KR101924786B1 - Pharmaceutical composition of ibuprofen for injection - Google Patents

Abstract

The present invention relates a pharmaceutical composition for injection of ibuprofen, comprising ibuprofen or a pharmaceutically acceptable salt thereof, and meglumine, and more specifically, to an injectable pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt, and meglumine as a solvent, and an EDTA salt as a stabilizer. The pharmaceutical composition according to the present invention comprises an ibuprofen solvent and a liquid solution of ibuprofen, and by including a stabilizer in the solution, may improve the stability of an ibuprofen preparation. Accordingly, the ibuprofen preparation, even when diluted to an administrable concentration for convenient use prior to being stored, does not suffer decomposition and pH changes, thus preventing the efficacy of drug from decreasing due to a decrease in the content of ibuprofen. According to the present invention, an injectable liquid ibuprofen preparation may be stably stored.

Description

[0001] PHARMACEUTICAL COMPOSITION OF IBUPROFEN FOR INJECTION [0002]

The present invention relates to injectable pharmaceutical compositions of ibuprofen comprising ibuprofen or a pharmaceutically acceptable salt thereof and meglumine.

2- (4-isobutylphenyl) -propionic acid (ibuprofen) is an analgesic, antipyretic, and antiinflammatory agent having the following structure:

[Chemical Formula 1]

Ibuprofen is a very well-known medicinal product since its invention in the 1960s and is now marketed under the trade names Motrin®, Advil®, and Nuprin® for oral administration in the pharmaceutical form for the treatment of pain, inflammation and fever.

Ibuprofen may be two enantiomers, (R) -biprofen or (S) -bipropene, although the (S) enantiomer is biologically active and the (R) enantiomer is active in vivo S), most of the preparations include the racemic mixture ((RS) -iboburophen). In the following, "ibuprofen" means one of the enantiomers of (R) or (S), or a racemate.

Although ibuprofen has many advantages over other analgesics such as aspirin and acetaminophen, its solubility in water is very low. Ibuprofen is a monoprotic acid with a pKa of 4.4. Thus, its solubility is closely related to the pH and can vary from 78 μg / mL at acidic pH to 291 mg / mL at basic pH. Thus, it has been difficult to develop a particular dosage form of ibuprofen, especially a injectable solution.

To address such problems, U.S. Patent No. 5,200,558 describes the enhanced analgesic effect of S (+) ibuprofen as a salt of L and D amino acids, including arginine, in a variety of dosage forms, including injectable solution forms . However, it requires the formation of a salt before solubilization, and the salt has the disadvantage that it must be separated and verified before producing the dosage form. Also, the ibuprofen formulation obtained through such a procedure has a molar ratio of amino acid or base to ibuprofen of at least 1: 1. From the point of view of both cost and development, it is advantageous not to separate and validate the salt form and produce it before producing the dosage form. Also, in most cases it is advantageous to minimize the amount of inactive ingredients, including salts, to minimize potential side effects. Moreover, in the case of injectable products, it is advantageous to produce a liquid dosage form of ibuprofen having a pH similar to the pH of the blood (pH 7.4).

International Patent Publication No. 2003-039532 describes a liquid pharmaceutical composition of ibuprofen which contains an amino acid such as arginine and has a pH value of less than 7.8 to improve the solubility of ibuprofen. The patent was previously marketed under the trade name Caldolor and is recommended for treatment of mild to severe pain and fever. This formulation contains 100 mg of ibuprofen (and thus 100 mg / mL of ibuprofen concentration) in injection water, and 78 mg of arginine per mL of solution at about pH 7.4 in a glass bottle containing 400 or 800 mg ibuprofen, 0.92: 1 arginine : Included as the molar ratio of ibuprofen. However, this formulation has been found to have some limitations. One of these limits is that ibuprofen contained in liquid ibuprofen preparations containing arginine and ibuprofen at a molar ratio of 0.92: 1 can be dissolved at a concentration of about 20 or 25 mg / mL at 100 mg / mL, And ibuprofen is insoluble until it is diluted to a concentration of 5 mg ibuprofen / mL and undergoes a phase transition which precipitates out of solution. Recently it has also been found that the product can be precipitated in polyolefin IV bags.

In addition, the conventional kneading roll injections do not use a stabilizer, and when they are diluted before administration, the stability is poor and the main ingredient is decomposed with time. Therefore, there is a need to find a method for improving the stability of the bupivacaine injectable preparation and preventing the content thereof from being lowered.

The conventional literature on the prior art can be exemplified in the following Patent Documents, and all of the contents of the following Patent Documents can be cited as a prior art in this specification.

U.S. Patent No. 5,200,558 (April 4, 1993) International Publication No. 2003-039532 (May 15, 2003)

It is an object of the present invention to provide a solution of ibuprofen soluble using an ibuprofen solubilizer to prepare a solution of ibuprofen suitable for injection.

It is still another object of the present invention to provide a syrupy ibuprofen solution which prevents degradation of ibuprofen, which is an active ingredient, during storage and prevents the syrup from being retained due to a decrease in the content thereof,

The present invention has been made to solve the problems of the prior art,

Ibuprofen or a pharmaceutically acceptable salt thereof, a solubilizer, and a stabilizer,

Wherein the solubilizing agent is meglumine,

Wherein the stabilizing agent is an EDTA salt.

Also, the present invention provides an injectable pharmaceutical composition of ibuprofen, wherein the pH of the composition is in the range of 6.0 to 8.0.

Also, the present invention provides a pharmaceutical composition for injecting ibuprofen, which further comprises a pH adjusting agent or a stabilizing agent.

In the present invention, the pH adjusting agent may be an acidic pH adjusting agent selected from acetic acid, anhydrous citric acid, hydrochloric acid, fumaric acid, malic acid, nitric acid and lactic acid; And at least one basic pH adjusting agent selected from ammonia, ammonium carbonate, diethanolamine, potassium hydroxide, sodium hydrocarbons, sodium borate, sodium carbonate, sodium hydroxide and trolamine, to provide an injectable pharmaceutical composition of ibuprofen .

In the present invention, the stabilizer may be at least one selected from the group consisting of glycine, diethanolamine, sulfurous acid salts, ethylenediaminetetraacetic acid, poloxamer, polysorbates, propylene glycol, sodium disulfide, sodium formaldehyde, sodium formaldehyde sulfoxylate , Thiourea, disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid tetrasodium, acetone sodium bisulfite, or a mixture thereof. The present invention also provides an injectable pharmaceutical composition of ibuprofen.

The present invention also provides an injectable pharmaceutical composition of ibuprofen, wherein the molar ratio of meglumine to ibuprofen or a pharmaceutically acceptable salt thereof is 0.3 to 0.9: 1.

The present invention also provides a pharmaceutical composition for injecting ibuprofen wherein the EDTA salt is ethylenediaminetetraacetic acid tetrasodium.

Also, in the present invention, the ibuprofen is one of (RS) - ibuprofen or (S) -biprofen.

The pharmaceutical composition according to the present invention comprises a liquid solution of ibuprofen solubilizer and ibuprofen, and the stability of the ibuprofen formulation can be improved by adding a stabilizer in the solution. According to the present invention, it is possible to prevent the drug efficacy from being maintained due to the lowering of the ibuprofen content since no degradation occurs and pH fluctuation does not occur even when the ibuprofen preparation is diluted and stored at a previously administered concentration for easy use. The liquid ibuprofen preparation can be stably stored.

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

In accordance with the above object, the present invention provides a pharmaceutical composition for injectable use of ibuprofen comprising ibuprofen or a pharmaceutically acceptable salt thereof.

The ibuprofen used in the composition of the present invention is both a racemic (RS) -bibrofen or an isomeric (S) -iibrophene.

Ibuprofen is more pharmacologically effective than smaller doses of dexibupropene ((S) - ibuprofen) compared to racemic mixtures ((RS) - ibuprofen) and the use of dexibupropene, along with side effects (RS) - ibuprofen or (S) - ibuprofen (dexibupropene) may be selected as a racemic mixture ((RS) - ibuprofen This will need to be taken into account in addition, as ibuprofen and (S) -ibbutene (dexibupropene) may be somewhat different in solubility, stability, and the like.

Pharmaceutically acceptable salts of ibuprofen are, for example, arginine, lysine, or histidine salts of ibuprofen. Other pharmaceutically acceptable salts of ibuprofen are disclosed in U.S. Patent Nos. 4,279,926, 4,873,231, 5,424,075, and 5,510,385, the contents of which are incorporated herein by reference.

In a preferred embodiment, the ibuprofen dissolver is meglumine.

The above-mentioned meglumine is a known compound having an IUPAC name of 6-methylaminohexane-1,2,3,4,5-pentol and a structure represented by the following general formula (2).

(2)

In the present invention, since ibuprofen is poorly soluble in water, meglumine is used as a dissolving agent in order to dissolve ibuprofen and formulate it.

Compared to arginine used in conventional kneaded roll injections, meglumine has high storage stability because it does not discolor even when stored at a relatively high temperature for a long period of time.

The pH of the composition is in the range of 6.0 to 8.0, preferably in the range of 6.8 to 7.8. If the pH of the composition deviates excessively from the pH of the blood (pH 7.4), pain may occur during injection and may cause phlebitis. In addition, when the pH is low, the solubility of ibuprofen is lowered, which is not preferable.

The pH of the composition may include a pH adjusting agent to reach the pH. In order to lower the pH, acidic pH regulators such as acetic acid, anhydrous citric acid, hydrochloric acid, fumaric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, and lactic acid may be used. In order to increase the pH, basic pH regulators such as ammonia, Diethanolamine, potassium hydroxide, sodium hydrogencarbonate, sodium borate, sodium carbonate, sodium hydroxide, and trollamine.

Particularly, in terms of the solubility of ibuprofen and the pH of the preparation, it is preferable that the molar ratio of meglumine to ibuprofen or a pharmaceutically acceptable salt thereof is 0.3 to 0.9: 1. If the content of meglumine is less than the above range, improvement in solubility of ibuprofen may be insufficient. If the content of meglumine is out of this range, pH adjustment may become difficult.

The composition may further comprise a stabilizer. Stabilization includes inhibition of coloring, inhibition of formation of ibuprofen-based substances, inhibition of precipitation, and the like. That is, the stabilizer of ibuprofen of the present invention includes a coloring inhibitor of ibuprofen, an inhibitor of the production of ibuprofen, a precipitation inhibitor and the like. Oxidation, hydrolysis and the like are considered as the cause of the coloring of ibuprofen. Further, the ibuprofen suppository contains ibuprofen decomposition product. In addition, since the stabilizer of the present invention inhibits the coloring of ibuprofen, it also suppresses the coloring of the aqueous composition containing ibuprofen.

Preferred stabilizing agents of the present invention include EDTA salts, non-limiting examples of which include ethylenediaminetetraacetic acid disodium, or ethylenediaminetetraacetic acid tetrasodium. Since EDTA itself is low in solubility as a stabilizer, insoluble fine particles and the like are likely to be formed. It is preferable that EDTA is in the form of a salt for use in injectable preparations.

Particularly preferred is ethylenediamine tetraacetic acid tetrasodium EDTA-4Na. The ethylenediaminetetraacetic acid tetrasodium is a known compound having a structure represented by the following general formula (3).

(3)

As will be described later, EDTA-4Na has better solubility than EDTA-2Na and does not cause pH fluctuation in the solution, thus making it more stable and uniform. A more detailed understanding of this may be made through Examples and Experimental Examples to be described later.

In addition, the compositions of the present invention may further comprise additional known stabilizers in addition to EDTA salts.

For example, there may be mentioned glycine, diethanolamine, sulfurous acids, ethylenediaminetetraacetic acid, poloxamers, polysorbates, propylene glycol, sodium disulfide, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediamine tetraacetate , Acetone sodium bisulfite, and the like.

The sulfites include sulfites, hydrogen sulfites, and pyrosulfites. Examples of the salt include a sodium salt and a potassium salt. Of these, sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite, and potassium pyrosulfite can be exemplified, and the sulfurous acid salts may be used singly or in combination of two or more kinds .

The amount of the stabilizer, that is, the amount of the stabilizer added to the composition is preferably such that the concentration of the stabilizer in the composition is about 0.01 to 0.1 w / v%, preferably about 0.03 to 0.1 w / v% , And still more preferably about 0.03 to 0.05 w / v%. The amount of the stabilizer to be used is preferably about 0.01 to 0.1 part by weight, more preferably about 0.03 to 0.1 part by weight, and still more preferably about 0.03 to 0.05 part by weight based on 1 part by weight of ibuprofen. Within this range, the ibuprofen can be sufficiently stabilized. Also, in the above range, the stabilizer is sufficiently dissolved in the composition.

Generally, the therapeutically effective amount of ibuprofen contained in the composition is from about 0.1% w / w to about 90% w / w, for example greater than 0.1% w / w.

Current intravenous compositions are prepared in the form of a solution in the form of a solution or suspension of U. 4 mL and 8 mL vials (100 mg / mL, respectively).

The therapeutically effective amount of (RS) -bibrofen contained in the composition of the present invention is from 100 mg to 800 mg (concentration of (RS) -bibrofen from 1 mg / mL to 8 mg / mL on a 4 mL vial). The therapeutically effective dose of dexibupropene, which is effective at smaller doses compared to (RS) -bibrofen, is 50 mg to 600 mg (concentration of (S) - ibuprofen from 0.5 mg / mL to 6 mg / mL) on a 4 mL vial.

The ibuprofen injections of the present invention may be in the range of 0.8 mg / mL to 400 mg / mL, preferably 50 mg / mL to 80 mg / mL, depending on the particular formulation or mode of administration and the packaging thereof, and the effective treatment of ibuprofen Dosages are well known in the art as long as therapeutically effective amounts are achieved.

For the 400 mg preparation, dilute 4 mL of this solution with 100 mL or more of the solution for oral administration (the following solution is 0.9% physiological saline solution, 5% glucose injection solution or lactose-added ring gel solution) Or more.

A suitable intravenous dose of ibuprofen according to the present invention, for example, is 800 mg for 6 hours of adult use for the treatment of pain. The adult dose for fever treatment is 800 mg in a 4 to 6 hour cycle. Patients with severe illness require more usage for fever treatment. In addition, for patients with serious illness, the dosage can be adjusted up to 800 mg within a range that does not exceed 3200 mg per day. The intuitively perceived use of pediatric fever treatment is 10 ~ 15mg / kg, which is less than 400mg per 4 hour period when used for oral use. Administration can be carried out, for example, by intravenous injection for 5 to 10 minutes.

Hereinafter, the present invention will be described in more detail by way of examples. It is to be understood that the following embodiments are for the purpose of illustration only and are not intended to limit the scope of the present invention.

Example

Megylumin, a solubilizer, and a stabilizer are added to the water for injection (distilled water) in order, and mixed and dissolved.

The main component, ibuprofen, was added to the solution, and the mixture was adjusted to pH 7.4 ± 0.01. The solution was prepared by adding water (distilled water) as a solvent so that the total amount of the composition became 100 mL.

The above-mentioned steps were sequentially carried out to prepare a liquid composition which can be used for main use. The components of Examples 1 to 5 were as shown in Table 1 below.

Purpose of blending Raw material name Amount (mg) Example 1 Example 2 Example 3 Example 4 Example 5 chief ingredient Dexibupropene 75.0 75.0 75.0 75.0 75.0 Solvent Meglumine 63.0 63.0 63.0 63.0 63.0 Stabilizer EDTA 2Na - - 0.05 - - EDTA 4Na - 0.05 - - - Sodium non-sulfide - - - 0.05 - Sodium sulphate - - 0.05 pH adjusting agent 1N NaOH Suitable amount

Comparative Example  ( Control Example )

Caldolor ™ Injection 400 mg / 4 ml (Ibuprofen) (manufactured by Cumberland Pharmaceuticals Inc.)

Experimental Example

Experimental Example 1: Acceleration test,

With respect to Examples 1 to 5 prepared above, the stability test was carried out by measuring the fluctuation of the content and properties at an acceleration test (40 ± 2 ° C./75 ± 5%). The results are shown in Table 2.

Test Items Comparative Example Example 1 Example 2 Example 3 Example 4 Example 5 Osmolality (msOmol) 204 332 333 330 329 332 Usage Concentration Osmolality (msOmol) 289 290 290 289 289 291 pH 7.4 7.4 7.4 7.4 7.4 7.4 Initial content (%) 99.94 99.42 99.37 99.27 99.36 99.73 Accelerated Storage After 1 month Content (%) 99.47 97.24 99.31 99.18 97.16 96.94 Appearance Colorless transparent liquid Colorless transparent liquid Colorless transparent liquid Colorless transparent liquid Colorless transparent liquid Colorless transparent liquid

As a result, the storage stability of Examples 1 and 2 using the EDTA salt was superior to that of the other stabilizers. In addition, there was no significant difference in stability in Example 2 using EDTA 4Na and in Example 3 and Comparative Example using EDTA 2Na.

Experimental Example 2: Stability test after dilution of concentration

For the Examples 1 to 5 prepared above, a stability test was carried out after dilution of the working concentration. The results are shown in Table 3.

Test Items Comparative Example Example 1 Example 2 Example 3 Example 4 Example 5 Early 99.96 99.27 99.43 99.22 99.48 99.65 3 hours 99.12 98.76 99.07 98.76 98.51 98.84 6 hours 98.53 98.06 98.44 98.43 97.21 97.32 24 hours 97.21 96.74 97.81 97.79 96.18 96.41 48 hours 95.17 95.43 97.47 97.43 95.43 95.87

As a result, it was found that the stabilizers of Examples 1 to 5 using the stabilizer were superior to those of Comparative Examples in which the stabilizer was not used. In particular, in Examples 2 and 3 using the EDTA salt as the stabilizer, And showed great stability.

Experimental Example  3: pH change test after use concentration dilution

For each of the above-prepared Examples 1 to 5, a test was performed to measure the degree of pH change after dilution of the used concentration. The results are shown in Table 4.

Test Items Comparative Example Example 1 Example 2 Example 3 Example 4 Example 5 Early 7.45 7.42 7.43 7.41 7.38 7.42 3 hours 7.45 7.44 7.43 7.29 7.40 7.43 6 hours 7.46 7.46 7.44 7.35 7.42 7.45 24 hours 7.51 7.48 7.44 7.41 7.47 7.49 48 hours 7.53 7.50 7.45 7.45 7.54 7.54 medium 7.48 7.46 7.44 7.38 7.43 7.47 Maximum deviation value 0.05 0.04 0.01 0.09 0.07 0.07

Comparative Examples and Examples all showed pH fluctuations within an acceptable range, but in Example 3, the fluctuation width was larger than the others, and in Example 2, there was little fluctuation in pH.

Claims (8)

Ibuprofen or a pharmaceutically acceptable salt thereof, a solubilizer, and a stabilizer,
Wherein the solubilizing agent is meglumine,
Wherein the stabilizer is ethylenediaminetetraacetic acid tetrasodium. ≪ Desc / Clms Page number 24 > The injectable pharmaceutical composition of ibuprofen according to claim 1, wherein the pH of the composition is in the range of 6.0 to 8.0. The injectable pharmaceutical composition of ibuprofen according to claim 1, further comprising a pH adjusting agent or a stabilizing agent. The method of claim 3, wherein the pH adjusting agent is an acidic pH adjusting agent selected from acetic acid, anhydrous citric acid, hydrochloric acid, fumaric acid, malic acid, nitric acid and lactic acid; And a basic pH adjusting agent selected from ammonia, ammonium carbonate, diethanolamine, potassium hydroxide, sodium hydrocarbons, sodium borate, sodium carbonate, sodium hydroxide and trollamine. 4. The composition of claim 3, wherein the stabilizer is selected from the group consisting of glycine, diethanolamine, sulfurous acids, ethylenediaminetetraacetic acid, poloxamers, polysorbates, propylene glycol, sodium disulfide, sodium formaldehyde, sodium formaldehyde sulfoxylate, Wherein said drug is selected from the group consisting of thiourea, disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid tetrasodium, acetone sodium bisulfite, or mixtures thereof. The injectable pharmaceutical composition of ibuprofen according to claim 1, wherein the molar ratio of meglumine to ibuprofen or a pharmaceutically acceptable salt thereof is 0.3 to 0.9: 1. delete The injectable pharmaceutical composition of claim 1, wherein the ibuprofen is one of (RS) -bibrofen or (S) -ibobrofen.