RU2724900C1 - Rocuronium preparation with improved stability - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: group of inventions relates to a rocuronium preparation. Injection preparation rocuronium in liquid form contains rocuronium and a buffer solution and having pH 3.5 or less, where concentration of the buffer solution ranges from 0.015 to 0.8 M. Also disclosed is a method of increasing or improving the stability of an injectable preparation of rocuronium and a method for preventing or reducing pain in injection and vascular irritation caused by an injectable rocuronium preparation.EFFECT: group of inventions provides improved stability of an injectable rocuronium preparation.11 cl, 1 dwg, 7 tbl, 12 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to a rocuronium preparation with improved stability, and a method for increasing the stability of a rocuronium preparation.

BACKGROUND OF THE INVENTION

Rockuronium (or rocuronium bromide) is known as the active ingredient in an anesthetic muscle relaxant or the like. (non-patent literature 1).

Rockuronium is relatively thermally unstable in an aqueous solution, and thus, its storage and / or transportation are time consuming and expensive. For example, ESLAX, which is known as a commercially available rocuronium preparation, needs to be cooled at a temperature of 2 to 8 ° C (Non-Patent Literature 1).

For this reason, attempts have been made to improve the stability of rocuronium in aqueous solution. For example, WO2008 / 065142 (Patent Literature 1) discloses a technique for stabilizing a rocuronium-containing aqueous solution by adding β-cyclodextrin or its pharmaceutically acceptable salt derivative of the sulfoalkyl ether derivative to the solution.

However, the method of this document requires the addition of a sulfoalkyl ether derivative of β-cyclodextrin or a pharmaceutically acceptable salt thereof, the use of which has been reported to cause renal dysfunction, etc. The document describes that the pH should be in the range from 3.5 to 7.5, and preferably from 5.5 to 7.5, to reduce pain during injection. In other words, this document recognizes the occurrence of pain during injection in the pH range from 3.5 to 7.5, and does not consider lowering the pH to 3.5 or less.

LIST OF QUOTATIONS

PATENT LITERATURE

Patent Literature 1: WO 2008/065142

NON-PATENT LITERATURE

Non-Patent Literature 1: Drug Interview Questionnaire for ESLAX IV 25 mg / 2.5 ml and ESLAX IV 50 mg / 5.0 ml, amended in October 2010

SUMMARY OF THE INVENTION

TECHNICAL PROBLEM

An object of the present invention is to provide a rocuronium preparation with excellent stability.

Another objective of the present invention is to provide a rocuronium preparation, the pH of which is greatly reduced.

Another object of the present invention is to provide a rocuronium preparation which does not cause irritation of blood vessels upon administration.

Another objective of the present invention is to provide a rocuronium preparation that does not cause or causes less pain during the injection.

THE SOLUTION OF THE PROBLEM

To achieve the above objectives, the authors of the present invention conducted intensive research and found that rocuronium preparation containing rocuronium and a buffer solution, and having a pH within a certain range, as well as lower than the pH of the commercially available ESLAX product (pH 4.0), to surprisingly demonstrates markedly increased or improved stability, and that despite the low pH, such a rocuronium preparation does not have physiologically unfavorable effects and, thus, can be administered in a safe manner, while the stability of the drug is improved or increased. Based on these data, the present inventors have completed the present invention.

That is, the rocuronium preparation of the present invention contains rocuronium and a buffer solution, and has a pH within a predetermined range (e.g., 3.5 or less). The pH of the rocuronium preparation may be, in particular, from about 2.5 to 3.5 (for example, from 2.8 to 3.2).

The buffer solution is not particularly limited provided that its pH can reach the desired value of the present invention, and can be at least one species selected from formate buffer solution, acetate buffer solution, citrate buffer solution, tartrate buffer solution, phthalate buffer solution, phosphate buffer solution, citric acid-phosphate buffer solution and glycine buffer solution. Specifically, the buffer solution may be at least one species selected from a buffer solution based on citric acid and sodium hydroxide, a buffer solution based on tartaric acid and sodium hydroxide, a buffer solution based on potassium hydrophthalate and hydrochloric acid, and a buffer solution based on glycine and hydrochloric acid.

Typical rocuronium preparations include a preparation having a pH of from 2.5 to 3.5 and containing a buffer solution based on glycine and hydrochloric acid, the concentration of which is 0.01 M or higher (for example, 0.015 M or higher).

The rocuronium preparation of the present invention has excellent stability. For example, after 6 months of storage at 40 ^° C., the rate of formation of co-impurity C (the value obtained by subtracting the initial percentage area of co-impurity C from the percentage of co-impurity C at each measurement point) may be 5% or less.

The rocuronium preparation of the present invention may be an injectable preparation. Such an injectable preparation, in addition to stability, has the effect of preventing or reducing pain during injection and vascular irritation (irritation of blood vessels). Thus, the rocuronium preparation (the injectable rocuronium preparation) of the present invention can be a rocuronium preparation that has a Rocuronium-associated impurity C level of 5% or less after 6 months storage at 40 ° C and which does not (or does not have the ability to cause ) or causes less pain during injection and / or vascular irritation (in particular, pain during injection and vascular irritation).

Thus, the rocuronium preparation of the present invention has excellent thermal stability, and thus can be a preparation that is well stored, in particular at room temperature.

According to the present invention, the stability of the rocuronium preparation can be increased or improved by adjusting the pH of the rocuronium preparation to a predetermined range. In this context, the present invention also relates to a method for increasing or improving the stability of a rocuronium preparation by adjusting the pH of a rocuronium preparation containing rocuronium and a buffer solution to 3.5 or less (in particular, a method for increasing or improving the stability of a rocuronium preparation so that the level of the impurity C associated with rocuronium after 6 months storage at 40 ° C is 5% or less).

In addition, as described above, the injection preparation of the present invention has the effect of preventing injection pain and vascular irritation. In this context, the present invention also relates to a method for preventing or reducing both injection pain and vascular irritation caused by the rocuronium injection drug and for increasing or improving the stability of the rocuronium injection drug so that the level of the accompanying rocuronium impurity C after 6 months storage is formed at 40 ° C was 5% or less, by adjusting the pH of the injection drug rocuronium containing rocuronium and a buffer solution to 3.5 or less.

According to these methods, it is possible to obtain a preparation (a rocuronium preparation or an injectable rocuronium preparation) so that it can be stored at room temperature.

Advantageous Effects of the Invention

In the present invention, a rocuronium preparation with excellent stability (in particular, thermal stability) can be obtained by adjusting the pH to a specific range. For example, the rocuronium preparation of the present invention decomposes slightly even when stored under uncooled conditions for a long period or under conditions of high temperature and high pressure. In addition, the change in pH can be clearly controlled, and thus, the drug rocuronium is extremely stable. Thus, the rocuronium preparation can be stored at normal temperature, and thus, it is extremely practical.

The rocuronium preparation of the present invention has no physiologically unfavorable effects (or has only insignificant adverse effects), and is also highly practical with respect to this. For example, the rocuronium preparation of the present invention does not cause a blood clot, perivascular inflammation or the like, and can be administered without vascular irritation. In addition, when administered, the drug does not cause or cause much less pain during injection than that caused by the commercial product (ESLAX). Thus, the rocuronium preparation of the present invention is also effective as a drug capable of preventing or reducing pain during injection and / or vascular irritation. In addition, the rocuronium preparation of the present invention achieves increased or improved stability without the component described in Patent Literature 1 (β-cyclodextrin sulfoalkyl ether derivative or a pharmaceutically acceptable salt thereof).

Thus, the preparation of the present invention is excellent both in terms of stability and safety, and is extremely useful.

As described above, the preparation of the present invention does not have physiologically unfavorable effects, which is very surprising given the fact that the pH of the commercial rocuronium preparation (ESLAX), as it was decided, should have a pH level (4.0) higher than the pH range of the present invention, taking into account physiologically adverse effects (cited from ESLAX analysis report).

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 is a graph showing the results of an assessment of pain during injection of the preparations of Example 2, Example 6, and Comparative Example 2 based on EMG.

DESCRIPTION OF EMBODIMENTS

The rocuronium preparation of the present invention contains rocuronium and a buffer solution and has a pH within a predetermined range. Rocuronium is rocuronium bromide (chemical name): (+) - (17β-acetoxy-3α-hydroxy-2β-morpholino-5α-androstan-16β-yl) -1-allyl-1-pyrrolidinium bromide) represented by the following formula.

The percentage of rocuronium in the preparation is not specifically limited and is appropriately selected depending on the state of the disease, dosage form, etc. The percentage may be, for example, from about 0.1 to 10% w / v, preferably from about 0.5 to 5% w / v. and more preferably from about 0.8 to 3% w / v.

The buffer solution is not particularly limited provided that it can achieve the desired pH of the present invention, and examples thereof include carboxylic acid based buffer solutions (e.g., formate buffer solution, acetate buffer solution, citrate buffer solution, tartrate buffer solution, phthalate buffer solution etc.), phosphate buffers (e.g. phosphate buffered saline, citric acid-phosphate buffered saline, etc.), amino acid buffers (e.g. glycine buffered saline, etc.), etc. To achieve the desired pH of the present invention, suitable buffer solutions may include citrate buffers (e.g., citric acid and sodium hydroxide buffers, etc.), tartrate buffers (e.g., tartaric acid buffers and sodium hydroxide, etc.), phthalate buffers (e.g., potassium hydrophthalate and hydrochloric acid buffers, etc.), and glycine buffers (e.g. glycine and hydrochloric buffers, etc. .). In particular, a buffer solution of glycine and hydrochloric acid can be used. These buffer solutions can be used individually or in combination of two or more. These buffer solutions can be prepared or purchased as commercially available products.

The concentration of the buffer solution in the preparation is not particularly limited and may be appropriately selected depending on the type of buffer solution, the desired pH, etc. The concentration can be selected from the range of 0.001 M or higher (for example, from 0.003 to 0.8 M), for example, 0.005 M or higher (for example, from 0.008 to 0.7 M), preferably 0.01 M or higher (for example, 0.015 to 0.5 M), more preferably 0.02 M or higher (e.g., 0.03 to 0.4 M), and particularly preferably 0.04 M or higher (e.g., 0.05 to 0.3 M).

In particular, when the buffer solution is a glycine-hydrochloric acid-based buffer solution, the concentration in the preparation may be, for example, 0.01 M or higher (e.g., from 0.015 to 0.8 M), preferably 0.02 M or higher ( for example, from 0.025 to 0.6 M), more preferably 0.03 M or higher (for example, from 0.04 to 0.5 M), and in particular about 0.05 M or higher (for example, from 0, 06 to 0.3 M).

A higher concentration of the buffer solution leads to more effective control of changes or variations in the pH of the drug.

The concentration of a buffer solution means the concentration of a component exhibiting buffering ability (buffer effect), for example, the concentration of glycine in the case of a buffer solution based on glycine and hydrochloric acid.

The pH of the rocuronium preparation of the present invention may be 3.5 or less (e.g., from 1.8 to 3.5), preferably 3.4 or less (e.g., from 2 to 3.35), and more preferably 3.3 or less (e.g., from 2.2 to 3.3). In particular, the pH of the rocuronium preparation can be, for example, from 2 to 3.5, preferably from 2.5 to 3.5 (for example, from 2.8 to 3.2), and typically less than 3.5 (e.g., 2 to 3.4). pH can be a value at a temperature of from 20 to 30 ^o C.

The rocuronium preparation of the present invention may contain other components (pharmaceutical carrier, etc.) mixed therein as necessary. Examples of other such components include a solvent, a solubilizer, a suspending agent, an isotonic agent, a sedative, etc. In addition, any known additives and pharmaceutically acceptable additives, typically used in the pharmaceutical field, for example, a preservative, antioxidant, stabilizer and oxidation inhibitor, can be used if necessary. These additives can be used individually or as a mixture of two or more components, if necessary, for the intended dosage form, etc. These additives may be commercially available products.

The solvent is not particularly limited, and examples thereof include purified water, ethanol, propylene glycol, polyethylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. The solubilizer is not particularly limited, and examples thereof include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc. The suspending agent is not particularly limited, and examples thereof include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, polyvinyl pyrrolidone, methyl cellulose, glycerol monostearate, sodium lauryl sulfate, lecithin, polyvinyl alcohol, etc. The isotonicity agent is not particularly limited, and examples thereof include glucose, D-sorbitol, sodium chloride, D-mannitol, glycerol, etc. The sedative is not particularly limited, and examples thereof include benzyl alcohol, etc.

The preservative is not particularly limited, and examples thereof include ethyl p-hydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, etc. The antioxidant is not particularly limited, and examples thereof include sodium sulfite, ascorbic acid, etc. The stabilizer is not particularly limited, and examples thereof include casein, sodium caseinate, etc. Examples of the oxidation inhibitor include tert-butylhydroquinone, butylhydroxyanisole, butylhydroxytoluene, α-tocopherol and derivatives thereof.

The preparation of the present invention may contain a specific component described in Patent Literature 1, namely, a sulfoalkyl ether derivative of β-cyclodextrin or a pharmaceutically acceptable salt thereof, but, as a rule, should not contain an impurity. Since there is no need for such a component in the present invention, a stabilized rocuronium preparation can be provided that is highly safe and free from the risk of causing renal dysfunction, etc.

The osmotic pressure of the rocuronium preparation of the present invention is not particularly limited, and may, for example, be from 250 to 1000 mosmol / kg or from 260 to 600 mosmol / kg.

The rocuronium preparation of the present invention can be obtained by, for example, mixing rocuronium with a buffer solution (and other components if necessary), but the production method is not particularly limited thereto.

The dosage form of the rocuronium preparation of the present invention is not particularly limited, but is usually a solution. Examples of the solution include parenteral preparations, such as injection preparations (for intravenous injection, intraarterial injection, intramuscular injection, subcutaneous injection, intradermal injection, intraperitoneal injection, intraspinal injection or epidural injection), ophthalmic preparations and intranasal preparations.

The route of administration of the rocuronium preparation of the present invention is not particularly limited, but in cases of parenteral administration by injection, it is preferable to appropriately choose the route of administration from the preferred routes of administration, including intravenous, intraarterial, subcutaneous, intradermal, intramuscular and intraperitoneal routes, depending on patient age, condition of the disease and / or other conditions.

The dose rate (dose administration) of the rocuronium preparation of the present invention varies depending on the age, gender and weight of the patient, the severity of the disease, etc., and thus is not specifically limited, but as a rule, the total daily dose of the active ingredient (namely, rocuronium) is typically from about 0.01 to 100 mg, and preferably from about 10 to 60 mg per adult. In addition, the dosage and route of administration vary depending on the age, gender and weight of the patient, the severity of the disease, etc. and thus is not particularly limited, but it is generally advisable that the total daily dose is administered once a day or as multiple (eg, from 2 to 4) fractional doses. In an exemplary method, rocuronium is administered intravenously at a dose of 0.6 mg / kg, and, as necessary, is additionally administered by continuous infusion at a dose of 0.1 to 0.2 mg / kg during surgery.

The rocuronium preparation of the present invention is preferably used for anesthesia, although this is not a necessary condition. The anesthetic is not particularly limited, and preferred examples thereof include an inhaled anesthetic and an intravenous anesthetic. The inhalation anesthetic is not particularly limited, and examples thereof include vaporizing inhalation anesthetics such as halothane, isoflurane, enflurane, methoxyflurane, sevoflurane and desflurane; and gaseous inhalation anesthetics such as ethylene, cyclopropane, diethyl ether, chloroform, nitric oxide and xenon. An intravenous anesthetic is not particularly limited, and examples thereof include propofol, midazolam, ketamine, tyletamine, thiopental, methohexital and etomidate. Propofol, midazolam, etc. are preferred. These anesthetics can be used individually or as a mixture of two or more of their types. These anesthetics may be commercially available products.

As described above, the rocuronium preparation of the present invention is highly stable. For example, after storage of a rocuronium preparation at 40 ° C for 3 months, the level of the resulting concomitant rocuronium impurity C is extremely low and is 2.5% or less (for example, from 0 to 2.3%), preferably 2% or less (for example , from 0.1 to 1.8%), more preferably about 1.5% or less (for example, from 0.2 to 1.3%). It is also possible to reduce the formation of concomitant rocuronium impurities C to 1% or less (for example, from 0.1 to 0.8%).

In addition, after storage of the rocuronium preparation at 40 ° C for 6 months, the level of the accompanying rocuronium impurity C may be 5% or less (for example, from 0 to 4.9%), preferably 4% or less (for example, from 0 01 to 3.9%), more preferably about 3% or less (for example, from 0.1 to 2.9%).

When the level of formation of concomitant rocuronium impurity C is 5% or less, the rocuronium preparation is evaluated as a pharmaceutical preparation stored at room temperature. Here, room temperature means from 1 to 30 ° C (Japanese Pharmacopoeia).

Thus, the rocuronium preparation of the present invention has excellent stability, and the level of the accompanying rocuronium impurity C after 3 months of storage can be reduced to a much lower level than 5%, which is the boundary value between stored and not stored at room temperature. Even after prolonged (6-month) storage, the level of education can still be lower than 5%, demonstrating that the drug can be stored at room temperature.

The accompanying impurity C is a major degradation product of rocuronium, and is an impurity described in the United States Pharmacopeia (USP) and in the European Pharmacopoeia (EP).

After thermal treatment of the rocuronium preparation at 121 ° C for 20 minutes, the level of impurity C associated with rocuronium is extremely low and is 0.7% or less (for example, from 0 to 0.6%), preferably 0.5% or less (e.g., from 0.01 to 0.45%), more preferably about 0.4% or less (e.g., from 0.05 to 0.35%). It is also possible to reduce the formation of impurity C associated with rocuronium to 0.3% or less (for example, from 0.01 to 0.3%).

In the present invention, the change in pH of the rocuronium preparation can also be minimized. For example, after storing a rocuronium preparation at 40 ° C for 6 months, the difference in pH (or its absolute value) before and after storage is as low as 0.25 or less (for example, from 0 to 0.22), preferably 0 2 or less (e.g., from 0 to 0.18), more preferably approximately 0.15 or less (e.g., from 0 to 0.12), and may also be 0.1 or less (e.g., from 0 to 0 , 08, preferably from 0 to 0.05, more preferably from 0 to 0.03). In addition, in cases where the rocuronium preparation is thermally treated at 121 ° C for 20 minutes, the difference in pH before and after thermal exposure can be selected from similar ranges.

Thus, in the present invention, an extremely high stability rocuronium preparation can be obtained by adjusting the pH (as well as selecting the appropriate type of buffer solution and adjusting the concentration of the buffer solution). In this context, the present invention also relates to a method for increasing or improving the stability of a rocuronium preparation by adjusting the pH of a rocuronium preparation containing rocuronium and a buffer solution to a predetermined range (e.g., 3.5 or less).

The rocuronium preparation of the present invention has a relatively low pH, but has almost no physiologically unfavorable effects. In particular, the rocuronium preparation of the present invention is able to prevent or reduce pain during injection and / or vascular irritation with high efficiency. In this context, the present invention also relates to a method for the prevention or reduction (relief) of pain during injection and / or vascular irritation (in particular, both pain during injection and vascular irritation) caused by rocuronium (in particular, caused by the administration of the drug rocuronium) , by adjusting the pH of the rocuronium preparation (an injectable rocuronium preparation) containing rocuronium and a buffer solution to a predetermined range (for example, 3.5 or less).

The present invention relates to embodiments in which the various structures described above are combined within the technical field of the present invention in such a way as to produce the effect of the present invention.

EXAMPLES

Further herein, the present invention will be illustrated in more detail by way of examples, but is not limited to them. Within the scope of technical thought, various modifications of the present invention can be made by those skilled in the art.

In the examples, various properties were determined or evaluated as follows.

pH

The measurement was carried out at from 20 to 30 ° C in accordance with the "determination of pH" in the Japanese Pharmacopoeia.

The level of formation of concomitant impurities (pollution) C

The measurement was carried out in accordance with the USP method for HPLC.

Vascular irritation

Before the introduction, at the injection site, each of six (three for each group) 14-week old male JW rabbits was removed using an electric hair clipper. Almost from the middle of the left posterior posterior vein, a 3-cm region was selected with fewer branches of small vessels (accumulation region), and both ends of this region were marked with an indelible marker, which was given the name of the central and peripheral hemostatic region. On the day of administration during anesthesia with sevoflurane (induction: 5%, maintenance: 3%), a point of 5 mm toward the peripheral hemostatic region was marked with an indelible marker, for use as an injection needle insertion site.

During administration, the clamp was attached to the peripheral portion of the injection needle insertion site to stop blood flow, and the injection needle was inserted from the injection needle insertion site, in the direction from the central region to the peripheral hemostatic region. A sample of the solution was injected in an amount of 0.025 ml, and it was confirmed that the local blood vessel was filled with an impurity sample. Then, the central hemostatic region was blocked with a clamp, 0.025 ml of a sample of the solution was additionally injected, and the peripheral hemostatic region was blocked with a clamp. Then, 0.2 ml of 2.5% wt./about. Sugammadex solution was quickly injected from the right ear vein. After 3 minutes of accumulation of the sample solution, the clamps were removed, and after the spontaneous respiration of the animal was confirmed, anesthesia was removed. For daily injection of a sample of the solution, the same accumulation area and the same injection needle insertion site was used whenever possible.

Number of doses: once a day for the next 8 days

Injection volume: 0.05 ml / area / day

The route of administration, the number of doses, the period of administration, and the volume of administration are selected in accordance with the method of Fukawa et al. (Nihon Yakurigaku Zasshi 71: 307-315, 1975).

Vascular irritation was evaluated once a day based on the macroscopic examination criterion presented below.

(Thrombus)

-: absence of a blood clot (0 mm)

+: small thrombus (1 to 4 mm)

++: medium-sized thrombus (5 to 14 mm)

+++: large blood clot (from 15 mm or more)

(Inflammation around the blood vessel (hyperemia, edema))

-: no change

+: mild inflammation (limited to 3 cm of the length of the hemostatic area)

++: moderate inflammation (1/3 of the center of the ear around the hemostatic region)

+++: severe inflammation (1/2 of the whole ear)

Pain during injection

Urethane was injected intraperitoneally to rats (8-week-old SD male rats, 11 animals in each group) at a dose of 1.1 g / kg, hairs around the treated area were removed and the skin was incised to expose blood vessels near the femoral artery. A PFA tube having a pre-tapered tip was injected approximately 2 cm into the caudal superficial epigastric artery in a manner against the natural flow of blood until it reached the area from which the femoral artery begins. A coaxial needle electrode (26 G) was inserted into the left posterior semitendinosus muscle. After the operation, the rats were kept at a temperature of approximately 37 ^° C. Prior to the introduction, the initial value was measured for 30 seconds. Each test solution in an amount of 50 μL was introduced through a PFA tube at a rate of 0.8 ml / min, and an electromyographic (EMG) measurement was performed 30 seconds after the start of administration. Each test solution was reintroduced every hour for 1 hour or longer. Before administration and after final administration, 1% propofol Maruishi (the name of the Japanese product) was administered to rats, and only those individuals that showed muscle contraction were used in the test. An analysis of the resulting electromyogram was performed using PowerLab (16sp, ADInstruments). Raw signals were cleaned and integrated to provide quantitative data (μV⋅s). The results are presented as percentages relative to the value before the introduction, taken as 100%.

Example 1

0.06 g of glycine, 0.67 g of sodium chloride, 30 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 100 ml.

The pH of the resulting preparation was 2.0. After this, the preparation was stored at 40 ° C for 3 months and 6 months, the pH and the level of formation of the concomitant rocuronium impurity C were determined. The pH was 2.0 in both cases (after 3 months of storage and 6 months of storage), and the level of formation The concomitant rocuronium impurity C was 1.24% (after 3 months of storage) and 2.52% (after 6 months of storage).

Example 2

0.55 g of glycine, 0.50 g of sodium chloride, 30 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and then injection water was added to bring the volume to 100 ml.

The pH of the resulting preparation was 3.0. After that, the drug was stored at 40 ° C for 3 months and 6 months, and the pH and the level of formation of concomitant rocuronium impurity C. were determined. The pH was 3.0 in both cases (after 3 months of storage and 6 months of storage), and levels the formation of concomitant rocuronium impurity C was 0.77% (after 3 months of storage) and 1.58% (after 6 months of storage).

Reference example 1

4.58 g of glycine, 30 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 100 ml.

The pH of the resulting preparation was 4.0. After that, the preparation was stored for 3 months and 6 months in the same manner as in Example 1, the pH was determined and the level of formation of concomitant rocuronium impurity C. The pH was 4.0 in both cases, and the levels of formation of concomitant rocuronium impurity C were 2.81 % (after 3 months of storage) and 5.36% (after 6 months of storage).

Comparative Example 1

A rocuronium preparation, the composition of which was identical to that of a commercial rocuronium preparation (acetate buffer, 0.15 M in relation to acetate ions, pH 4.0) was obtained in the same manner as in Example 1. After that, the preparation was stored for 3 months and 6 months in the same manner as in example 1, pH and determined the level of formation of concomitant rocuronium impurity C. The pH was 4.0 in both cases, and the levels of formation of concomitant rocuronium impurity C were 2.53% (after 3-month storage) and 5 , 46% (after 6 months of storage).

The results are summarized in table 1.

Table 1

At the time of receipt After 3 months of storage at 40 ^o C After 6 months of storage at 40 ^o C pH Hydrochloric acid concentration
(M) Glycine concentration
(M) The level of formation of concomitant rocuronium impurity C (%) pH The level of formation of concomitant rocuronium impurity C (%) pH Example 1 2.0 0,03 0.007 1.24 2.0 2,52 2.0 Example 2 3.0 0,073 0.77 3.0 1,58 3.0 Reference example 1 4.0 0.61 2.81 4.0 5.36 4.0 Comparative Example 1 4.0 - - 2,53 4.0 5.46 4.0

Example: Example

Ref. Example: Reference example

Comp. Example: Comparative Example

The results in Table 1 clearly demonstrate that by adjusting the pH to a predetermined range, the formation of the concomitant rocuronium impurity C decreases markedly and stability is increased compared to the case when the pH is 4.0.

In particular, a comparison of Example 1, Example 2 and Reference Example 1 showed amazing behavior, with a decrease in pH, the formation of rocuronium-related impurity C did not simply decrease, but began to increase. In addition, in these examples, the pH did not change, which demonstrated that the rocuronium preparations were extremely stable. Additionally, a comparison of Reference Example 1 and Comparative Example 1 showed that such stability was independent of the type of buffer solution.

Example 3

1.17 g of glycine, 0.37 g of sodium chloride, 45 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 100 ml.

The pH of the resulting preparation was 3.0. After the preparation was thermally treated at 121 ° C for 20 minutes, the pH and the level of formation of the concomitant rocuronium impurity C. were determined. The pH was 3.0 and the level of formation of the concomitant rocuronium impurity C was 0.28%.

Example 4

The preparation obtained in Example 2 (pH 3.0) was thermally treated in the same manner as in Example 3, and then the pH was determined and the formation of rocuronium-related impurity C. The pH was 3.0 and the formation of rocuronium-related impurity C was 0 , 23%.

Example 5

0.18 g of glycine, 0.64 g of sodium chloride, 20 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 100 ml.

The pH of the resulting preparation was 3.0. After the preparation was heat-treated in the same manner as in Example e3, the pH and the level of formation of the rocuronium concomitant impurity C. were determined. The pH was 3.1 and the formation level of the concomitant rocuronium impurity C was 0.23%.

Comparative Example 1

The preparation obtained in comparative example 1 (pH 4.0) was thermally treated in the same manner as in example 3, and then the pH and the level of formation of concomitant rocuronium impurity C. were determined. The pH was 4.0 and the level of formation of concomitant rocuronium impurity C was 0.75%.

The results are summarized in table 2.

table 2

At the time of receipt After heat treatment at 121 ° C for 20 minutes pH Hydrochloric acid concentration
(M) Glycine concentration
(M) The level of formation of concomitant rocuronium impurity C (%) pH Example 3 3.0 0,045 0.16 0.28 3.0 Example 4 0,03 0,073 0.23 3.0 Example 5 0.02 0,024 0.23 3,1 Comparative Example 1 4.0 - - 0.75 4.0

The results in Table 2 clearly demonstrate that in cases where the pH is a fixed value, despite the difference in the concentration of the buffer solution, the level of formation of impurity C accompanying rocuronium is markedly reduced. Even after heat treatment, the pH did not change much.

Reference example 2

0.90 g of sodium chloride, 15 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 100 ml.

The pH of the resulting preparation was 3.0. After the preparation was thermally treated, in the same manner as in Example 3, the pH was determined. The pH was 3.3.

The results of reference example 2 and example 5 are summarized in table 3.

Table 3

At the time of receipt After heat treatment at 121 ° C for 20 minutes pH Hydrochloric acid concentration
(M) Glycine concentration
(M) pH Example 5 3.0 0.02 0,024 3,1 Reference example 2 0.015 0 3.3

The results in Table 3 clearly demonstrate that, without buffering, the pH was much changed by heat treatment.

Example 6

0.55 g of glycine, 0.50 g of sodium chloride, 51 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 100 ml.

The pH of the resulting preparation was 2.5. After the preparation was heat-treated, in the same manner as in Example 3, the pH was determined and the level of formation of concomitant rocuronium impurity C. The pH was 2.5 and the level of formation of concomitant rocouronium impurity C was 0.10%.

Example 7

0.55 g of glycine, 0.50 g of sodium chloride, 38 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 100 ml.

The pH of the resulting preparation was 2.8. After the preparation was heat-treated, in the same manner as in Example 3, the pH was determined and the level of formation of concomitant rocuronium impurity C. The pH was 2.8 and the level of formation of concomitant rocouronium impurity C was 0.14%.

Example 8

0.55 g of glycine, 0.50 g of sodium chloride, 27 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 100 ml.

The pH of the resulting preparation was 3.2. After the preparation was heat-treated, in the same manner as in Example 3, the pH was determined and the level of formation of concomitant rocuronium impurity C. The pH was 3.2 and the level of formation of concomitant rocouronium impurity C was 0.27%.

Example 9

0.55 g of glycine, 0.50 g of sodium chloride, 21 g of 0.1 M HCl and 1.0 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 100 ml.

The pH of the resulting preparation was 3.5. After the preparation was heat-treated, in the same manner as in Example 3, the pH was determined and the level of formation of concomitant rocuronium impurity C. The pH was 3.5 and the level of formation of concomitant rocouronium impurity C was 0.31%.

The results are summarized in table 4. In table 4, the results of example 4 and comparative example 1, which were already demonstrated in table 2, are presented together for reference.

Table 4

At the time of receipt After heat treatment at 121 ° C for 20 minutes pH Hydrochloric acid concentration
(M) Glycine concentration
(M) The level of formation of concomitant rocuronium impurity C (%) pH Example 6 2,5 0,051 0,073 0.10 2,5 Example 7 2,8 0,038 0.14 2,8 Example 4 3.0 0,03 0.23 3.0 Example 8 3.2 0,027 0.27 3.2 Example 9 3,5 0,021 0.31 3,5 Comparative Example 1 4.0 - - 0.75 4.0

The results in Table 4 clearly demonstrate that in cases where the pH is in a predetermined range, despite differences in pH, the formation of rocuronium-related impurity C is markedly reduced. In addition, no significant pH change was observed, i.e. pH change is markedly reduced.

Example 10

15 g of 0.1 M hydrochloric acid, 0.45 g of sodium chloride, 0.42 g of potassium hydrogen phthalate and 0.50 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 50 ml.

The pH of the resulting preparation was 3.0. After the preparation was heat-treated, in the same manner as in Example 3, the pH was determined and the level of formation of concomitant rocuronium impurity C. The pH was 3.0 and the level of formation of concomitant rocouronium impurity C was 0.25%.

Example 11

0.45 g of sodium chloride, 0.34 g of citric acid hydrate, 2.46 g of 0.1 M sodium hydroxide solution and 0.50 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 50 ml

The pH of the resulting preparation was 3.0. After the preparation was heat-treated, in the same manner as in Example 3, the pH was determined and the level of formation of concomitant rocuronium impurity C. The pH was 3.0 and the level of formation of concomitant rocuronium impurity C was 0.19%.

Example 12

0.45 g of sodium chloride, 0.23 g of tartaric acid, 2.50 g of 0.1 M sodium hydroxide solution and 0.50 g of rocuronium bromide were dissolved in water for injection, and water for injection was additionally added to bring the volume to 50 ml

The pH of the resulting preparation was 3.0. After the preparation was heat-treated, in the same manner as in Example 3, the pH was determined and the level of formation of concomitant rocuronium impurity C. The pH was 3.0 and the level of formation of concomitant rocuronium impurity C was 0.28%.

The results are summarized in table 5. In table 5, the results of comparative example 1, which were already presented in table 2, are presented together for reference.

Table 5

At the time of receipt After heat treatment at 121 ° C for 20 minutes pH Buffer solution The level of formation of concomitant rocuronium impurity C (%) pH Example 10 3.0 Hydrochloric acid-potassium phthalate 0.25 3.0 Example 11 Citric Acid Sodium Hydroxide 0.19 3.0 Example 12 Tartaric Acid Sodium Hydroxide 0.28 3.0 Comparative Example 1 4.0 Acetic Acid Sodium Acetate 0.75 4.0

The results in Table 5 clearly demonstrate that in cases where the pH is in a predetermined range, despite the differences in the type of buffer solution, the level of impurity C associated with rocuronium after heat treatment is markedly reduced, and the pH change is also markedly reduced.

Assessment of vascular irritation

The rocuronium preparation obtained in Example 6 (pH 2.5) and the commercial rocuronium preparation (trade name: ESLAX (registered trademark) intravenously 50 mg / 5.0 ml, acetate buffer solution, 0.15 M in relation to acetate ions, pH 4.0) (Comparative Example 2) were separately evaluated for vascular irritation.

The results are presented in table 6.

Table 6

Getting ID
No. results Time after administration (day) 0 1 2 3 4 five 6 7 8 Example 6 1 Thrombus - - - - - - - - - Inflammation - - - - - - - - - 2 Thrombus - - - - - - - - - Inflammation - - - - - - - - - 3 Thrombus - - - - - - - - - Inflammation - - - - - - - - - Reference Example 2 4 Thrombus - - - - - - - - - Inflammation - - - - - - - - - five Thrombus - - - - - - - - + Inflammation - + - - - - - - - 6 Thrombus - - - - - - - - - Inflammation - - - - - - - - -

The results in table 6 clearly demonstrate that although the pH is lower than the pH in comparative example 2 as a commercial product, vascular irritation was not observed. Thus, in the present invention, the stability of the rocuronium preparation is increased without causing irritation of the blood vessels.

Injection pain assessment

The rocuronium preparation obtained in Example 2 (pH 3.0), the rocuronium preparation obtained in Example 6 (pH 2.5) and Comparative Example 2 were separately evaluated for injection pain.

The results are presented in table 7 and in FIG. 1.

Table 7

Getting Integrated EMG
(percentage relative to value before administration) % Standard error Example 2 104.8 3.8 Example 6 167.9 29.5 Saving example 2 309.0 51,2

The results in table 7 clearly demonstrate that the rocuronium preparations of examples 2 and 6, compared with the commercial product, significantly reduced the pain during injection to a statistically significant difference. As a result, it was found that the present invention relates to a rocuronium preparation, which has increased stability and does not cause pain during injection.

APPLICABILITY IN INDUSTRY

The present invention increases the stability (storage stability, etc.) of a rocuronium preparation suitable as a muscle relaxant or the like.

Claims (11)

1. An injection preparation of rocuronium in liquid form containing rocuronium and a buffer solution and having a pH of 3.5 or less, where the concentration of the buffer solution is from 0.015 to 0.8 M. 2. An injectable rocuronium preparation according to claim 1, having a pH of from 2.5 to 3.5. 3. An injection preparation of rocuronium according to claim 1 or 2, having a pH of from 2.8 to 3.2. 4. Injection drug rocuronium according to any one of paragraphs. 1-3, where the buffer solution is at least one species selected from formate buffer solution, acetate buffer solution, citrate buffer solution, tartrate buffer solution, phthalate buffer solution, phosphate buffer solution, citric acid and phosphate and glycine buffer solution buffer solution. 5. Injectable drug rocuronium according to any one of paragraphs. 1-4, where the buffer solution is at least one species selected from a buffer solution based on citric acid and sodium hydroxide, a buffer solution based on tartaric acid and sodium hydroxide, a buffer solution based on potassium hydrophthalate and hydrochloric acid. 6. The injection drug rocuronium according to any one of paragraphs. 1-5, where the buffer solution is at least one species selected from a buffer solution based on citric acid and sodium hydroxide, a buffer solution based on tartaric acid and sodium hydroxide, a buffer solution based on potassium hydrophthalate and hydrochloric acid, and where the concentration of the buffer the solution is from 0.015 to 0.5 M. 7. Injectable drug rocuronium according to any one of paragraphs. 1-6, in which the level of concomitant rocuronium impurity C formed after 6-month storage at 40 ° C is 5% or less and which prevents or reduces both pain during injection and vascular irritation caused by the injection drug rocuronium. 8. Injectable rocuronium preparation according to any one of paragraphs. 1-7, which is stored at room temperature. 9. A method of increasing or improving the stability of an injectable rocuronium preparation by adjusting the pH of the rocuronium preparation in liquid form containing rocuronium and a buffer solution to 3.5 or less, where the concentration of the buffer solution is from 0.015 to 0.8 M. 10. A method for preventing or reducing pain during injection and vascular irritation caused by the rocuronium injectable preparation by adjusting the pH of the injectable rocuronium preparation in liquid form containing rocuronium and a buffer solution to 3.5 or less, where the concentration of the buffer solution is from 0.015 to 0 , 8 M. 11. The method according to p. 9 or 10, where the specified drug rocuronium can be stored at room temperature.

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