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JP-7857158-B2 - Injectable pharmaceutical compositions for use in dialysis patients

JP7857158B2JP 7857158 B2JP7857158 B2JP 7857158B2JP-7857158-B2

Inventors

  • 内山 琢麻
  • 一色 信行

Assignees

  • キッセイ薬品工業株式会社
  • 丸石製薬株式会社

Dates

Publication Date
20260512
Application Date
20220520

Claims (9)

  1. A pharmaceutical composition for the treatment of pruritus in dialysis patients, comprising diferikephalin or a pharmacoacceptable salt thereof, The aforementioned pharmaceutical composition is characterized in that, under the following conditions (1) to (4), a specified amount of diferikephalin is administered based on the patient's dry weight classification. The aforementioned pharmaceutical composition; (1) Administer 17.5 μg of diferikephalin (in free form equivalent) to dialysis patients with a dry weight of less than 45 kg. (2) Administer 25.0 μg of diferikephalin (in free form equivalent) to dialysis patients with a dry weight of 45 kg or more but less than 65 kg. (3) Administer 35.0 μg of diferikephalin (in free form equivalent) to dialysis patients with a dry weight of 65 kg or more but less than 85 kg. (4) Administer 42.5 μg of diferikephalin (in free form equivalent) to dialysis patients with a dry weight of 85 kg or more.
  2. An injectable preparation for the treatment of pruritus in dialysis patients, containing diferikephalin or a pharmacoacceptable salt thereof, The aforementioned injectable preparation is intended for administering the following specified amount of diferikephalin based on the patient's dry weight classification under the conditions (1) to (4) below: The injectable preparation contains diferikephalin in an amount of 17.5 μg, 25.0 μg, 35.0 μg, or 42.5 μg on a free form basis; (1) Administer 17.5 μg of diferikephalin (in free form equivalent) to dialysis patients with a dry weight of less than 45 kg. (2) Administer 25.0 μg of diferikephalin (in free form equivalent) to dialysis patients with a dry weight of 45 kg or more but less than 65 kg. (3) Administer 35.0 μg of diferikephalin (in free form equivalent) to dialysis patients with a dry weight of 65 kg or more but less than 85 kg. (4) Administer 42.5 μg of diferikephalin (in free form equivalent) 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, administer 17.5 μg of diferikephalin (in free form equivalent) using an injectable preparation containing 17.5 μg of diferikephalin. For dialysis patients with a dry weight of 45 kg or more but less than 65 kg, administer 25.0 μg of diferikephalin in free form using an injectable preparation containing 25.0 μg of diferikephalin in free form. For dialysis patients with a dry weight of 65 kg or more but less than 85 kg, administer an injectable preparation containing 35.0 μg of diferikephalin in free form equivalent, or a combination of two injectable preparations containing 17.5 μg of diferikephalin in free form equivalent, to administer 35.0 μg of diferikephalin in free form equivalent. For dialysis patients with a dry weight of 85 kg or more, administer an injectable formulation containing 42.5 μg of diferikephalin in free form, or an injectable formulation containing 17.5 μg of diferikephalin in free form and an injectable formulation containing 25.0 μg of diferikephalin in free form, to a total amount of 42.5 μg of diferikephalin in free form. The aforementioned injectable agent.
  4. The injectable preparation according to claim 2, For dialysis patients with a dry weight of less than 45 kg, administer 17.5 μg of diferikephalin (in free form equivalent) using an injectable preparation containing 17.5 μg of diferikephalin. For dialysis patients with a dry weight of 45 kg or more but less than 65 kg, administer 25.0 μg of diferikephalin in free form using an injectable preparation containing 25.0 μg of diferikephalin in free form. For dialysis patients with a dry weight of 65 kg or more but less than 85 kg, administer an injectable preparation containing 35.0 μg of diferikephalin in free form equivalent, or a combination of two injectable preparations containing 17.5 μg of diferikephalin in free form equivalent, to administer 35.0 μg of diferikephalin in free form equivalent. For dialysis patients with a dry weight of 85 kg or more, an injectable formulation containing 17.5 μg of diferikephalin (in free form equivalent) and an injectable formulation containing 25.0 μg of diferikephalin (in free form equivalent) should be administered, resulting in a total dose of 42.5 μg of diferikephalin (in free form equivalent). The aforementioned injectable agent.
  5. The injectable preparation according to claim 2, For dialysis patients with a dry weight of less than 45 kg, administer 17.5 μg of diferikephalin (in free form equivalent) using an injectable preparation containing 17.5 μg of diferikephalin. For dialysis patients with a dry weight of 45 kg or more but less than 65 kg, administer 25.0 μg of diferikephalin in free form using an injectable preparation containing 25.0 μg of diferikephalin 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 diferikephalin (in free form equivalent) are administered in combination, resulting in a total dose of 35.0 μg of diferikephalin (in free form equivalent). For dialysis patients with a dry weight of 85 kg or more, an injectable formulation containing 17.5 μg of diferikephalin (in free form equivalent) and an injectable formulation containing 25.0 μg of diferikephalin (in free form equivalent) should be administered, resulting in a total dose of 42.5 μg of diferikephalin (in free form equivalent). The aforementioned injectable agent.
  6. The pharmaceutical composition according to claim 1, for use in dialysis patients, administered by injection into the venous side of the dialysis circuit three times a week during blood return at the end of dialysis.
  7. An injectable preparation according to any one of claims 2 to 5, for use in dialysis patients, administered by injection into the venous side of the dialysis circuit three times a week during blood return at the end of dialysis.
  8. The pharmaceutical composition according to claim 1, which reduces human error and labor associated with dosage preparation in medical settings.
  9. An injectable preparation according to any one of claims 2 to 5, which aims to reduce human error and labor associated with dosage preparation in medical settings.

Description

This invention relates to a pharmaceutical composition for use in dialysis patients, containing a pharmaceutical, particularly difericephalin or a pharmaceutically acceptable salt thereof. The causes of pruritus in dialysis patients are not fully understood, and it is considered a difficult condition to treat. Multiple factors are involved in the development of pruritus, including skin dryness, accumulation of endogenous substances, and overproduction of chemical mediators such as histamine and substance P. Furthermore, changes in immune function and opioid imbalance are also contributing factors. It is believed that in dialysis patients with pruritus, the μ-opioid system, which induces itching, is dominant over the κ-opioid system, which suppresses itching. Treatment for pruritus in dialysis patients includes topical treatment with moisturizers such as lotions and creams, steroids, topical or oral treatment with antihistamines and anti-allergic drugs, and phototherapy using broad-wavelength ultraviolet light. In Japan, nalfurafine hydrochloride, an oral κ-opioid receptor (KOR) agonist, is used for patients whose condition is inadequately treated with existing therapies such as topical or oral medications. Difericephalin is a novel peptide-based KOR agonist being developed overseas as a treatment for pruritus (Non-Patent Literature 1). Similar development is also underway in Japan. The peptide structure of difericephalin differs significantly from previously developed low-molecular-weight heterocyclic compound KOR agonists with central nervous system (CNS) activity. Due to its physicochemical properties, it has low membrane permeability and limited cross-transition to the CNS. Therefore, it exhibits high selectivity for κ-opioid receptors and weak effects on other opioid receptors, does not easily cross into the CNS, and is a drug with excellent safety and tolerability, making early market launch highly desirable. Patent No. 5807140Patent No. 5244810 Steven Fishbane et al., *Kidney International Reports*, 2020, Vol. 5, pp. 600-610. 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).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.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. The embodiments of the present invention will be described in more detail below. In this invention, unless otherwise specified, each term has the following meanings. Difelikefalin (INN) is a compound represented by the following formula. In this invention, difericephalin may be prepared as a pharmaceutically acceptable salt by conventional methods, if necessary. Examples of such difericephalin 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. Preferably, difericephalin acetate (JAN) is used. In this invention, "pharmacologically acceptable salts of diferikephalin" also include solvates with pharmaceutically acceptable solvents such as water and ethanol. The diferikephalin of the present invention can be manufactured by known methods. For example, it can be manufactured by the methods described in Patent Documents 1 and 2, or by similar methods. One embodiment of the injectable pharmaceutical composition of the present invention is an injectable preparation, preferably a single-use injectable preparation that reduces human error associated with dosage preparation in a medical setting and reduces labor during administration. Examples of such injectable preparations include injectable preparations in which the entire pre-filled drug solution is used up, and injectable preparations in which the entire pre-filled drug solution is drawn up with a syringe and then used up completely. Examples of injectable preparations that can be used in this way include pre-filled syringe preparations, vial preparations, and ampoule preparations. The injectable pharmaceutical composition of the present invention can be provided as an injectable preparation in multiple strengths with different concentrations of diferike