JPH08333245A - Ibuprofen suspension - Google Patents

Abstract

PURPOSE: To obtain an ibuprofen suspension liquid having improved stability of ibuprofen, eliminating or alleviating an irritating feeling and bitterness during administration. CONSTITUTION: This ibuprofen-containing suspension liquid comprises 0.001-10wt.% of a thickening agent (e.g. xanthan gum) and a 0.001-10wt.% of a surfactant (e.g. sucrose fatty acid ester). An antiseptic and a sweetener are completely dissolved in an aqueous solution having pH2 to pH5 in which a pH adjuster (e.g. phosphoric acid buffer solution) is dissolved. The thickening agent and the surfactant are dispersed into the solution, which is mixed with ibuprofen and optionally other pharmacodynamically effective components, a spice, etc., and heat-treated at 55-65 deg.C for 10-20 minutes to give the objective ibuprofen suspension liquid. The ibuprofen suspension liquid contains 1-60mg/ml ibuprofen.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an ibuprofen suspension for internal use in which the stability of ibuprofen is improved and the irritation sensation and bitterness upon administration are eliminated or reduced.

[0002]

BACKGROUND OF THE INVENTION Suspensions containing ibuprofen are
Due to the strong irritation and bitter taste of ibuprofen when taken, a satisfactory feeling of taking was not obtained. It is considered that the stimulating sensation and bitterness are caused by the release of ibuprofen, the growth of the crystals, and the precipitation / aggregation.
Regarding the masking of the bitterness of the ibuprofen suspension agent, JP-A-1-258618 and JP-A-2-258618 are known.
Although the technology described in No. 286615 is known,
I still don't get a satisfactory feeling.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a stable ibuprofen suspension which suppresses the release of ibuprofen, that is, an ibuprofen suspension in which the irritation sensation and bitterness upon administration are eliminated or reduced. With the goal.

[0004]

Means for Solving the Problems In order to ensure the stability of the ibuprofen suspension agent, the present inventors have diligently studied the quantitative and qualitative effects of the thickener and the surfactant, and as a result, By heat-treating in the presence of an agent and a surfactant, the adsorption of ibuprofen to the thickener is increased, which improves the stability and also removes or reduces the irritation and bitterness during administration. As a result, they have completed the present invention.

The present invention is a suspension containing ibuprofen, which is characterized in that it is heat-treated in the coexistence of ibuprofen, a thickener and a surfactant.

In the present invention, the thickener is xanthan gum, pullulan, dextran, hyaluronic acid, chondroitin sulfate, carrageenan, guar gum, tara gum, locust bean gum, sodium alginate, chito acid,
It is a thickener such as tamarind gum having a small emulsion stability effect, and one or more of these are blended. The blending amount of these thickeners is 0.001 to 10% by weight, preferably 0.01 to 3% by weight, based on the total amount of the preparation.

The surfactant in the present invention means sucrose fatty acid esters, stearic acid polyoxyls,
It is a surfactant that is difficult to dissolve in ethers such as polyoxyethylene polyoxypropylene glycols and polyoxyethylene monofatty acid esters, and one or more of these are blended. The amount of these surfactants to be blended is 0.001 to 10% by weight, preferably 0.001 based on the total amount of the preparation.
It is 0025 to 2% by weight.

The suspension of the present invention can be manufactured by the following method. A preservative and a sweetener are added to an aqueous solution (pH 2.0 to 5.0) in which a pH adjusting agent of an organic acid type or an inorganic acid type such as a citrate buffer solution or a phosphate buffer solution is dissolved, and completely dissolved. After adding surfactant and thickener to the solution and uniformly dispersing, add ibuprofen and other antipyretic analgesics, muscle relaxants, antispasmodics, antihistamines, sympathomimetics, fragrances, etc., and mix. Disperse the whole uniformly with a homomixer. Furthermore, add purified water to bring the total volume to 100.
After adjusting to the weight%, heat treatment is performed for 10 to 20 minutes.

The temperature of the heat treatment is in the range of 55 to 65 ° C, preferably 60 ° C. The pH range of the suspension of the present invention is 2.0 to 5.0, preferably 2.5 to 4.0.

The suspension of the present invention contains 1 part of ibuprofen.
-60 mg / ml can be blended. If necessary, other antipyretic analgesics, muscle relaxants, antispasmodics, antihistamines, sympathomimetics and the like can be added.

[0011]

INDUSTRIAL APPLICABILITY According to the present invention, a stable ibuprofen suspension which suppresses the release of ibuprofen is provided, and an ibuprofen suspension in which irritation and bitterness during administration are removed or reduced is provided.

[0012]

EXAMPLES Next, the present invention will be described in detail by showing Examples and Test Examples. Example 1 An aqueous solution in which a pH adjusting agent (phosphate buffer solution) was dissolved (pH
A preservative and a sweetener were added to 3.0) and completely dissolved. To the solution, TO10M as a surfactant and xanthan gum as a thickener were added and uniformly dispersed, and then ibuprofen and dihydrocodeine phosphate as another drug were added, and the entire mixture was uniformly dispersed with a homomixer. Purified water was added to adjust the total amount to 100%, and then heat treatment was performed at 55 to 65 ° C. for 20 minutes. (In 30 ml) Ibuprofen 144 mg TO10M 3.75 mg Xanthan gum 90 mg Sweetener 10000 mg Preservative proper amount.

Example 2 In the same manner as in Example 1, a suspension containing the following components was obtained. (In 30 ml) Ibuprofen 144 mg TO10M 3.75 mg Xanthan gum 60 mg Sweetener 10000 mg Preservative proper amount.

Example 3 In the same manner as in Example 1, a suspension containing the following components was obtained. (In 30 ml) Ibuprofen 150 mg Dihydrocodeine phosphate 8 mg TO10M 7.5 mg Xanthan gum 60 mg Sweetener 10000 mg Preservative A suitable amount.

Example 4 In the same manner as in Example 1, a suspension containing the following components was obtained. (In 30 ml) ibuprofen 100 mg acetaminophen 200 mg chlorpheniramine maleate 2.5 mg methylephedrine hydrochloride 20 mg TO10M 7.5 mg xanthan gum 60 mg sweetener 10000 mg preservative proper amount.

Example 5 In the same manner as in Example 1, a suspension containing the following components was obtained. (In 30 ml) ibuprofen 200 mg dihydrocodeine phosphate 8 mg chlorpheniramine maleate 2.5 mg dl-methylephedrine hydrochloride 20 mg lysozyme chloride 30 mg (potency) TO10M 7.5 mg xanthan gum 90 mg sweetener 10000 mg preservative proper amount.

Example 6 In the same manner as in Example 1, a suspension containing the following components was obtained. (In 30 ml) ibuprofen 200 mg dihydrocodeine phosphate 8 mg bromhexine hydrochloride 12 mg chlorpheniramine maleate 2.5 mg dl-methylephedrine hydrochloride 20 mg lysozyme chloride 30 mg (potency) TO10M 7.5 mg dextran 45 mg sweetener 10000 mg preservative.

Test Example 1 [Study of Surfactant Concentration] <Experimental Method> The liquid formulation shown in the following formulation example was used at room temperature or 60
After heating for 20 minutes at ℃ and cooling to room temperature, leave it at room temperature overnight, remove the ibuprofen particles by centrifugation, and then filter the supernatant with a 0.2 μm filter and HPLC.
The free ibuprofen concentration was quantified by the method.

Formulation Example (in 30 ml) Ibuprofen 450 mg Surfactant (TO10M) 0.0025 to 0.100% by weight pH 3.0 <Results> The results are shown in Table 1 below. Surfactant (TO1
0M) Suitable concentration is a very low concentration 0.0025 to 0.05
It was effective at wt%, and the free ibuprofen concentration was significantly reduced by the heat treatment at 60 ° C. for 20 minutes.

[0020]

[Table 1]

Test Example 2 [Study of Concentration of Thickener (Polymer)] <Experimental Method> The liquid formulation shown in the following formulation example was used at room temperature or 60
After heating for 20 minutes at ℃ and cooling to room temperature, leave it at room temperature overnight, remove the ibuprofen particles by centrifugation, and then filter the supernatant with a 0.2 μm filter and HPLC.
The free ibuprofen concentration was quantified by the method.

[0022]

[Table 2]

<Results> It was found that the behavior of free ibuprofen differs depending on the type of polymer, and that a polymer having a small surfactant-like action is effective. Also, 60 ℃,
The heat treatment for 20 minutes significantly reduced the free ibuprofen concentration.

[0024]

[Table 3]

ND: not determined.

Test Example 3 [Study on Stability] <Experimental Method> Water containing the thickening agent, surfactant, preservative, sweetening agent, pH adjusting agent, perfume and ibuprofen in the formulation of Comparative Example 1 in Table 4. Prepare the suspension with a homogenizer and
After heating at ~ 70 ° C for 20 minutes, cool to room temperature with water, and store at a temperature of 5, 25, 40, 50, 65 ° C for 1 week on the next day,
After returning to room temperature, stability was evaluated.

[0027]

[Table 4]

<Results> The results are shown in Table 5. Stability at low temperature by preparing an aqueous suspension containing a thickener, a surfactant, a preservative, a sweetener, a pH adjuster, a fragrance, and ibuprofen with a homogenizer and heating at 60 to 70 ° C for 20 minutes. Has improved.

[0029]

[Table 5]

* Evaluation method Appearance: The whiteness of the suspension is visually judged, and the whiteness of the suspension does not change to almost the same as pass (○), and the change-remarkably changes (whitening) does not. Pass (x), in between
Expressed as (△). Crystal precipitation: The size of the precipitated crystal is visually judged, and if the crystal size does not change to almost no change, it passes (○),
Those that increased to significantly increased were represented as rejects (x), and those in between were represented as (Δ).

Test Example 4 [Study of low temperature stability] <Experimental method> The components of Test Example 3 were blended, and the mixture was further heated at 65 ° C. for 2 hours.
After heating for 0 minutes, cool to room temperature with water,
It was stored at a temperature of 40, 50, and 65 ° C. for 1 week, returned to room temperature, and then examined for stability.

<Results> The results are shown in Table 6. Japanese Patent Laid-Open No. 1-258618 and Japanese Patent Laid-Open No. 2-8618 as in Comparative Example 1
The composition example shown in -286615 (surfactant.
1% or more of CMC-Na-added system) is unfavorable for commercial use because the stability of the suspension at a low temperature of 5 ° C is poor. The composition of the present invention was excellent in both low temperature stability and high temperature stability.

[0033]

[Table 6]

* Evaluation method Appearance: The whiteness of the suspension is visually judged, and if the whiteness does not change to almost no, it is acceptable (○), and if there is change to significant change (lightening), it is not. Pass (x), in between
Expressed as (△). Crystal precipitation: The size of the precipitated crystal is visually judged, and if the crystal size does not change to almost no change, it passes (○),
Those that increased to significantly increased were represented as rejects (x), and those in between were represented as (Δ).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display location A61K 47/34 A61K 47/34 H 47/36 47/36 Z J L (72) Inventor Toshiaki Nakajima 3-24-1 Takada, Toshima-ku, Tokyo Within Taisho Pharmaceutical Co., Ltd. (72) Inventor Kenji Tsunoda 3-24-1, Takada, Toshima-ku, Tokyo Within Taisho Pharmaceutical Co., Ltd.

Claims (7)

[Claims] 1. A suspension containing ibuprofen, which is heat-treated in the coexistence of ibuprofen, a thickener and a surfactant. 2. The ibuprofen suspension agent according to claim 1, wherein the thickener is xanthan gum, pullulan, dextran, hyaluronic acid, chondroitin sulfate, carrageenan, guar gum, tara gum, locust bean gum, sodium alginate, chito acid, tamarind gum. . 3. The ibuprofen suspension agent according to claim 1, wherein the thickener is xanthan gum, dextran, pullulan, sodium chondroitin sulfate, or sodium alginate. 4. The surfactant is sucrose fatty acid ester,
The ibuprofen suspension agent according to claim 1, which is a polyoxyl stearate, a polyoxyethylene polyoxypropylene glycol, or a polyoxyethylene monofatty acid ester. 5. A 1 to 60 mg amount of ibuprofen, 0.001 to 10% by weight of a thickening agent, and 0.001 to 10% by weight of a surfactant are added per 1 ml of a suspension agent. The ibuprofen suspension agent according to 1. 6. A suspension formulation containing 1 to 60 mg of ibuprofen, 0.001 to 3% by weight of a thickening agent, and 0.0025 to 2% by weight of a surfactant. The ibuprofen suspension agent according to 1. 7. The ibuprofen suspension agent according to claim 1, which is heat-treated in the range of 55 to 65 ° C.