium hydroxide.

[0027] The solvent used in the injectable pharmaceutical composition of the present invention is not particularly limited as long as it is usable for injections, 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 adjusted to 5.0 or less, more preferably in the range of 4.0 to 5.0.

[0029] The injectable pharmaceutical composition of the present invention is typically provided as an injectable preparation having multiple sizes with different difelikefalin contents. In one embodiment of the present invention, the injectable preparation is provided to a medical institution as an injectable preparation having multiple strength sizes pre-filled with a specified amount of difelikefalin according to the patient's dry weight category. The number of strength sizes (sizes) is not particularly limited as long as it is acceptable in medical practice, but is preferably 4 or less, and more preferably 3 or less. The number of sizes is typically the same as the number of patient dry weight categories; however, if it is possible to substitute a high-strength injectable preparation by combining lower-strength injectable preparations, the injectable preparation may be provided as an injectable preparation with a number of sizes fewer than the number of patient dry weight categories.

[0030] The term "dry weight" refers to the target weight after fluid removal in hemodialysis treatment, which is set as an index for treatment planning tailored to the individual patient's condition. The Japanese Society for Dialysis Therapy defines it as "a weight at which the body fluid volume is appropriate, no excessive drop in blood pressure occurs during dialysis, and the cardiovascular system is not burdened over the long term." In other words, it refers to a weight that is not in a state of excessive fluid retention. Dry weight is usually determined by a physician and is set, for example, to be as close as possible to the post-urination weight of a patient with normal renal function. Therefore, dry weight can also refer to the lowest weight that can be safely achieved after hemodialysis without experiencing symptoms of hypotension associated with excessive fluid removal, such as convulsions.

[0031] Dry weight can be set according to commonly adopted criteria, such as no significant drop in blood pressure during dialysis, blood pressure at the end of dialysis not higher than at the start, no peripheral edema, no 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 prescribed amount of difelikefalin based on a patient's dry weight category. This avoids the complex administration method of adjusting the dosage in increments of 1 kg of body weight each time a drug is administered, reducing human error and labor involved in dosage preparation in clinical settings. In the present invention, the prescribed amount of difelikefalin based on the patient's dry weight category may be, for example, 17.5 μg for an adult patient with a dry weight of less than 45 kg, 25.0 μg for a patient with a dry weight of 45 kg to less than 65 kg, 35.0 μg for a patient with a dry weight of 65 kg to less than 85 kg, and 42.5 μg for a patient with a dry weight of 85 kg or more.

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

[0034] When the injectable pharmaceutical composition of the present invention is applied to a dialysis patient, the pharmaceutical composition can be used, for example, by injecting the pharmaceutical composition into the venous side of the dialysis circuit three times a week when blood is returned at the end of dialysis. If administration through the dialysis circuit is not possible due to a problem with the dialysis circuit, administration can also be by intravenous injection. If dialysis is performed a fourth time a week as an emergency, administration can also be performed four times a week.

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

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

[0037] The NRS, arguably the most representative index, evaluates the most intense itching experienced during the day using an integer between 0 and 10, with 0 representing "no itching" and 10 representing "the most intense itching imaginable." Generally, an NRS score of 1 to less than 4 indicates mild itching, 4 to less than 7 indicates moderate itching, and 7 or greater indicates severe itching. The VAS is evaluated by marking the position representing the most intense itching experienced during the day, with the left end of a 100mm line representing "no itching" and the right end representing "the most intense itching imaginable," and measuring the distance from the left end of the line. While NRS and VAS ratings are correlated, the NRS is a more convenient evaluation method. The NRS score for itching is widely used in clinical trials as a method for evaluating pruritus.

[0038] The Shiratori severity scale is based on a scale of 0 to 4, ranging from "no symptoms" to "extreme itching," and subjects themselves assess and rate their daytime and nighttime symptoms. The Shiratori severity scale is widely used in the field of dermatology in Japan to assess the degree of itching, and uses the impact on daily life as a criterion for judging severity.

[0039] The Skindex-16 is assessed using a score range of 0 to 6, ranging from "never bothered" to "always bothered." The Skindex-16 has been applied to assess quality of life related to skin diseases.

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

[0041] The PGIC assesses the overall symptoms of itching on a seven-point scale: "much improved," "better," "slightly improved," "no change," "slightly worse," "worse," and "much worse."

[0042] The effectiveness of a drug against itching can also be confirmed by evaluating the amount of change in score in the above-mentioned evaluation method. Specifically, the degree of itching before administration of the drug (baseline) is compared with the degree of itching after administration of the drug, and if the degree of itching is improved, it can be evaluated that the itching has been alleviated. In the present invention, from the perspective of improving the patient's QOL, it is preferable that the effectiveness against itching is confirmed not only by improvement in NRS or VAS score but also by improvement in QOL score (Shiratori severity scale, 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 the dry weight categories. Specifically, it is preferable that an improvement in pruritus is observed in all dry weight categories, or that no significant fluctuations are observed in the pre-dialysis trough value (plasma drug concentration (plasma difelikephalin (unchanged) concentration) immediately before administration), or both are satisfied. The plasma concentration of difelikephalin can be measured by a general method, for example, by LC-MS / MS.

[0044] One embodiment of the injectable pharmaceutical composition of the present invention is a kit comprising (a) the injectable pharmaceutical composition of the present invention; and (b) one or more labels or package inserts attached to or provided with a container. In the present invention, "including a package insert" includes not only cases where an instruction manual is enclosed, but also cases where a means for making the information containing the contents of the package insert available is clearly indicated. The case where a means for making the information containing the contents of the package insert available is clearly indicated includes, but is not limited to, any means that allows the contents to be confirmed, and includes, for example, a means for making the information available via an electronic communication line. Specifically, a commercially available pharmaceutical formulation may include a QR code (registered trademark) or a URL. [Example]

[0045] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. In the examples, the amount of difelikefalin refers to the amount administered as difelikefalin acetate in the free form (free form equivalent). Example 1 Clinical trial in hemodialysis patients with pruritus (double-blind, parallel-group comparative study) 1. Test Method (1) Administration method A total of 247 patients were divided into groups A (61 patients), B (61 patients), C (62 patients), and a placebo group (63 patients). Each study drug was administered three times a week for eight weeks by injecting it into the venous side of the dialysis circuit at the time of blood return at the end of dialysis. The study period consisted of a pre-observation period (two weeks before the start of the treatment period), a treatment period (eight weeks), and a post-observation period (two weeks after the end of the treatment period). No study drug was administered during the pre-observation and post-observation periods. (2) Investigational drug Group A: Injection solution of difelikephalin at 0.025 mg / mL in 0.04 M isotonic acetate buffer solution (pH 4.5) Group B: Injection solution of difelikephalin at 0.05 mg / mL in 0.04 M isotonic acetate buffer solution (pH 4.5) Group C: Injection solution of difelikephalin at 0.1 mg / mL in 0.04 M isotonic acetate buffer solution (pH 4.5) Placebo group: 0.04M isotonic acetate buffer solution (pH 4.5) (3) Dosage The dosage of the investigational drug solution and the dosage of difelikefalin for each administration group were determined based on the dry weight of each patient on the day of administration, according to the table below.

[0046] [Table 1]

[0047] 2.Efficacy and safety evaluation items Efficacy was evaluated based on the following subjective symptoms related to itching. For each of the following scores, week 0 of the treatment period was used as the baseline, and the difference from the baseline was used as the amount of change. (1) NRS score The most intense itching experienced during the day was rated on a scale from 0 to 10, with 0 being "no itching" and 10 being "the most intense itching imaginable." (2) Itching score based on Shiratori's severity criteria Once a day, the degree of itching from the time participants woke up the day before the evaluation until the time they woke up on the day of evaluation (including while sleeping) was scored from 0 to 4, ranging from "no symptoms" to "extreme itching," and each symptom was evaluated during the day and at night. (3) Skindex-16 score At the first visit of the week (before administration of the study drug), the frequency of itching in the past week was assessed. Responses were scored from 0 to 6, ranging from "never bothered" to "always bothered." (4) 5-D Itch Scale score At the first visit of the week (before administration of the study drug), the itching conditions over the past two weeks were reviewed and five components of itching (duration, severity, tendency, adverse effects, and distribution) were assessed. (5) PGIC score At the first visit of the week, the overall symptoms of itching compared to the pre-observation period were evaluated on a 7-point scale: "much improved," "better," "slightly improved," "no change," "slightly worse," "worse," or "much worse."

[0048] For the analysis method, 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, with group, observation time point, and the interaction between group and observation time point as fixed effects, the baseline mean score, use of previous medication for itch, and the presence or absence of specific signs or symptoms confirmed during the observation period as covariates, and subject as a random effect. For the itch score based on Shiratori's severity criteria, the change in score was used as the dependent variable, with group, observation time point, and the interaction between group and observation time point as fixed effects, the baseline mean score as a covariate, and subject as a random effect.

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

[0050] The change in NRS score at 8 weeks of treatment was -2.86 in the placebo group, -2.97 in group A, -3.65 in group B, and -3.64 in group C, with groups B and C showing significant improvement compared to the placebo group (MMRM, P<0.05). (2) The changes in NRS scores for each dry weight category in Groups B and C at Week 4 of the treatment period, when efficacy was maximized, are shown in Figures 2 and 3. As shown in Figures 2 and 3, improvements in NRS scores were confirmed in both Groups B and C for each dry weight category. (3) The change in itching score based on the Shiratori severity criteria at 8 weeks of treatment (the larger change in either the daytime or nighttime score) was -1.00 in the placebo group, -1.14 in Group A, -1.31 in Group B, and -1.31 in Group C, showing significant improvement in Groups B and C compared to the placebo group (MMRM, P<0.05). (4) The change in the Skindex-16 total score at 8 weeks of treatment was -24.04 in the placebo group, -24.25 in Group A, -27.79 in Group B, and -22.69 in Group C, with a tendency for improvement observed in Group B. (5) The change in the 5-D Itch Scale total score at 8 weeks of treatment was -5.8 in the placebo group, -6.6 in Group A, -6.5 in Group B, and -6.8 in Group C, and a tendency for improvement was observed with doses higher than Group A. (6) The percentages of subjects who scored "improved" and "very improved" on PGIC at the final evaluation of the treatment period were 24.2% and 17.7% in the placebo group, 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, showing significant improvements in groups B and C compared to placebo (two-sample Wilcoxon test, P<0.01). (7) The incidence of adverse events during the treatment period increased dose-dependently, from 66.7% in the placebo group to 72.1% in group A, 77.0% in group B, and 85.5% in group C, and the incidence in group C was significantly higher than that in the placebo group (Fisher's exact test, P<0.05).

[0051] The incidence of side effects during the treatment period increased dose-dependently, from 11.1% in the placebo group to 14.8% in groups A, B, and C, with the incidence in group C being significantly higher than that in the placebo group (Fisher's exact test, P<0.05).

[0052] The above results showed a significant improvement in pruritus in hemodialysis patients in groups B and C. On the other hand, no significant improvement was observed in group A. Furthermore, the incidence of adverse events and side effects during the treatment period in group B did not show a significant difference compared to the placebo group, confirming that group B was a dose with excellent safety and tolerability. 4. Pharmacokinetic endpoints (1) Measurement method: In Groups B and C, "plasma drug concentration: plasma difelikefalin (unchanged) concentration" was measured by LC-MS / MS. (2) Results: The geometric mean values ​​of pre-dialysis trough values ​​(pre-dialysis plasma difelikefalin concentrations) at 7 weeks in 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), and 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. The geometric mean pre-dialysis trough values ​​(pre-dialysis plasma difelikefalin concentrations) at 7 weeks in dry weight categories of 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), and 85 kg or more (2 cases)) were 0.9306 ng / mL, 0.9700 ng / mL, 1.0671 ng / mL, and 1.0396 ng / mL, respectively.

[0053] From the above results, no significant differences were observed in the range of fluctuation of plasma difelikephalin concentrations among the dry weight categories within Group B. Similar results were observed in Group C.

[0054] The results of the Examples showed that Group B was effective and safe for treating pruritus in hemodialysis patients of various weights, without the need to adjust the dosage in increments of 1 kg of individual patient weight. Therefore, it was demonstrated that the injectable pharmaceutical composition of the present invention can reduce human errors and labor involved in dose preparation in clinical settings. [Industrial Applicability]

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

Claims

1. A pharmaceutical composition for treating pruritus in dialysis patients, comprising difelikefalin or a pharmacologically acceptable salt thereof, The pharmaceutical composition is characterized in that the following prescribed amount of difelikefalin is administered based on the dry weight classification of a patient under the following conditions (1) to (4): the pharmaceutical composition; (1) Administer 17.5 μg of diphenylkephalin in free form to dialysis patients with a dry weight of less than 45 kg. (2) Administer 25.0 μg of diphenylkephalin in free form to dialysis patients with a dry weight of 45 kg or more but less than 65 kg. (3) Administer 35.0 μg of diphenylkephalin in free form to dialysis patients with a dry weight of 65 kg or more but less than 85 kg. (4) Administer 42.5 μg of diphenylkephalin, calculated as free form, to dialysis patients with a dry weight of 85 kg or more.

2. An injectable preparation for treating pruritus in dialysis patients, comprising difelikefalin or a pharmacologically acceptable salt thereof, The injection is for administering the following prescribed amount of difelikefalin based on the dry weight classification of a patient under the following conditions (1) to (4): the injectable preparation contains difelikephalin in an amount of 17.5 μg, 25.0 μg, 35.0 μg, or 42.5 μg calculated as free form; (1) Administer 17.5 μg of diphenylkephalin in free form to dialysis patients with a dry weight of less than 45 kg. (2) Administer 25.0 μg of diphenylkephalin in free form to dialysis patients with a dry weight of 45 kg or more but less than 65 kg. (3) Administer 35.0 μg of diphenylkephalin in free form to dialysis patients with a dry weight of 65 kg or more but less than 85 kg. (4) Administer 42.5 μg of diphenylkephalin, calculated as free form, to dialysis patients with a dry weight of 85 kg or more.

3. The injectable preparation according to claim 2, For dialysis patients with a dry weight of less than 45 kg, 17.5 μg of difelikephalin is administered in a free-form equivalent amount using an injection containing 17.5 μg of difelikephalin in a free-form equivalent amount. For dialysis patients with a dry weight of 45 kg or more but less than 65 kg, an injection containing 25.0 μg of difelikephalin in free form is used to administer 25.0 μg of difelikephalin in free form. For dialysis patients with a dry weight of 65 kg or more but less than 85 kg, administer 35.0 μg of difelikephalin in free form using an injection containing 35.0 μg of difelikephalin in free form, or administer 2 injections containing 17.5 μg of difelikephalin in free form in combination to administer 35.0 μg of difelikephalin in free form. For dialysis patients with a dry weight of 85 kg or more, administer 42.5 μg of difelikephalin in free form using an injection containing 42.5 μg of difelikephalin in free form, or administer 42.5 μg of difelikephalin in free form using an injection containing 17.5 μg of difelikephalin in free form and an injection containing 25.0 μg of difelikephalin in free form. The injectable preparation.

4. The injectable preparation according to claim 2, For dialysis patients with a dry weight of less than 45 kg, 17.5 μg of difelikephalin is administered in a free-form equivalent amount using an injection containing 17.5 μg of difelikephalin in a free-form equivalent amount. For dialysis patients with a dry weight of 45 kg or more but less than 65 kg, an injection containing 25.0 μg of difelikephalin in free form is used to administer 25.0 μg of difelikephalin in free form. For dialysis patients with a dry weight of 65 kg or more but less than 85 kg, administer 35.0 μg of difelikephalin in free form using an injection containing 35.0 μg of difelikephalin in free form, or administer 2 injections containing 17.5 μg of difelikephalin in free form in combination to administer 35.0 μg of difelikephalin in free form. For dialysis patients with a dry weight of 85 kg or more, an injection containing 17.5 μg of difelikephalin in free form and an injection containing 25.0 μg of difelikephalin in free form are used to administer 42.5 μg of difelikephalin in free form. The injectable preparation.

5. An injectable preparation according to claim 2, For dialysis patients with a dry weight of less than 45 kg, 17.5 μg of difelikephalin is administered in a free-form equivalent amount using an injection containing 17.5 μg of difelikephalin in a free-form equivalent amount. For dialysis patients with a dry weight of 45 kg or more but less than 65 kg, an injection containing 25.0 μg of difelikephalin in free form is used to administer 25.0 μg of difelikephalin in free form. For dialysis patients with a dry weight of 65 kg or more but less than 85 kg, two injections containing 17.5 μg of difelikephalin in free form are combined to administer 35.0 μg of difelikephalin in free form. For dialysis patients with a dry weight of 85 kg or more, an injection containing 17.5 μg of difelikephalin in free form and an injection containing 25.0 μg of difelikephalin in free form are used to administer 42.5 μg of difelikephalin in free form. The injectable preparation.

6. The injectable preparation according to any one of claims 2 to 5, which is a prefilled syringe preparation, a vial preparation, or an ampoule preparation.

7. The injectable preparation according to claim 6, which is a prefilled syringe formulation.

8. The injectable preparation according to claim 7, which is a disposable injectable preparation.

9. The pharmaceutical composition described in claim 1 for use in a dialysis patient by injection into the venous side of the dialysis circuit three times a week when blood is returned at the end of dialysis.

10. An injectable preparation according to any one of claims 2 to 5 for use in a dialysis patient by injection into the venous side of the dialysis circuit three times a week when blood is returned at the end of dialysis.

11. The pharmaceutical composition of claim 1, intended to reduce human error and labor involved in dose preparation in medical settings.

12. An injectable preparation according to any one of claims 2 to 5, intended to reduce human error and labor involved in dose preparation in medical settings.

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