KR100509432B1 - Syrup Formulation Containing S(+)-Ibuprofen And Its Process - Google Patents

Abstract

          The present invention relates to a syrup composition containing S (+)-ibuprofen, a poorly water-soluble agent, which is a syrup for oral administration that stably suspends the pharmacologically active S (+)-ibuprofen, and has no irritation A composition of the removed S (+)-ibuprofen-containing agent and a method for producing the same.

Description

Syrup Formulation Containing S (+)-Ibuprofen and Method for Making the Same {Syrup Formulation Containing S (+)-Ibuprofen And Its Process}

The present invention relates to a pharmaceutical composition containing S (+)-ibuprofen as an active ingredient and a method for producing the same.

S (+)-Ibuprofen is a well-known nonsteroidal anti-inflammatory analgesic compound. It is a white crystalline powder, has a peculiar smell and bitter taste, and has little physicochemical properties.

Various formulation studies have been actively conducted to solubilize poorly soluble S (+)-ibuprofen to increase solubility and improve dissolution rate to provide high pharmacological activity.

Typically, solubilization using co-solvent such as ethanol, or solubilizing salts such as strong acids or strong bases by attaching counter ions to poorly soluble substances, and solubilizing soluble complexes by combining high molecular compounds or ligands Although attempted, these methods had the disadvantage of delamination due to instability of the formulation.

  The present invention relates to liquid formulations, in particular syrups for oral administration, in which non-glycerin and polyoxyl 40-cured castor oil are used as plasticizers and agar, kaolin and xanthan as suspending agents for the solubilization of S (+)-ibuprofen, which is poorly soluble in water. It was able to maintain a stable suspension by adding gum, and also added sweeteners, cyclodextrin and dissorbitol liquids, liquid fructose, aspartame and stevioside as sweeteners to give improved taste with no irritation. It is an object of the present invention to provide a new, stable S (+) ibuprofen-containing syrup composition having added antiseptic effect.

    1) 1.0 to 2.0 wt% of S (+)-Ibuprofen as an active active substance, 2) 3 to 5 wt% of concentrated glycerin as a plasticizer, 0.1 to 0.5 wt% of polyoxyl 40 hardened castor oil, and 3) as a suspending agent. Kaolin 0.5 to 0.7% by weight, xanthan gum 0.05 to 3.0% by weight, agar 0.1 to 0.5% by weight, 4) 60 to 80% by weight as a sweetener, 2 to 8% by weight of cyclodextrin solution, dissorbitol solution (70%) 2 S (+)-Ibuprofen syrup composition having a pH of 3.0 to 9.0 consisting of -8 wt%, liquid fructose, aspartame, stevioside and 5) fragrances, colorants, preservatives, purified water and a viscosity of 500 to 2,500 centipoise Furthermore,

In the present invention, 1) a predetermined amount of purified water, which is a solvent, 60 to 80% by weight, 3 to 5% by weight of concentrated glycerin, and 2 to 8% by weight of dissorbitol solution (70%) are dissolved, and 2) purified water is added thereto. 0.05-3.0% by weight of xanthan gum dissolved in the solution and 0.1-0.5% by weight of agar solution were added and stirred to prepare a solution. 3) 0.5-0.7% by weight of kaolin and 2-8% by weight of cyclodextrin were added to another container. Stir and mix 1.0-2.0 wt% of S (+)-ibuprofen with liquid fructose, aspartame and stevioside, add 0.1-0.5 wt% of polyoxyl 40-cured castor oil and stir to obtain a solution. 4) A method for preparing a S (+)-ibuprofen syrup composition having a pH of 3.0 to 9.0 and a viscosity of 500 to 2,500 centipoise, which is prepared by adding a small amount of purified water and fragrance added with a colorant. To provide.

The present invention provides a pharmaceutical composition consisting of 1.5% by weight of physiologically acceptable S (+)-ibuprofen. It contains at least one conventional pharmaceutical excipient in addition to the physiological amount of S (+)-ibuprofen.

Preferred embodiments of the present invention are suspension syrups for oral administration. Such formulations may optionally contain other conventional excipients such as S (+)-ibuprofen, plasticizers, suspending agents, preservatives, sweeteners, fragrances and the like.

Examples of suitable preservatives include methyl paraoxybenzoate, propyl paraoxybenzoate, sodium benzoate and the like.

Suitable plasticizers may be used as a mixture of components capable of maintaining a stable formulation of S (+)-ibuprofen, such as concentrated glycerin and polyoxyl 40 hardened castor oil, in which case 3 to 5% by weight of concentrated glycerin and 0.1 to 4 polyoxyl hardened castor oil. The use of 0.5% by weight is the amount that can be recommended for the plasticizing effect of the present invention.

Suitable suspending agents include agar, kaolin, xanthan gum and the like, in which case a mixed use of 0.5 to 0.7% by weight of kaolin, 0.05 to 3.0% by weight of xanthan gum and 0.1 to 0.5% by weight of agar is preferred. Layer separation begins.

Suitable sweeteners include sweeteners such as white sugar, cyclodextrin liquid, dissorbitol liquid, liquid fructose, aspartame, stevioside, and the like, in which case 60 to 80% by weight of white sugar, 2 to 8% by weight of cyclodextrin liquid, dissorbitol liquid ( It is preferable to contain 70%) of the amount in the range of 2 to 8% by weight to remove not only the stability of the preparation but also the bitter taste.

Suitable flavoring agents include strawberry flavor, grape flavor, peppermint flavor and mint flavor.

Preferred compositions according to the present invention have a suitable pH range of 3.0 to 9.0 in terms of stability of the formulation as a syrup suspending agent.

Experimental Example 1

       Dissolution Test of S (+)-Ibuprofen with pH Change

Experimental Method: Adjust the pH of each s-ibuprofen syrup to 3,5, 7, 9 by adding 0.1N NaOH and citric acid, and take 15 ml of this syrup and perform the dissolution test in purified water, pH 1.2 and pH 6.8. It was.

Experimental results: At pH 1.2, each sample (pH 3, 5, 7, 9) did not significantly affect elution, and the higher the pH, the higher the dissolution rate (see Fig. 1).

In addition, at pH 6.8, the dissolution rate is over 80% within 30 minutes.

The higher the pH, the faster the dissolution rate can be seen (see Figure 2).

In dissolution rate experiments in purified water, S (+)-ibuprofen syrup, pH 9, showed a rapid dissolution rate, and as the pH was lowered, the dissolution rate was slower (see Fig. 3).

Experimental Example 2

Viscosity change with increasing amount of thickener

Experimental Method: In order to measure the appropriate viscosity for the stable suspension of S-Ibuprofen, the final viscosity of the syrup was measured by subtracting the amount of agar and xanthan gum used for thickening purposes.

Experimental results: It was observed that the viscosity of the syrup increased and the precipitation phenomenon decreased significantly as the content of the thickener increased. A moderate viscosity with a formulation as a syrup without double precipitation occurred was observed between 500 and 2500 centipoise. (See Fig. 4)

Experimental Example 3

       Dispersion Test of S (+)-Ibuprofen with Content of Suspending Agent

Test Method: Kaolin as a suspending agent to disperse the aggregated S (+)-ibuprofen particles well. Dispersion degree of S (+)-ibuprofen was measured using a polarizing microscope for a sample in which S (+)-ibuprofen was dispersed in purified water and a sample of 0, 0.7 and 3% according to the content of kaolin.

Experimental Results: In this experiment, S (+)-ibuprofen dispersed in purified water showed a clustered state on the microscope (Fig. 5a), and S (+)-ibuprofen syrup containing 0% kaolin also showed the same pattern. (FIG. 5B). It was also observed that the syrup containing 0.7% kaolin was well dispersed in the particles (FIG. 5C), and the syrup containing 3% kaolin was better dispersed. (FIG. 5D)

Experimental Example 4

Stability of S (+)-Ibuprofen Syrup

Experimental method: S (+)-ibuprofen syrup prepared according to Example 1 of the present invention at room temperature (25 ℃) and acceleration conditions (40 ℃, 75% RH) according to the Food and Drug Administration Notice No. 2000-7 Properties and content tests were carried out.

Experimental results: As shown in Tables 1 and 2, stability was secured under both conditions.

Table 1. Stability test results of S (+)-Ibuprofen syrup (25 ℃)

Table 2. Stability test results of S (+)-Ibuprofen syrup (40 ℃, 75% RH)

Example 1

 Prescription Stable Suspension Syrup Containing S (+)-Ibuprofen

 In approximately 100 ml of this

Main ingredient: 1.5 g of S (+)-ibuprofen

Plasticizer: 4.0 g of concentrated glycerin

Plasticizer: Polyoxyl 40 Cured Castor Oil 150 mg

Suspending Agent: Agar 200 mg

Suspending Agent: Xanthan Gum 80 mg

Suspending Agent: 700 mg kaolin

Sweetener: 65.0 g per bag

Sweetener: 5.0 g cyclodextrin solution

Sweetener: 5.0 g of dissorbitol solution (70%)

Sweetener: 4.0 g liquid fructose

Sweetener: Aspartame 150 mg

Sweetener: Stevioside 50 mg

Air freshener

Colorant

Preservative

Solvent

S (+)-Ibuprofen Syrup Preparation Method

1) Put a preservative in 30 ml of 90 ℃ purified water and dissolve.

2) After cooling 1) at 80 ℃, add sugar, concentrated glycerin and dissorbitol solution (70%) to dissolve and maintain at 80 ℃.

3) Slowly add xanthan gum and agar to 15 ml of purified water at 80 ° C and stir for about 1 hour while gelatinizing.

4) Add 3) liquid to 2) liquid and stir.

5) 4) After confirming that the solution is completely dissolved, cool the temperature to room temperature.

6) Put kaolin in 15 ml of purified water in another container, disperse for 20 minutes, add cyclodextrin and stir.

7) After mixing S (+) ibuprofen with liquid fructose, aspartame and stevioside, add 6). After stirring for 20 minutes, add polyoxyl 40 hardened castor oil, stir, and add to the cooling solution of 5).

8) Dissolve the colorant in a small amount of purified water and mix.

9) Add flavor and mix.

10) Set the mark with purified water.

A syrup composition containing poorly water-soluble S (+)-ibuprofenol, which contains concentrated glycerin and polyoxyl 40 hardened castor oil as a plasticizer, and contains agar, kaolin and xantham gum as suspending agents, and other sucrose, cyclodextrin and Dispersitol solution, liquid fructose, sweeteners and coloring agents and preservatives of aspartame and stevioside were added to obtain a stable and layered S (+)-ibuprofen-containing syrup composition with no irritation and improved taste.

1 is a graph showing the dissolution rate in a pH 1.2 eluting solvent.

( : pH 3, : pH 5, : pH 7, pH 9)

2 is a graph showing the dissolution rate in a pH 6.8 eluting solvent.

( : pH 3, : pH 5, : pH 7, pH 9)

3 is a diagram showing the dissolution rate in purified water.

( : pH 3, : pH 5, : pH 7, pH 9)

4 is a view showing a change in viscosity according to the thickener content.

( Agar, Xanthan gum)

5 is a view showing a change in dispersion force according to the kaolin content.

Claims (2)

1) 1.0 to 2.0 wt% of S (+)-Ibuprofen as an active active substance, 2) 3 to 5 wt% of concentrated glycerin as a plasticizer, 0.1 to 0.5 wt% of polyoxyl 40-cured castor oil, 3) 0.5 to kaolin as a suspending agent 0.7% by weight, xanthan gum 0.05-3.0% by weight, agar 0.1-0.5% by weight, 4) 60-80% by weight per bag as sweetener, 2-8% by weight of cyclodextrin solution, 2-8% by weight of dissorbitol (70%) %, Liquid fructose, aspartame, stevioside, and 5) S (+)-ibuprofen syrup composition having a pH of 3.0 to 9.0 and a viscosity of 500 to 2,500 centipoise consisting of a fragrance, a colorant, a preservative, and purified water. 1) Add a preservative, 60 to 80% by weight, 3 to 5% by weight of concentrated glycerin, 2 to 8% by weight of dissorbitol solution (70%), and dissolve in a certain amount of purified water as a solvent. 2) Xanthan dissolved in purified water 0.05-3.0% by weight of gum and 0.1-0.5% by weight of agar solution were added and stirred to prepare a solution. 3) 0.5-0.7% by weight of kaolin and 2-8% by weight of cyclodextrin were added and stirred in another container. 1.0 to 2.0% by weight of S (+)-Ibuprofen, liquid fructose, aspartame and stevioside were added and mixed, and 0.1 to 0.5% by weight of polyoxyl 40-cured castor oil was added to the solution. 4) A method for preparing S (+)-ibuprofen syrup composition having a pH of 3.0 to 9.0 and a viscosity of 500 to 2,500 centipoise, which is prepared by adding a small amount of purified water and aroma added thereto.