KR20190141871A - Ibuprofen Pharmaceutical Composition with Improved Stability - Google Patents

Abstract

The present invention provides a liquid pharmaceutical composition for dilution, which contains ibuprofen and arginine; and a transparent injection for intravenous injection which is obtained by diluting the liquid pharmaceutical composition. According to the present invention, active components do not precipitate for at least 24 hours when being diluted, and thus the pharmaceutical composition exhibits remarkably improved stability compared to conventional commercially available ibuprofen formulations.

Description

Ibuprofen Pharmaceutical Composition with Improved Stability

The present invention relates to ibuprofen pharmaceutical compositions with improved stability. More particularly, the present invention relates to an injectable solution composition for dilution, which has been used to improve stability so that ibuprofen does not precipitate when diluted.

Therapeutic agents for the treatment of pain, inflammation and fever include analgesics, anti-inflammatory and antipyretic agents. Nonsteroidal anti-inflammatory drugs (NSAIDs) are one type of such therapeutic agent. These include propionic acid derivatives, acetic acid derivatives, phenoic acid derivatives, biphenylcarboxylic acid derivatives, oxycams and cyclooxygenase-2 (COX-2) selective NSAIDs. Propionic acid includes, for example, ibuprofen, naproxen and ketoprofen, and especially ibuibuprofen is widely used.

Ibuprofen has been shown to be effective in reducing pain, fever and inflammation, improving blood flow, reducing infarct size and inhibiting cerebral plaque formation in local ischemia.

The common name for ibuprofen is 2- (4-isobutylphenyl) propionic acid and has a molecular weight of 206.28, (R) enantiomer, (S) enantiomer, or racemate Available as).

Ibuprofen has low solubility in water, making it particularly difficult to develop as an injectable solution. In order to solve this problem, U.S. Patent No. 5,200,558 proposed an injectable solution form containing the salts of L and D amino acids of S (+) ibuprofen as active ingredients, which synthesized the ibuprofen amino acid salt and verified its formation before solubilization. It has the disadvantage of doing it.

In addition, US Pat. No. 6,005,005 describes an oral liquid composition containing ibuprofen and arginine, but does not provide a transparent composition in which the active ingredient is 100% solubilized. In the case of oral administration solution, 100% solubilization does not have to be achieved, but the injection composition has a risk of blocking Ringer's tube during human administration even though a very small amount is precipitated, unlike oral administration.

Throughout this specification, numerous documents are referenced and their citations are indicated. The disclosures of the cited documents are hereby incorporated by reference in their entirety, so that the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly explained.

Republic of Korea Patent Publication No. 10-0851679

The present inventors tried to improve the problem of blocking the Ringer's tube during human administration when the ibuprofen injection composition, which is currently commercially available, is diluted according to the dosage amount, and as a result, the main component is controlled by adjusting the amount of arginine and pH. The present invention has been completed by improving the precipitation phenomenon.

Accordingly, an object of the present invention is to provide an injectable pharmaceutical composition for injection using diluent containing ibuprofen and arginine, which has improved stability so that ibuprofen does not precipitate upon dilution.

It is another object of the present invention to provide a transparent intravenous injectable drug obtained by diluting the injection stock solution pharmaceutical composition containing the ibuprofen and arginine with intravenous sap.

Still another object of the present invention is to provide a method for preparing an injection stock pharmaceutical composition comprising the ibuprofen and arginine.

Still other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings.

One aspect of the present invention provides a diluent injection pharmaceutical composition comprising ibuprofen and arginine, wherein the molar ratio of arginine to 1 mol of ibuprofen is 1 to 1.28 and the pH of the composition is greater than 7.5 to less than 8.0. To provide.

Ibuprofen is a compound having the structure of Formula 1 and exists as two enantiomers and racemic mixtures thereof.

Ibuprofen, which is included as an active ingredient in the pharmaceutical composition of the present invention, is a representative component of nonsteroidal anti-inflammatory drugs (NSAIDs), and exhibits an effect of reducing pain, fever and inflammation, and (R) enantiomer, (S) One or more selected from the group consisting of enantiomers and racemates can be used.

Ibuprofen has several advantages over other analgesics such as aspirin and acetaminophen, but has a disadvantage in that it is difficult to develop, especially as an injection, due to its low solubility in water. In the past, a pharmaceutical composition comprising ibuprofen salt as an active ingredient has been provided by first preparing an ibuprofen salt (eg, ibuprofen arginine salt) with an amino acid to solve this problem, and dissolving the salt in water. While there is a disadvantage in that ibuprofen amino acid salt must be prepared and identified first, the present invention includes ibuprofen itself as an active ingredient, and thus the synthesis and identification of ibuprofen amino acid salt is not required.

The composition of the present invention contains arginine as a dissolution aid for solubilizing the active ingredient. Arginine is available in both D and L forms as an amino acid having a molecular weight of 174.20. In the present invention, a D or L form of arginine or a mixture of (D) -arginine and (L) -arginine may be used.

The molar ratio of arginine to 1 mole of ibuprofen in the composition of the present invention is 1 to 1.28, preferably 1.01 to 1.1, more preferably 1.02.

The pharmaceutical composition of the present invention may be adjusted to a pH of greater than 7.5 to less than 8.0 and preferably to pH 7.7 to 7.79, more preferably pH 7.7.

The pharmaceutical composition of the present invention is a dilute injection stock solution, and it is necessary to dilute the composition with intravenous sap so that the concentration of ibuprofen is 4 mg / mL or less before intravenous administration.

The concentration of ibuprofen contained in the pharmaceutical composition of the present invention is not particularly limited to 50 to 110 mg / mL, preferably 60 to 105 mg / mL, 70 to 103 mg / mL, 80 to 102 mg / mL or 90 to 90 It may be included at a concentration of 101 mg / mL, more preferably may be included at a concentration of 100 mg / mL.

The content of nibuprofen contained in the pharmaceutical composition of the present invention is not particularly limited, but may be determined within 5 to 3000 mg, preferably 10 to 2000 mg, 50 to 1000 mg, or 100 to 800 mg, In one embodiment the ibuprofen content included in the pharmaceutical composition may be 100 mg, 400 mg or 800 mg.

An effective amount of ibuprofen means an amount that has the effect of reversing or reducing the rate of progression of the disease and / or to some extent alleviate (preferably eliminate) one or more symptoms associated with the disease. The pharmaceutical composition of the present invention may be administered by appropriately adjusting the dose and frequency of administration according to the treatment target and patient condition of the patient, and according to a preferred embodiment, up to 3200 mg of ibuprofen per day may be administered.

In one embodiment, the pharmaceutical composition of the present invention may be administered one or more times as necessary to a content selected from 5 to 3200 mg for pain control, antipyretic and / or anti-inflammatory, and narcotic analgesics for moderate and severe pain control It may also be administered as adjuvant of (morphine).

The dilute liquid pharmaceutical composition of the present invention may be diluted with a diluent such that the final concentration is 4 mg / mL or less before administration, and when diluted, a clear solution free of precipitation may be formed.

The diluent is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also dilutes the compound in solution. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.

When the composition of the present invention is administered intravenously, the diluent may be an intravenous sap selected from saline solution, glucose injection solution and lactose-added ring gel solution.

Existing commercially available ibuprofen preparations (Caldolor) should be used within 24 hours when diluted with intravenous sap so that the concentration of ibuprofen is 4 mg / mL or less. It is necessary to go through the process of visual inspection to see if there is any discoloration. It should never be used if opaque particles, other contaminants or discoloration are observed or if the solution becomes cloudy.

On the other hand, the injectable stock pharmaceutical composition of the present invention contains ibuprofen and arginine in a specific molar ratio, and after dilution with intravenous sap so that the concentration of ibuprofen is 4 mg / mL or less due to the pH being limited to a critical range of values. It is characterized in that stability is greatly improved by maintaining a transparent state even after 24 hours.

The present invention thus provides a transparent intravenous infusion for which the stability is greatly improved by diluting the pharmaceutical composition with intravenous sap so that the concentration of ibuprofen is 4 mg / mL or less.

In addition, the present invention comprises the steps of dissolving arginine and ibuprofen in water so that the molar ratio of arginine to 1 mol of ibuprofen is 1 to 1.28; And adjusting the pH to more than 7.5 to less than 8.0. The method provides a method for preparing an injection stock pharmaceutical composition comprising ibuprofen and arginine.

According to one embodiment, arginine is added to water, mixed until the arginine is dissolved to form an arginine solution, ibuprofen is added to the arginine solution such that the molar ratio of arginine to 1 mol of ibuprofen is 1 to 1.28, and The pH of the solution can be adjusted to greater than 7.5 to less than 8.0 using techniques known in the art and the resulting solution can be sterilized.

According to another embodiment, arginine is added to water, mixed until the arginine is dissolved to form an arginine solution, add and mix ibuprofen to the arginine solution and add sufficient water to achieve the desired concentration of ibuprofen. And optionally, filtration or centrifugation to separate any precipitates to produce a colorless transparent aqueous solution, to adjust the pH of the resulting solution, and finally to sterilize the resulting solution.

Injectable stock pharmaceutical composition of the present invention used in dilution has an effect of significantly improved stability compared to conventional commercially available ibuprofen preparations because the active ingredient does not precipitate for more than 24 hours when diluted.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.

Example

Preparation of Ibuprofen Composition

Example 1

Into an aqueous solution in which 100 mg of ibuprofen and 86 mg of L-arginine are dissolved, a suitable amount of water for injection is mixed so that the concentration of ibuprofen in the finished product (injectable stock solution) is 100 mg / ml and the pH is 7.7. Was added to prepare an injection stock solution having a ibuprofen concentration of 100 mg / ml and a pH of 7.7.

Example 2

In an aqueous solution of 100 mg of ibuprofen and 108 mg of L-arginine, which are the main ingredients, a suitable amount of water for injection is mixed so that the concentration of ibuprofen in the finished product (injectable stock solution) is 100 mg / ml and the pH is 7.55. Was added to prepare an injection stock solution having a ibuprofen concentration of 100 mg / ml and a pH of 7.55.

Example 3

Into an aqueous solution in which 100 mg of ibuprofen and 108 mg of L-arginine are dissolved, a suitable amount of water for injection is mixed so that the concentration of ibuprofen in the finished product (injectable stock solution) is 100 mg / ml and the pH is 7.9. Was added to prepare an injection stock solution having a ibuprofen concentration of 100 mg / ml and a pH of 7.9.

Comparative Example 1

Into an aqueous solution in which 100 mg of ibuprofen and 78 mg of L-arginine are dissolved, a suitable amount of water for injection is mixed so that the concentration of ibuprofen in the finished product (injection stock solution) is 100 mg / ml and the pH is 7.4. Was added to prepare an injection stock solution having a ibuprofen concentration of 100 mg / ml and a pH of 7.4.

Comparative Example 2

In an aqueous solution of 100 mg of ibuprofen and 98 mg of L-arginine, which are the main ingredients, a suitable amount of water for injection is mixed so that the concentration of ibuprofen in the finished product (injection stock solution) is 100 mg / ml and the pH is 7.2. Was added to prepare an injection stock solution having a ibuprofen concentration of 100 mg / ml and a pH of 7.2.

Comparative Example 3

Into an aqueous solution in which 100 mg of ibuprofen and 98 mg of L-arginine are dissolved, an appropriate amount of water for injection is mixed so that the concentration of ibuprofen in the finished product (injection stock solution) is 100 mg / ml and the pH is 7.5. Was added to prepare an injection stock solution having a ibuprofen concentration of 100 mg / ml and a pH of 7.5.

Comparative Example 4

Into an aqueous solution in which 100 mg of ibuprofen and 108 mg of L-arginine are dissolved, a suitable amount of water for injection is mixed so that the concentration of ibuprofen in the finished product (injectable stock solution) is 100 mg / ml and the pH is 7.4. Was added to prepare an injection stock solution having a ibuprofen concentration of 100 mg / ml and a pH of 7.4.

Comparative Example 5

Into an aqueous solution in which 100 mg of ibuprofen and 108 mg of L-arginine are dissolved, a suitable amount of water for injection is mixed so that the concentration of ibuprofen in the finished product (injection stock solution) is 100 mg / ml and the pH is 8.0, and a pH adjuster (hydrochloric acid) Was added to prepare an injection stock solution having a ibuprofen concentration of 100 mg / ml and pH 8.0.

Precipitation test after dilution of ibuprofen injection stock solution

An appropriate amount of intravenous sap was added to the injection stock solutions prepared in Examples 1 to 3 and Comparative Examples 1 to 5 to dilute so that the final concentration of ibuprofen in the solution was 4 mg / mL.

Thus, the prepared diluent was left for 25 hours at 25 ℃, room lighting conditions and then visually confirmed the precipitation, and the results of the precipitation confirmation test are shown in Table 1 and Table 2.

As a result of the test, the dilutions obtained by diluting the injection solutions of Examples 1 to 3 with intravenous sap remained clear even after 30 hours of dilution, whereas the dilutions of Comparative Examples 1 to 5 became cloudy and precipitated. .

Claims (9)

A diluent injectable stock pharmaceutical composition comprising ibuprofen and arginine, wherein the molar ratio of arginine to 1 mol of ibuprofen is 1 to 1.28 and the pH of the composition is greater than 7.5 to less than 8.0. The pharmaceutical composition according to claim 1, wherein the concentration of ibuprofen is 50 to 110 mg / mL. The pharmaceutical composition according to claim 2, wherein the composition is administered intravenously after diluting so that the concentration of ibuprofen is 4 mg / mL or less. The pharmaceutical composition according to claim 2, wherein the composition forms a clear solution when diluted with intravenous sap so that the concentration of ibuprofen is 4 mg / mL or less. The pharmaceutical composition according to claim 4, wherein the intravenous sap is selected from physiological saline, glucose injection solution and lactose-added ring gel solution. The pharmaceutical composition according to claim 1, wherein the molar ratio of arginine to 1 mole of ibuprofen is 1.01 to 1.1. The pharmaceutical composition of claim 1, wherein the composition is for treating one or more selected from pain, inflammation, and fever. A transparent intravenous injectable, wherein the pharmaceutical composition according to claim 1 is diluted with intravenous fluid so that the concentration of ibuprofen is 4 mg / mL or less. Dissolving arginine and ibuprofen in water such that the molar ratio of arginine to 1 mol of ibuprofen is 1 to 1.28; And
adjusting the pH to greater than 7.5 and less than 8.0
Characterized in that the method for producing an injection stock solution pharmaceutical composition used for dilution.