# US 10,869,876 B2 · Rocuronium preparation with improved stability

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- Number: US 10,869,876 B2
- Document ID: US10869876B2
- Status: Granted
- Kind: B2
- Application number: 15/319,919
- Filed: 2014-06-26
- Published: 2017-05-11
- Granted: 2020-12-22
- Earliest claimed: 2014-06-26
- Assignees: Maruishi Pharmaceutical Co., Ltd.
- Applicants: Maruishi Pharmaceutical Co., Ltd.
- Inventors: Yutaka Itsuji; Hironori Nagahara; Keisuke Jinbo
- Web page: https://patentgrep.com/patent/US10869876B2

## CPC

- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 31/5355: Non-condensed oxazines and containing further heterocyclic rings
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 23/00: Anaesthetics
- C23C 16/345: {Silicon nitride}
- C23C 16/455: characterised by the method used for introducing gases into reaction chamber or for modifying gas flows in reaction chamber
- C23C 16/45546: {specially adapted for a substrate stack in the ALD reactor}
- C23C 16/45561: {Gas plumbing upstream of the reaction chamber}
- C23C 16/45563: {Gas nozzles}
- C23C 16/45578: {Elongated nozzles, tubes with holes}
- H10P 14/60: of insulating materials
- H10P 14/6339: {deposition by cyclic CVD, e.g. ALD, ALE or pulsed CVD}
- H10P 14/6682: {the compound being a silane, e.g. disilane, methylsilane or chlorosilane}
- H10P 14/69433: {the material being a silicon nitride not containing oxygen, e.g. SixNy or SixByNz}
- H10P 72/0434: {mainly by convection}
- H10P 72/0602: {Temperature monitoring}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C23C: COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL (making metal-coated products by extrusion B21C23/22; covering with metal by connecting pre-existing layers to articles, see the relevant places, e.g. B21D39/00, B23K; metallising of glass C03C; metallising mortars, concrete, artificial stone, ceramics or natural stone C04B41/00; enamelling of, or applying a vitreous layer to, metals C23D; treating metal surfaces or coating of metals by electrolysis or electrophoresis C25D; single-crystal film growth C30B; by metallising textiles D06M11/83; decorating textiles by locally metallising D06Q1/04)
- H10P: GENERIC PROCESSES OR APPARATUS FOR THE MANUFACTURE OR TREATMENT OF DEVICES COVERED BY CLASS H10

## Abstract

The present invention provides a rocuronium preparation with an excellent stability. The rocuronium preparation contains rocuronium and a buffer solution and having an adjusted pH of 3.5 or less (for example, 2.5 to 3.5). The buffer solution may be a citric acid-sodium hydroxide buffer solution, a tartaric acid-sodium hydroxide buffer solution, a potassium hydrogen phthalate-hydrochloric acid buffer solution, a glycine-hydrochloric acid buffer solution, or the like. Such a rocuronium preparation has, for example, after 6-month storage at 40° C., a generation rate of rocuronium-related substance C of 5% or less.

## Claims

### Claim 1

A rocuronium preparation in a liquid form consisting of rocuronium and a buffer solution, and optionally a solvent and optionally an isotonizing agent, and having a pH of 1.8 to 3.5, wherein the buffer solution is at least one selected from the group consisting of a formate buffer solution, a citrate buffer solution, a tartrate buffer solution, a phthalate buffer solution, a phosphate buffer solution, a citric acid-phosphate buffer solution and a glycine buffer solution, and wherein the preparation is stable after 6 months of storage at 40° C. by generating 3% or less of a rocuronium-related substance C.

### Claim 2 (depends on 1)

The rocuronium preparation of claim 1, having a pH of 2.5 to 3.5.

### Claim 3 (depends on 1)

The rocuronium preparation of claim 1, having a pH of 2.8 to 3.2.

### Claim 4 (depends on 1)

The rocuronium preparation of claim 1, wherein the buffer solution is at least one selected from the group consisting of a citric acid-sodium hydroxide buffer solution, a tartaric acid-sodium hydroxide buffer solution, a potassium hydrogen phthalate-hydrochloric acid buffer solution, and a glycine-hydrochloric acid buffer solution.

### Claim 5 (depends on 1)

The rocuronium preparation of claim 1, wherein the pH is 2.5 to 3.5 and the buffer solution is a glycine-hydrochloric acid buffer solution of which the concentration is 0.01 M or higher.

### Claim 6

A liquid rocuronium injection preparation consisting of rocuronium and a buffer solution, and optionally a solvent and optionally an isotonizing agent, and having a pH of 1.8 to 3.5, wherein the buffer solution is at least one selected from the group consisting of a formate buffer solution, a citrate buffer solution, a tartrate buffer solution, a phthalate buffer solution, a phosphate buffer solution, a citric acid-phosphate buffer solution and a glycine buffer solution, and wherein a rate of generated rocuronium-related substance C after 6-months storage at 40° C. is 3% or less.

### Claim 7 (depends on 1)

The rocuronium preparation of claim 1, which is storable at room temperature.

### Claim 8

A method for increasing or improving the stability of a rocuronium preparation, comprising adjusting the pH of a rocuronium preparation in a liquid form consisting of rocuronium and a buffer solution, and optionally a solvent and optionally an isotonizing agent, to 1.8 to 3.5, wherein the buffer solution is at least one selected from the group consisting of a formate buffer solution, a citrate buffer solution, a tartrate buffer solution, a phthalate buffer solution, a phosphate buffer solution, a citric acid-phosphate buffer solution and a glycine buffer solution, so that the rate of generated rocuronium-related substance C after 6-months storage at 40° C. is 3% or less.

### Claim 9

A method for preventing or reducing both injection pain and vascular irritation caused by a rocuronium injection preparation and for increasing or improving the stability of the rocuronium injection preparation so that the rate of generated rocuronium-related substance C after 6-months storage at 40° C. is 3% or less, comprising adjusting the pH of a rocuronium injection preparation in a liquid form consisting of rocuronium and a buffer solution, and optionally a solvent and optionally an isotonizing agent, to 1.8 to 3.5, wherein the buffer solution is at least one selected from the group consisting of a formate buffer solution, a citrate buffer solution, a tartrate buffer solution, a phthalate buffer solution, a phosphate buffer solution, a citric acid-phosphate buffer solution and a glycine buffer solution, so that the rate of generated rocuronium-related substance C after 6-months storage at 40° C. is 3% or less.

### Claim 10 (depends on 8)

The method of claim 8, wherein the preparation is prepared so as to be storable at room temperature.