KR100405161B1 - Pharmaceutical composition for intramuscular injection containing loxoprofen - Google Patents

Abstract

The present invention relates to an intramuscular injection composition containing loxoprofen of formula (1) or a pharmaceutically acceptable salt thereof having excellent anti-inflammatory analgesic effect as an active ingredient:

[Formula 1]

Description

Pharmaceutical composition for intramuscular injection containing loxoprofen}

The present invention relates to a novel formulation of loxoprofen. More specifically, the present invention relates to an intramuscular injection formulation containing roxofene or a pharmaceutically acceptable salt thereof having excellent anti-inflammatory analgesic effect as an active ingredient.

Roxopropene (chemical name: 2- [4- (2-oxocyclopentyl) phenyl] propionic acid) is a propion-based nonsteroidal anti-inflammatory analgesic agent (NSAID) represented by the following general formula (1), which is mainly a sodium salt of roxofene It is used in the form ie loxoprofen Na:

Loxoprofen Sodium is effective for chronic arthritis, deformed arthrosis, low back pain, periarthritis of the shoulder, and systolic syndrome. In addition, it is known to be effective for pain after surgery, post-traumatic and post-treatment. It is used.

This drug has less gastrointestinal disorders than other propionic acid nonsteroidal anti-inflammatory drugs, but when taken for a long time, it causes side effects such as gastrointestinal disorders and peptic ulcer. Therefore, it has recently been developed as a transdermal drug such as a sustained release transdermal patch. Research is being conducted [PCT / JP1997 / 02936, Korean Patent Application No. 98-41351 (October 1, 1998), US Patent No. 4,740,374 (April 26, 1988), PCT / WO95 / 16440 (1995. 6. 22), Korean Patent Application No. 96-38430 (September 5, 1996). However, in the case of such transdermal drugs, there are aspects that can reduce side effects or discomfort associated with the administration to patients who have difficulty in oral administration or require long-term oral administration, but also like polymers such as conventional transdermal patches. Since it is used as a transdermal absorption agent, it may cause allergic symptoms such as rash or itching due to prolonged skin (transdermal) adhesion, and may cause other side effects such as discomfort in the activity of the patient. In addition, although the rate of absorption of the drug through the skin can be controlled, depending on the pain area and the individual's constitution, the transdermal administration rate or absorption of the drug is different, so it takes a long time to obtain the expected therapeutic effect. The disadvantage is that it can not be used for emergency patients.

On the other hand, lysopropene sodium has a different mechanism of action from the well-known propion-based nonsteroidal anti-inflammatory drugs, ketoprofen or ibuprofen, and the prostaglandin, a substance that causes inflammation and pain. By suppressing biosynthesis, excellent anti-inflammatory analgesic effect is shown. In other words, the drug is a pro-drug that is metabolized by ketone reductase in the body upon oral administration, resulting in a trans-OH metabolite, namely 2- [para- (trans-2-hydroxycyclopentyl) phenyl] It becomes propionic acid, and this metabolite shows excellent anti-inflammatory analgesic effect through inhibitory activity against cyclooxygenase, a prostaglandin synthase [Matsuda et. al., Japanese Journal of Inflammation, Vol. 2, No. 3, Summer, pp 263-266 (1983). Ketone-reductase is mainly present in the liver or kidney [Tanaka et. al., Japanese Journal of Inflammation, Vol. 3, No. 2, Spring, pp151-155 (1983)] It shows its anti-inflammatory effect by metabolizing roxofene sodium into trans-OH metabolite during oral administration and shows strong anti-inflammatory analgesic effect. It is known to represent (US Pat. No. 4,740,374 (April 26, 1988)). For this reason, oral preparations such as tablets using roxofene or a pharmaceutically acceptable salt thereof as an active ingredient have been commercialized and widely sold (Loxonin or Loxfen), and recently, There are studies on external preparations, namely, transdermal patch or patch, but there has been no report on intramuscular injection of the drug.

As mentioned above, in the case of the previously developed orally administered loxoprofen, it is difficult to use in patients with severe or difficult gastrointestinal disorders, and a lot of researches are being carried out through transdermal absorption. In the case of such a case, the development has not been completed yet, and even if it is developed as an external preparation, many supplements such as absorption accelerators for skin penetration of the drug must be used, which may result in other side effects such as skin rashes. Being attached to the body can cause a lot of inconvenience, including behavioral restrictions. In particular, since most of the inflammation and pain symptoms occur in the joint area, the patch-type transdermal absorption topical preparations are expected to have a lot of difficulties in continuously displaying the desired medicinal effects such as the external preparations easily come off from the skin by the movement of the joints during the activity after attachment. .

Therefore, there has been a great demand for the development of new roxofene formulations that can be applied to patients who have difficulty in oral administration as well as solve problems associated with transdermal administration.

Therefore, the present inventors have conducted continuous research to develop a novel roxofene penetrate formulation, and as a result, it is converted to trans-OH metabolite by ketone reductase in the skin as well as in the muscle, and excellent anti-inflammatory pain. New and surprising facts can be found. On the basis of this fact, the present inventors can not only apply the intramuscular injection of Roxoprofen to patients with difficulty in oral administration, but also obtain an anti-inflammatory effect equivalent to or more with a small amount of drugs than when administered orally. It was confirmed that the effect can be obtained at the same time to solve the side effects accompanying the time, to complete the present invention.

1 is a comparative distribution curve of drug blood concentrations of roxofene tablets and intramuscular injections.

The present invention relates to an intramuscular injection composition containing Roxoprofen of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

In the composition of the present invention, the pharmaceutically acceptable salt of roxofene is preferably the sodium salt of roxofene.

Hereinafter, the present invention will be described in more detail.

As described above, roxofene or a pharmaceutically acceptable salt thereof is absorbed as an inactive substance in the gastrointestinal tract upon oral administration, converted to trans-OH metabolites by ketone reductase in the liver or kidney, and also in the skin during transdermal administration. It has been reported to convert to trans-OH metabolites by reductase, which shows an excellent anti-inflammatory analgesic effect. However, the present inventors can exhibit an excellent anti-inflammatory analgesic effect by converting the drug into trans-OH metabolites by ketone reductase not only in the skin but also in the muscle, and in particular, by administering the drug by intramuscular injection, For example, it was confirmed that even an amount equal to or greater than 1/2 to 2/3 of the tablet dosage can be achieved. In addition, since the anti-inflammatory analgesic effect is the first required effect in the treatment of pain patients, it was confirmed that through the development of such intramuscular injections can also obtain a fast-acting effect that meets the purpose.

Therefore, the present invention is inconvenient in the use of oral preparations, such as tablets, such as restrictions on use for patients with difficulty in oral administration, causing side effects such as gastrointestinal disorders during long-term administration, and external preparations such as transdermal patches. And intramuscular formulations of loxoprofen, which may have been constrained for use due to skin allergy or the like or may be conveniently used, especially for patients expecting fast drug efficacy.

Injectable intramuscular injection of loxoprofen according to the present invention can be prepared by a suitable prescription, in order to ensure product stability according to the distribution of the injection formulation, pH by using a buffer solution such as an aqueous solution or phosphate that can be used as an injection By adjusting, it can be prepared into injections which are very stable both physically and chemically.

More specifically, the composition of the present invention is dissolved in lysopropene or a pharmaceutically acceptable salt thereof in water for injection with a stabilizer or dissolution aid and then sterilized by sterilization, in particular, by autoclaving or aseptic filtration. Can be prepared. As the water for injection, distilled water for injection or buffer for injection, for example, a phosphate buffer solution in the range of pH 3.5 to 7.5 or sodium dihydrogen phosphate (NaH ₂ PO ₄ ) -citric acid buffer solution can be used. The phosphates used may be in the form of sodium or potassium salts or in the form of anhydrides or hydrates, and in the form of citric acid or anhydrides or hydrates.

Meanwhile, the stabilizer used in the present invention includes sodium pyrosulfite, sodium bisulfite (NaHSO ₃ ), sodium metabisulfite (Na ₂ S ₂ O ₃ ) or ethylenediaminetetraacetic acid, Dissolution aids include bases such as sodium hydroxide (NaOH), sodium bicarbonate (NaHCO ₃ ), sodium carbonate (NaCO ₃ ) or potassium hydroxide (KOH), or acids such as hydrochloric acid (HCl) or acetic acid (CH ₃ COOH). will be.

The composition according to the invention is preferably a liquid composition in the range of pH 3.5 to 7.5, or a powder composition prepared by lyophilization after sterilization, the concentration of the active ingredient is preferably in the range of 2 to 20%.

The present invention will be described in more detail with reference to the following examples, which, however, are not intended to limit the scope of the invention in any way.

Preparation of Injectables

Example 1:

The intramuscular injection was made by dissolving roxofene sodium and sodium pyrosulphite in distilled water for injection and then sterilizing by autoclaving in a 1 ml ampoule (Table 1).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.2% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Example 2:

Muscle injection was prepared by dissolving roxofene sodium and sodium sulfite in distilled water for injection, adding dilute hydrochloric acid to a pH of 6, and sterilizing the solution by sterilization by autoclaving or aseptic filtration in 1 ml ampoule. Table 2).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.1% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml Dilute hydrochloric acid Appropriate (adjust with pH 6)

Example 3:

After dissolving roxofene sodium and sodium pyrosulphite in distilled water for injection, dilute hydrochloric acid was added to pH 5 and sterilized by autoclaving or aseptic filtration into a 1 ml ampoule Prepared (Table 3).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.1% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml Dilute hydrochloric acid Dose (adjusted to pH 5)

Example 4:

After dissolving roxofene sodium and sodium metabisulfite in distilled water for injection, dilute hydrochloric acid was added to pH 4, and the solution obtained by sterilization by high-temperature autoclaving or aseptic filtration was filled into 1 ml ampoules to prepare an intramuscular injection. It was.

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium metabisulfite (Na ₂ S ₂ O ₅ ) 0.2% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml Dilute hydrochloric acid Dose (adjusted to pH 4)

Example 5:

Potassium dihydrogen phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare a phosphate buffer at pH 6.5. Muscle injection was prepared by dissolving roxofene sodium and sodium pyrosulphite in the prepared phosphate buffer and then sterilizing the solution by autoclaving or aseptic filtration in 1 ml ampoule (Table 5).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.2% (W / V) Potassium Dihydrogen Phosphate (KH ₂ PO ₄ ) 0.68% (W / V) Sodium Hydroxide (NaOH) 0.06% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Example 6:

Sodium dihydrogen phosphate, dihydrate and citric acid were dissolved in distilled water for injection to prepare a sodium dihydrogen phosphate-citric acid buffer solution of pH 5.4. Muscle injection was prepared by dissolving roxofene sodium and sodium pyrosulphite in the prepared buffer and then sterilizing the solution by sterilization by autoclaving or aseptic filtration in a 1 ml ampoule (Table 6).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.2% (W / V) Sodium dihydrogen phosphate, dihydrate (NaH ₂ PO ₄ 12H ₂ O) 1.45% (W / V) Citric acid 0.53% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Example 7:

Potassium dihydrogen phosphate and anhydrous sodium dihydrogen phosphate were dissolved in distilled water for injection to prepare a phosphate buffer at pH 6.8. After dissolving roxofene sodium and sodium pyrosulphite in the prepared buffer solution, the solution obtained by sterilization by autoclaving was filled in 1 ml ampoule to prepare a muscle injection (Table 7).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.2% (W / V) Potassium Dihydrogen Phosphate (KH ₂ PO ₄ ) 0.34% (W / V) Anhydrous Sodium Dihydrogen Phosphate (Na ₂ HPO ₄ ) 0.34% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Example 8:

Potassium dihydrogen phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare a phosphate buffer at pH 7.0. After dissolving sodium roxofene and sodium pyrosulphite in the prepared buffer solution, the solution obtained by sterilization by autoclaving was filled in 1 ml ampoules to prepare a muscle injection (Table 8).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.2% (W / V) Potassium Dihydrogen Phosphate (KH ₂ PO ₄ ) 0.68% (W / V) Sodium Hydroxide (NaOH) 0.12% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Example 9:

Potassium dihydrogen phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare a phosphate buffer at pH 7.4. After dissolving sodium roxofene and sodium pyrosulphite in the prepared buffer solution, the solution obtained by sterilization by autoclaving was filled in 1 ml ampoules to prepare a muscle injection (Table 9).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.4% (W / V) Potassium Dihydrogen Phosphate (KH ₂ PO ₄ ) 0.68% (W / V) Sodium Hydroxide (NaOH) 0.16% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Example 10:

Muscle injection was prepared by dissolving roxofene sodium, sodium pyrosulphite and mannitol in distilled water for injection and then sterilizing by autoclaving in a 1 ml ampoule (Table 10).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.4% (W / V) Mannitol 5.0% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Preparation of Powder Injection

Example 11:

Sodium roxofene and mannitol were dissolved in distilled water for injection, followed by complete dissolution by addition of sodium pyrosulphite. The solution was sterile filtered and placed in a vial, lyophilized to prepare a dry powder product. In use, 1 ml of distilled water for injection, separately packaged, was added to this dry powder vial to completely dissolve and prepared as an intramuscular injection (Table 11).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.4% (W / V) Mannitol 20.0% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Example 12:

Potassium dihydrogen phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare a phosphate buffer at pH 6.5. Manitol, lysopropene sodium, and sodium pyrosulphite were completely dissolved in the prepared solution, aseptically filtered, put into a vial, and lyophilized to prepare a dry powder product. In use, 1 ml of distilled water for injection, separately packaged, was added to this dry powder vial to completely dissolve and prepared as a muscle injection (Table 12).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene sodium 6.81% (W / V) Sodium pyrosulphite 0.4% (W / V) Potassium Dihydrogen Phosphate (KH ₂ PO ₄ ) 20.0% (W / V) Sodium Hydroxide (NaOH) 0.06% (W / V) Mannitol 25.0% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Example 13:

The solution of lysopropene and sodium bicarbonate dissolved in distilled water for injection was adjusted to 1 ml and completely dissolved by addition of sodium pyrosulphite. The solution was sterile filtered and placed in a vial, lyophilized to prepare a dry powder product. In use, 1 ml of distilled water for injection, separately packaged, was added to this dry powder vial to completely dissolve and prepared as an intramuscular injection (Table 13).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene 6.25% (W / V) Sodium pyrosulphite 0.4% (W / V) Sodium bicarbonate (NaHCO ₃ ) 2.13% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Example 14:

The solution in which roxofene and sodium hydroxide were dissolved in distilled water for injection was adjusted to 1 ml and dissolved completely by addition of sodium pyrosulphite. The solution was sterile filtered and placed in a vial, lyophilized to prepare a dry powder product. In use, 1 ml of distilled water for injection, separately packaged, was added to this dry powder vial to completely dissolve and prepared as a muscle injection (Table 14).

Composition per ml of Roxoprofen intramuscular injection ingredient content Roxofene 6.25% (W / V) Sodium pyrosulphite 0.4% (W / V) Sodium Hydroxide (NaOH) 1.02% (W / V) Distilled water for injection Adjust the total liquid volume to 1 ml

Experimental Example 1 Comparative Test of Drug Blood Concentration of Loxoprofen Tablet and Intramuscular Injection Using Rat

The blood concentration of roxofene is determined as a control for the roxofene penetrate intramuscular injection prepared by the method of Example 1 and the like. It was measured using an SD rat.

The dose was administered orally once at a dose of 10 mg / kg for rats in the control group and a single intramuscular injection at a dose of 5 mg / kg in rats in the experimental group. Rat blood was collected in units of 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 120 minutes, and 180 minutes after drug administration and analyzed for blood drug concentrations. The results are expressed as blood concentration (µg / ml) versus time (min) of roxofene.

Comparison of Plasma Drug Concentrations of Loxoprofen Tablets and Intramuscular Injections Minutes Blood drug concentration in the experimental group (muscle injection) (㎍ / ㎖) Blood drug concentration of the control (tablet) (㎍ / ㎖) 2 4.0 4.1 5 4.5 5.5 10 5.6 5.8 20 6.5 7.4 60 5.4 6.5 120 4.1 5.0 180 2.8 3.7

As shown in Table 15, since the drug of the experimental group (muscle injection) was administered only 50% of the drug of the control group (tablet), the blood concentration was slightly lower, but the blood concentration of the drug was changed in the control group (tablet) and the experimental group. (Muscle injection) was confirmed to form a similar curve (see Fig. 1).

Experimental Example 2: Stability Test of Muscle Injection

Samples of the intramuscular injection of roxofene prepared by the method of Example 1 were collected at intervals of 1 week, 3 weeks and 4 weeks under storage conditions at room temperature, 50 ° C. and 60 ° C., respectively. Was measured, and the results are shown in Table 16.

Changes in Drug Content of Roxoprofen Muscle Injection Storage temperature Early 1 week later 3 weeks later 4 weeks later Room temperature (R.T) 100.1% 99.8% 99.7% 99.9% 50 ^o ℃ 99.6% 98.6% 99.5% 99.8% 60 ℃ 99.6% 100.1% 99.3% 98.9%

Changes in pH of Roxoprofen Intramuscular Injection Storage temperature Early 1 week later 3 weeks later 4 weeks later Room temperature (R.T) 6.46 6.43 6.43 6.42 50 ℃ 6.44 6.44 6.44 6.44 60 ℃ 6.44 6.44 6.44 6.45

As shown in Table 16, in the case of the loxoprofen intramuscular injection according to the present invention it was confirmed that the stability of the drug content and pH is kept constant without any change.

Experimental Example 3: Comparative test of foot edema of tablets and intramuscular injection of loxoprofen using rats

Experimental Animals: Male 6-week-old SD rats without specific pathogens

2) Test Substance and Drug Dose: An edema-inducing substance, 1% carrageenan lamda type IV (Sigma Co.), was injected subcutaneously into the plantar rat to induce foot edema. By intramuscular injection of lysopropene sodium, a 5 mg / 2 ml solution and a 10 mg / 10 ml solution were prepared using a phosphate buffer solution according to the method of Example 5, and the intramuscular administration was 5 mg / 2 ml / kg. At the dose, oral administration was administered at 10 mg / 10 mL / kg doses, respectively.

3) Test Methods and Formulas: After the reference point was marked on the ankle joint of the left hind paw of the rat, the foot volume before drug administration was measured using a HUGO Sacks Coulbourn. Twenty minutes after the test drug was administered by oral or intramuscular injection, a 1% carrageenan solution, an edema inducer, was injected subcutaneously in a 0.1 ml dose for each individual in the left hind paw. Two and a half hours after the edema-inducing substance, the volume of the foot was measured and the edema rate and edema inhibition rate were calculated by the following equation:

4) Evaluation Criteria: The variance analysis (ANOVA) of the drug-free edema inhibition rate was tested by variance analysis (ANOVA), and it was determined that edema was suppressed when the efficacy value was 0.05 or less (p <0.05).

5) Edema rate and edema inhibition test results: Table 17 shows the results of foot edema test.

Foot edema comparison test of roxofene tablets and intramuscular injection Test group Route of administration Drug dosage per weight Number of test animals Edema rate (%) Edema inhibition rate (%) Control Nonadministration - 4 horses 133.2 ± 8.3 - Roxofene sodium injection Intramuscular injection 5 mg / kg 4 horses 36.0 ± 18.8 ^* 73.0 Roxofene sodium tablets Oral administration 10 mg / kg 4 horses 31.7 ± 19.0 ^* 76.2

*: P <0.05 vs. Control group, edema rate was expressed as the mean ± standard deviation.

As shown in Table 17, the edema inhibition rate was 73.0% when intramuscularly administered loxoprofen sodium at 5 mg / kg dose, and the edema inhibition rate was 76.2% when administered orally at 10 mg / kg dose. In the case of oral administration, even when only 50% of the weight of the drug was administered, the edema inhibition rate was almost similar.

Experimental Example 4: Comparative test of analgesic efficacy of tablets of loxoprofen and intramuscular injection using mouse

Experimental Animals: Male 5-week-old ICR mice without specific pathogens

2) Test Substance and Drug Dose: Inject the roxofene sodium into the muscle using 5 mg / 2 ml solution and 10 mg / 10 ml solution using phosphate buffer solution according to the method of Example 5, etc. Administration was at a 5 mg / 2 ml / kg dose and oral administration at a 10 mg / 10 ml / kg dose, respectively. 20 minutes after administration of test substance, pain-causing substance was intraperitoneally administered 10% / kg of aqueous acetic acid in DW at 10 ml / kg dose to induce pain, and the number of writhing was measured at intervals of 10 minutes after 5 minutes. .

3) Analgesic efficacy test results: Table 18 shows the analgesic effect test results.

Analyzes of Analgesic Effects of Roxoprofen Tablets and Injections Test group Route of administration Drug dosage per weight Number of test animals Writhing Pain suppression rate (%) Control Nonadministration - 18 horses 35.6 ± 10.8 - Roxofene sodium injection Intramuscular injection 5 mg / kg 13 horses 16.5 ± 10.4 ^* 53.7 Roxofene sodium tablets Oral administration 10 mg / kg 15 horses 17.7 ± 8.0 ^* 64.0

*: P <0.05 vs. In the control group, the number of writhing was expressed as the mean ± standard deviation.

As shown in Table 18, the pain inhibition rate was 53.7% when intramuscularly administered loxoprofen sodium at 5 mg / kg dose, and the pain inhibition rate was 64.0% when orally administered at 10 mg / kg dose. In the case of oral administration, even when only 50% of the weight per drug is administered, the pain suppression rate is almost similar.

The intramuscular injection of loxoprofen according to the present invention is applicable not only to patients who have difficulty in oral administration, but also can obtain an anti-inflammatory or analgesic effect equal to or more than a small amount of the drug compared to oral administration, and eliminates side effects associated with transdermal administration. And at the same time you can get a quick effect.

Claims (12)

An intramuscular injection composition containing Roxoprofen of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1] The composition of claim 1, wherein the pharmaceutically acceptable salt of roxofene is the sodium salt of roxofene. The composition of claim 1, wherein the composition is prepared by dissolving roxofene or a pharmaceutically acceptable salt thereof in water for injection with a stabilizer or dissolution aid and then sterilizing. The composition according to claim 3, which is prepared by sterilization by high temperature autoclaving or aseptic filtration. The composition of claim 3 wherein the water for injection is distilled water for injection or buffer for injection. 6. The composition of claim 5, wherein the injectable buffer is a phosphate buffer in the range of pH 3.5-7.5 or sodium dihydrogen phosphate (NaH ₂ PO ₄ ) -citric acid buffer. The composition of claim 6 wherein the phosphate is in the form of sodium or potassium salts or in the form of anhydrides or hydrates, and the citric acid is in the form of anhydrides or hydrates. 4. The stabilizer of claim 3 wherein the stabilizer is selected from the group consisting of sodium pyrosulfite, sodium bisulfite (NaHSO ₃ ), sodium metabisulfite (Na ₂ S ₂ O ₃ ) and ethylenediaminetetraacetic acid Composition. 4. The dissolution aid according to claim 3 from the group consisting of sodium hydroxide (NaOH), sodium bicarbonate (NaHCO ₃ ), sodium carbonate (NaCO ₃ ), potassium hydroxide (KOH), hydrochloric acid (HCl) and acetic acid (CH ₃ COOH). Composition selected. The liquid formulation according to claim 3, which has a pH in the range of 3.5 to 7.5. The powder composition of claim 3, prepared by lyophilization after sterilization. The composition of claim 1 wherein the concentration of the active ingredient is in the range of 2-20%.