KR102427941B1 - Injectable formulation with enhanced stability containing ibuprofen and afginine - Google Patents

Abstract

The present invention contains ibuprofen and arginine, and based on 400 parts by weight of the ibuprofen, the content of arginine is 344 parts by weight to 500 parts by weight, and the pH is 6.5 to 8.5. it's about

Description

Injection formulation with improved stability containing ibuprofen and arginine {INJECTABLE FORMULATION WITH ENHANCED STABILITY CONTAINING IBUPROFEN AND AFGININE}

The present invention relates to an injectable formulation containing ibuprofen and arginine with improved stability.

Ibuprofen [2-(4-isobutylphenyl)-propionic acid] is a drug well known as an analgesic, antipyretic and anti-inflammatory drug, currently under the trade names Motrin®, Advil® and Nuprin®. It is marketed as a formulation for oral administration for the treatment of pain, inflammation and fever.

Ibuprofen can be the two enantiomers, (R)-ibuprofen or (S)-ibuprofen, and although (S) enantiomer is biologically active, in vivo the (R) enantiomer is in the active form ( Since it is converted to S), most of the preparations contain a racemic mixture ((RS)-ibuprofen).

Although ibuprofen has many advantages over other analgesics such as aspirin and acetaminophen, its solubility in water is very poor. Ibuprofen is a monoprotic acid with a pKa=4.4. Therefore, its solubility is closely related to pH and can vary from 78 μg/mL at acidic pH to 291 mg/mL at basic pH. Therefore, there is a problem in that it is difficult to develop a specific dosage form of ibuprofen, particularly a formulation for injection.

Korean Patent Publication No. 10-0851679 (2008.08.05.)

The present invention contains ibuprofen and arginine, and the content of arginine is 344 parts by weight to 500 parts by weight based on 400 parts by weight of the ibuprofen, and the pH is 6.5 to 8.5. would like to provide

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

The present invention provides an injectable formulation with improved stability, characterized in that it contains ibuprofen and arginine, the content of arginine is 344 parts by weight to 500 parts by weight based on 400 parts by weight of the ibuprofen, and the pH is 6.5 to 8.5 to provide.

The ibuprofen may be (RS)-ibuprofen or (S)-ibuprofen.

The arginine may be L-arginine or D-arginine.

The injectable formulation may further include sodium chloride or glucose as an isotonic agent.

The injectable formulation may have a pH of 6.5 to 8.5, an osmolality of 0.1 osmol/kg to 1.0 osmol/kg, and a specific gravity of 1.0 g/mL to 2.0 g/mL.

After the injection formulation is stored under accelerated conditions (temperature of 40° C. and relative humidity of 75%) for 4 weeks, the change in the content of ibuprofen may be within 12% by weight.

In one embodiment of the present invention, the method comprises adding arginine and ibuprofen to water for injection in order, based on 400 parts by weight of the ibuprofen, the content of the arginine is 344 parts by weight to 500 parts by weight, and the pH is 6.5 It provides a method for preparing an injectable formulation with improved stability, characterized in that it is to 8.5.

The injectable formulation containing ibuprofen and arginine according to the present invention and having improved stability, based on 400 parts by weight of the ibuprofen, contains 344 parts by weight to 500 parts by weight (preferably, 376 parts by weight to 408 parts by weight). ), and it is characterized in that the pH is 6.5 to 8.5, and through the high content of arginine and pH adjustment, the main component is not precipitated and thus a precipitate may not be generated. In addition, it has the advantage of excellent stability of the formulation for injection under accelerated conditions.

In addition, the injectable formulation is in a form in which the ibuprofen is pre-diluted according to the usage and dosage, and thus has the advantage of excellent convenience and economical efficiency.

1 shows whether the ibuprofen dilutions prepared in Examples 1 to 10 and Comparative Examples 1 to 4 were precipitated.

The present inventors have found that, in preparing dilute ibuprofen, by containing arginine in a high content that can act simultaneously as a solubilizer and a pH adjuster, the stability of the injectable formulation under accelerated conditions is improved without precipitation of the main component (that is, without the occurrence of precipitates). It was confirmed that it could be improved, and the present invention was completed.

Hereinafter, the present invention will be described in detail.

The present invention provides an injectable formulation with improved stability, characterized in that it contains ibuprofen and arginine, the content of arginine is 344 parts by weight to 500 parts by weight based on 400 parts by weight of the ibuprofen, and the pH is 6.5 to 8.5 to provide.

First, the preparation for injection according to the present invention contains ibuprofen as a main component. The ibuprofen may include ibuprofen represented by the following Chemical Formula 1, and the ibuprofen represented by the following Chemical Formula 1 may be (RS)-ibuprofen or (S)-ibuprofen. In this case, since the salt form of ibuprofen represented by the following formula (1) is excluded, it has the advantage that isolation thereof is not required.

[Formula 1]

The concentration of ibuprofen in the injectable formulation may be determined in consideration of usage and dose, and may be 0.1 mg/mL to 10 mg/mL, preferably 0.4 mg/mL to 4 mg/mL, but is not limited thereto. does not

Next, the preparation for injection according to the present invention contains arginine for dissolving ibuprofen, which has low solubility in water, and at the same time adjusting the pH. The arginine may be represented by the following Chemical Formula 2, and the arginine represented by the following Chemical Formula 2 may be L-arginine or D-arginine.

[Formula 2]

Based on 400 parts by weight of the ibuprofen, the content of arginine is characterized in that it is 344 parts by weight to 500 parts by weight, and preferably 376 parts by weight to 408 parts by weight, but is not limited thereto. As such, the high content of arginine can smoothly dissolve ibuprofen and adjust the pH at the same time, so it has the advantage of excellent stability of the injectable formulation under accelerated conditions. In particular, as the content of arginine increases, the stability of the injectable formulation under accelerated conditions can be further improved. However, when the content of arginine is too high, there is a problem in that the stability of the injectable formulation is rather greatly lowered due to the increase in cationicity by the arginine molecule.

Accordingly, the concentration of the arginine in the injection formulation may be 0.344 (w/v)% to 0.500 (w/v)%, preferably 0.376 (w/v)% to 0.408 (w/v)% However, the present invention is not limited thereto.

Meanwhile, in order to set the concentrations of the ibuprofen and the arginine in the preparation for injection according to the present invention as described above, it is necessary to be diluted in water for injection. At this time, as an isotonic agent in the water for injection, sodium chloride or glucose may be additionally included. Specifically, 0.1 to 2.0% physiological saline injection, 1 to 10% glucose injection, or lactose-added ring gel may be used as the water for injection. .

In addition, the pH of the injectable formulation according to the present invention may be 6.5 to 8.5, and the pH is preferably 6.5 to 7.5, but is not limited thereto. Hydrochloric acid and the like may be further included to adjust the pH. At this time, when the pH is less than 6.5, there is a problem due to precipitation of the main component (ie, precipitate generation), and when the pH exceeds 8.5, there is a problem in that the generation and growth of microorganisms cannot be inhibited.

In addition, the osmolality of the injectable formulation according to the present invention may be 0.1 osmol/kg to 1.0 osmol/kg.

In addition, the specific gravity of the injection formulation according to the present invention may be 1.0 g / mL to 2.0 g / mL.

In addition, the injectable preparation according to the present invention has the advantage of excellent stability of the injectable preparation under accelerated conditions without precipitation of the main component (ie, without the occurrence of precipitates).

Specifically, after storing the injection formulation under accelerated conditions (temperature of 40° C. and relative humidity of 75%) for 4 weeks, the change in the content of ibuprofen may be within 12% by weight, and within 3% by weight. Preferably, it is more preferably within 1% by weight, but is not limited thereto.

In addition, the present invention includes the step of sequentially adding arginine and ibuprofen to water for injection, and based on 400 parts by weight of the ibuprofen, the content of arginine is 344 parts by weight to 500 parts by weight, and the pH is 6.5 to 8.5. It provides a method for preparing an injectable formulation with improved stability, characterized in that.

As described above, the injectable formulation containing ibuprofen and arginine according to the present invention and having improved stability is based on 400 parts by weight of the ibuprofen, and the content of the arginine is 344 parts by weight to 500 parts by weight (preferably, 376 parts by weight). parts to 408 parts by weight), and characterized in that the pH is 6.5 to 8.5, and through high content of arginine and pH adjustment, the main component is not precipitated, so that a precipitate may not be generated. In addition, it has the advantage of excellent stability of the formulation for injection under accelerated conditions.

In addition, the injectable formulation is in a form in which the ibuprofen is pre-diluted according to the usage and dosage, and thus has the advantage of excellent convenience and economical efficiency.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

Examples 1 to 10 and Comparative Examples 1 to 4: Preparation of ibuprofen dilutions

Injection formulations were prepared with the compositions of Tables 1 and 2 below. Specifically, L-arginine and (RS)-ibuprofen were added to water for injection, and sodium chloride or glucose as an isotonic agent was added in order and then dissolved. Then, as a pH adjuster, by adding hydrochloric acid to adjust the pH, a diluted ibuprofen stock having a final volume of 100 mL was prepared.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 chief ingredient (RS)-Ibuprofen
(mg) 400 400 400 400 400 400 400 400 400 400 Dissolution
supplements
(pH regulator) L-Arginine
(mg) 344 376 408 440 472 344 376 408 440 472 isotonic agent sodium chloride
(mg) 900 900 900 900 900 - - - - - glucose
(mg) - - - - - 5000 5000 5000 5000 5000 pH
modifier Hydrochloric acid
(mg) appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount solvent water for injection
(mL) appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount pH 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 Osmotic pressure (osmol/kg) 0.313 0.315 0.318 0.322 0.323 0.371 0.372 0.375 0.376 0.378 Specific gravity (g/mL) 1.0 1.0 1.0 1.0 1.0 1.1 1.1 1.1 1.1 1.1

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 chief ingredient (RS)-Ibuprofen
(mg) 400 400 400 400 Solubilizer (pH adjuster) L-Arginine
(mg) 312 312 376 376 isotonic agent sodium chloride
(mg) 900 - 900 900 glucose
(mg) - 5000 - - pH adjuster Hydrochloric acid
(mg) appropriate amount appropriate amount appropriate amount appropriate amount solvent water for injection
(mL) appropriate amount appropriate amount appropriate amount appropriate amount pH - - 5.5 8.5 Osmotic pressure (osmol/kg) - - 0.318 0.315 Specific gravity (g/mL) - - 1.0 1.0

Experimental Example 1: Confirmation of precipitation of ibuprofen dilutions

Whether precipitation occurred within 24 hours in the diluted ibuprofen prepared in Examples 1 to 10 and Comparative Examples 1 to 4 was visually checked, and the results are shown in FIG. 1 .

As shown in FIG. 1 , it was confirmed that the main component was precipitated and precipitates were generated in the diluted ibuprofen prepared in Comparative Examples 1 to 3, whereas the main component was not precipitated in the diluted ibuprofen prepared in Examples 1 to 10. It is confirmed that no sediment is generated and a transparent appearance is maintained.

On the other hand, in the case of the diluent ibuprofen prepared in Comparative Example 4, no precipitate was generated, but there was a problem in that the generation and growth of microorganisms could not be inhibited due to the high pH.

Experimental Example 2: Stability evaluation of ibuprofen dilutions

To evaluate the stability of the diluents of ibuprofen prepared in Examples 1 to 10 under accelerated conditions, the dilutions of ibuprofen prepared in Examples 1 to 10 were filled and packaged in glass vials to prepare samples, and each sample was accelerated (40 The stability was evaluated for about 2 weeks and about 4 weeks in a stability chamber under conditions of a temperature of ℃ and a relative humidity of 75%). Specifically, the relative content of (RS)-ibuprofen was measured after storage for about 2 weeks and about 4 weeks compared to the content (injection amount) of (RS)-ibuprofen through the high-purity liquid chromatography method, and the results are shown in Table 3 indicated.

After storage for about 2 weeks and about 4 weeks (RS)-relative content of ibuprofen (% by weight) Early after about 2 weeks after about 4 weeks Example 1 100.42% 99.87% 98.12% Example 2 100.56% 100.21% 99.90% Example 3 100.54% 100.34% 100.02% Example 4 100.13% 97.48% 92.01% Example 5 100.84% 96.88% 91.81% Example 6 100.31% 99.15% 98.02% Example 7 100.28% 100.19% 99.77% Example 8 100.55% 100.40% 99.92% Example 9 100.50% 95.14% 91.38% Example 10 100.49% 95.01% 90.22%

As shown in Table 3, when L-arginine contains 304 parts by weight to 472 parts by weight, like the ibuprofen diluted strain prepared in Examples 1 to 10, the stability of the ibuprofen diluted strain under accelerated conditions is confirmed to be excellent. However, when the content of L-arginine exceeds 408 parts by weight, it is confirmed that there is a problem in that the stability of the ibuprofen diluent is rather greatly lowered due to the increase in cationicity by the L-arginine molecule.

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (7)

A dilute injectable preparation comprising ibuprofen, arginine, sodium chloride or glucose, hydrochloric acid, and water for injection,
Based on 400 parts by weight of the ibuprofen, the content of arginine is 376 parts by weight to 408 parts by weight,
The concentration of the arginine in the diluted injectable formulation is 0.408 (w/v)% or less, and the pH is less than 6.5 to 8.5,
After storing the diluted injectable formulation under accelerated conditions (temperature of 40°C and relative humidity of 75%) for 4 weeks, the change in the content of ibuprofen is within 1% by weight
Diluted injectable formulation with improved stability.
The method of claim 1,
The dilute injectable formulation with improved stability, wherein the ibuprofen is (RS)-ibuprofen or (S)-ibuprofen.
The method of claim 1,
The arginine is L-arginine or D-arginine, a diluted injectable formulation with improved stability.
delete The method of claim 1,
The osmolality of the injectable formulation is 0.1 osmol/kg to 1.0 osmol/kg, and the specific gravity is 1.0 g/mL to 2.0 g/mL, the dilute injectable formulation with improved stability.
delete A method for preparing a diluted injectable formulation comprising the step of sequentially adding arginine, ibuprofen, sodium chloride or glucose, and hydrochloric acid to water for injection,
Based on 400 parts by weight of the ibuprofen, the content of arginine is 376 parts by weight to 408 parts by weight,
The concentration of the arginine in the diluted injectable formulation is 0.408 (w/v)% or less, and the pH is less than 6.5 to 8.5,
After storing the diluted injectable formulation under accelerated conditions (temperature of 40°C and relative humidity of 75%) for 4 weeks, the change in the content of ibuprofen is within 1% by weight
A method for preparing a diluted injectable formulation with improved stability.

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