JP5426195B2 - Stabilized oral fluid containing ibuprofen - Google Patents

Description

  The present invention relates to a technique for allowing ibuprofen to exist in an oral solution for a long period of time with excellent stability and uniformity.

  The suspension containing ibuprofen has a strong irritation feeling and bitterness when taken, and therefore a satisfactory feeling of taking cannot be obtained. This irritation and bitterness is thought to result from the release of ibuprofen, the growth of crystals, and precipitation / aggregation. Although there is a report on the bitterness masking of ibuprofen suspension, a satisfactory feeling of taking is not yet obtained (Patent Documents 1 and 2). In addition, in order to ensure the stability of the ibuprofen suspension, heat treatment in the presence of a thickener and a surfactant increases the adsorptivity of ibuprofen to the thickener, which improves the stability. Furthermore, it is known that the irritation and bitterness at the time of taking can be removed or reduced, but a sufficient stabilizing effect is not recognized (Patent Document 3).

JP-A-1-258618 JP-A-2-286615 JP-A-8-333245

  In order to solve the above-described problems as described above, the present inventor has conducted intensive research for many years on uniform dispersion of ibuprofen in the preparation process of ibuprofen oral solution. The present invention has been completed. In addition, the present inventor studied in order to solve the problems related to the prevention of sedimentation in the preparation of the suspension and the refinement of the target substance for ensuring uniform redispersibility. That is, until now, there has been a problem that it is difficult to pulverize with a low-melting-point material, or the cost is high.

The present invention is described below. That is, the present invention is (1) an oral liquid containing ibuprofen which has been emulsified by heating and melting in purified water and then converted into fine-crystal crystals.
(2) Furthermore, the internal use liquid as described in (1) containing surfactant and a thickener,
(3) The internal liquid according to (2), further containing a dispersant,
(4) The internal use liquid according to (3), wherein the surfactant is polyoxyethylene hydrogenated castor oil, the dispersant is hydroxypropylmethylcellulose, and the thickener is xanthan gum,
(5) The content of polyoxyethylene hydrogenated castor oil is 100-300 mg / 90 ml in the total amount of the liquid agent, the content of hydroxypropylmethylcellulose is 300-500 mg / 90 ml in the total amount of the liquid agent, and the content of xanthan gum Is the internal use liquid according to (4), wherein the total amount of the liquid is 150 to 300 mg / ml,
(6) The internal liquid according to any one of (1) to (5), wherein the median diameter of ibuprofen is 40 μm or less,
(7) The internal liquid according to any one of (1) to (5), wherein the median diameter of ibuprofen is 20 μm or less,
(8) The ratio of the median diameter of ibuprofen after storage and after production when the particle size distribution after storage at 40 ° C. for 3 months is measured by a laser diffraction method is 2.0 or less, (1)-( The internal use liquid according to any one of 5) selected from 5).

  The internal liquid containing ibuprofen obtained by the present invention has a median diameter in the ibuprofen solution that is within a certain range. This is useful because the state of the solution does not change.

The ibuprofen content of the internal liquid of the present invention is 300-500 mg / 90 ml, preferably 450 mg / 90 ml in the total amount of the liquid.
“Surfactant” means sucrose fatty acid esters, sugar esters, β-cyclodextrin, polyoxyethylene sorbitan monooleate (eg, polysorbate 80), polyoxylstearate, polyoxyethylene polyoxypropylene glycols, Surfactants such as polyoxyethylene hydrogenated castor oil and polyoxyethylene monofatty acid esters, preferably polyoxyethylene hydrogenated castor oil (for example, polyoxyethylene hydrogenated castor oil 60). The content of these surfactants is 100-700 mg / 90 ml in the total amount of the liquid agent. When used in combination with a dispersant, it is preferably 200 mg / 90 ml. When not used in combination with a dispersant, 400-700 mg / ml.

  The “dispersing agent” is a dispersing agent such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, and preferably hydroxypropyl methylcellulose. The content of these thickeners is 300-500 mg / 90 ml, preferably 400 mg / 90 ml, in the total amount of the liquid agent.

  `` Thickener '' is a thickener such as xanthan gum, pullulan, dextran, hyaluronic acid, chondroitin sulfate, carrageenan, guar gum, tara gum, locust bean gum, sodium alginate, chito acid, tamarind gum, Xanthan gum. The content of these thickeners is 50-250 mg / 90 ml, preferably 220 mg / 90 ml, in the total amount of the liquid preparation.

The “median diameter” is the particle diameter (cumulative average diameter) at which the cumulative curve becomes 50% when the cumulative curve is obtained with the total volume of one group of particle bodies as 100%.
In the present invention, various additives usually used in a suspending agent can be further contained. For example, sweeteners, preservatives, acidulants, fragrances, flavoring agents, thickeners, pH adjusters and the like.
Further, the product can be treated so as not to come into contact with oxygen, for example, by passing nitrogen gas through the preparation liquid or filling the space with nitrogen gas.

(General manufacturing method)
The internal liquid preparation of the present invention can be produced by the following method.
(1) Ibuprofen, surfactant and purified water are heated to 60-90 ° C. (preferably 75-85 ° C.), and ibuprofen and surfactant (preferably HCO-60, manufactured by Nikko Chemicals Co., Ltd.) The polyoxyethylene hydrogenated castor oil 60) is melted and then emulsified using a homomixer.
(2) After cooling the emulsion prepared in (1), a thickener dispersed in a base (for example, concentrated glycerin) is added to pre-warmed purified water and dissolved, and then emulsified in (1). Mix and disperse in addition to the liquid.
(3) Furthermore, after adding the liquid which melt | dissolved various additives in purified water, it prepares with purified water.

  The features of the present invention are (1) heating and melting ibuprofen in the presence of purified water, and solves the problem that it was difficult to pulverize with a low melting point material such as ibuprofen. In addition, the present invention is characterized by (2) a stable liquid agent by heating and melting ibuprofen in purified water, emulsifying by adding a surfactant, and further adding a thickener and a dispersing agent to prepare a liquid agent. Is adjusting. If the content of the surfactant, thickener and dispersant is too much or too little, a stable solution cannot be obtained. In the liquid preparation after adjustment, ibuprofen is suspended as particles having a uniform and suitable particle size. However, if the surfactant, thickener, dispersant, etc. are too much or too little, the particles become non-uniform due to repeated liquefaction and solidification, and the stability as a suspension is reduced. End up. A non-uniform suspension does not cause a problem only in the stability as a liquid for internal use, and is also a problem because it impairs the feeling of taking.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited by these examples.

Example 1
Take 5.0 g of ibuprofen, 5.0 g of HCO-60 and 60 g of purified water, heat to about 80 ° C., melt ibuprofen and HCO-60, and then emulsify this solution using a homomixer to obtain an emulsion. It was. After cooling the emulsified liquid, 1.5 g of xanthan gum dispersed in concentrated glycerin was added to and dissolved in pre-warmed purified water, and mixed and dispersed in the emulsified liquid. Further, 270 g of purified sucrose, 0.039 g of d-chlorpheniramine maleate, 0.533 g of dextromethorphan hydrobromide, 2.778 g of guaiacol sulfonic acid, 0.833 g of anhydrous caffeine, 1.0 g of sodium benzoate, citric acid After adding 2.778 g and a solution of sodium citrate dissolved in purified water, the solution was finally adjusted with purified water to produce 1 L of an oral solution.

(Example 2)
Take ibuprofen 5.0 g, HCO-60 5.0 g, sugar ester 0.5 g and 60 g of purified water, heat to about 80 ° C. and melt the ibuprofen and below, then emulsify this solution using a homomixer. A liquid was obtained. After cooling the emulsified liquid, 1.0 g of xanthan gum dispersed in concentrated glycerin was added to and dissolved in pre-warmed purified water, and added to the emulsified liquid and mixed and dispersed. Further, 270 g of purified sucrose, 0.039 g of d-chlorpheniramine maleate, 0.533 g of dextromethorphan hydrobromide, 2.778 g of guaiacol sulfonic acid, 0.833 g of anhydrous caffeine, 1.0 g of sodium benzoate, citric acid After adding 2.778 g and a solution of sodium citrate dissolved in purified water, the solution was finally adjusted with purified water to produce 1 L of an oral solution.

(Example 3)
Take 5.0 g of ibuprofen, 6.667 g of β cyclodextrin, 0.667 g of polysorbate 80 and 60 g of purified water, heat to about 80 ° C., melt the ibuprofen and below, and then emulsify this solution using a homomixer. A liquid was obtained. After cooling the emulsified liquid, 1.0 g of xanthan gum dispersed in concentrated glycerin was added to and dissolved in pre-warmed purified water, and added to the emulsified liquid and mixed and dispersed. Further, 270 g of purified sucrose, 0.039 g of d-chlorpheniramine maleate, 0.533 g of dextromethorphan hydrobromide, 2.778 g of guaiacol sulfonic acid, 0.833 g of anhydrous caffeine, 1.0 g of sodium benzoate, citric acid After adding 2.778 g and a solution of sodium citrate dissolved in purified water, the solution was finally adjusted with purified water to produce 1 L of an oral solution.

Example 4
Take 5.0 g of ibuprofen, 2.222 g of HCO-60 and 50 g of purified water, heat to about 80 ° C., melt ibuprofen and HCO-60, and then emulsify the liquid using a homomixer to obtain an emulsion. It was. After cooling the emulsified liquid, a solution prepared by dissolving 4.444 g of hydroxypropyl methylcellulose in 60 g of purified water is heated and added, and emulsified again. After cooling the emulsified liquid, xanthan gum (2.444 g) dispersed in concentrated glycerin was dissolved in pre-warmed purified water, added to the emulsified liquid, and mixed and dispersed. Furthermore, 260 g of purified sucrose, 0.083 g of dl-chlorpheniramine maleate, 0.266 g of dihydrocodeine phosphate, 0.666 g of dl-methylephedrine hydrochloride, 0.833 g of anhydrous caffeine, 0.75 g of sodium benzoate, 2. citric acid After adding a solution of 778 g and sodium citrate dissolved in purified water, the solution was finally adjusted with purified water to produce 1 L of an oral solution.

(Comparative Example 1)
The same amount of the same component as in Example 1 was measured, and each component was dispersed or dissolved in purified water using a homomixer to prepare an internal liquid. Ibuprofen was finely pulverized and dispersed without melting.
(Comparative Example 2)
The same amount of the same components as in Example 3 was measured, and each component was dispersed or dissolved in purified water using a homomixer to prepare an internal liquid. Ibuprofen was finely pulverized and dispersed without melting.

(Test example)
1. The particle size distribution of ibuprofen immediately after the preparation of the oral solution was measured by laser diffraction method, and the median diameter was determined as follows.

In Example 1-3, a finer particle size than Comparative Examples 1 and 2 was obtained. It was considered that the particle size largely depends on the particle size of the raw material before dispersion. When a low melting point material such as ibuprofen is used, industrially pulverizing by a normal method causes a problem such as melting-adhering to a pulverizer and a large loss, and when using a jet mill or the like. Therefore, it was thought that the inconvenience occurred that the facilities became large and that the production efficiency was unavoidable. However, according to the present invention, since ibuprofen is once melted and then subjected to steps of emulsification and suspension generation, it is not necessary to preliminarily define the particle size of the raw material, and it is excellent in that a uniform and fine particle size can be obtained. ing. In particular, Example 4 is superior in that a suspension of finer particles can be obtained than Example 1-3 by using a surfactant and a dispersant in combination.
2. The particle size distribution of ibuprofen after storing the oral solution at 40 ° C. for 3 months was measured by a laser diffraction method to determine the median diameter. The ratio of the median diameter after storage and immediately after production was determined.

実施例１−４では経時的に結晶の成長が少ないうえ、経時後の結晶の粒度も試験例の製造直後と変わりなく、服用に適するものであった。特に分散剤を併用した実施例４では粒度の変化はほとんど見られなかった。しかし、比較例１、２では結晶の成長が著しく、服用時にざらつき感を感じることがあると考えられる。本発明によれば微細な粒度が得られるだけでなく、安定性も優れていることが証明された。

In Example 1-4, there was little crystal growth over time, and the crystal grain size after the lapse of time was the same as that immediately after the production of the test example and was suitable for taking. Particularly in Example 4 in which a dispersant was used in combination, almost no change in particle size was observed. However, in Comparative Examples 1 and 2, the crystal growth is remarkable, and it is considered that a rough feeling may be felt at the time of taking. According to the present invention, it was proved that not only a fine particle size is obtained, but also the stability is excellent.

(Measurement of particle size distribution by laser diffraction method)
<Measurement conditions>
1. Equipment used: Laser diffraction / scattering particle size distribution analyzer (HORIBA LA-910)
2. Equipment conditions: Number of data acquisition: 20 times, relative refractive index: 1.28-0.00i, stirring (stirring speed of measuring solution tank): 3, circulation (circulating speed of measuring solution): 2, sonication: none 3 . Dispersion medium: purified water Measurement value display condition: Particle diameter standard: Volume, Frequency distribution scale: Fixed, Graph axis: LogX-LinearY
<Measurement procedure>
1. 1. Add dispersion medium to measurement solution tank Turn on stirring and circulation and wait for the noise to disappear (about 1 minute)
3. Perform a blank measurement (this resets the transmission to 100%)
4). Add the sample to the measurement solution tank (adjust the amount so that the transmittance is about 65 to 75%)
5. 5. When the measurement result is displayed, print the result. 6. Drain the solution from the measurement solution tank. Add purified water to clean the flow path system and turn on stirring and circulation (repeat twice)
8). After discarding the wash water, perform the next measurement (repeat 1-7)

Claims (7)

In purified water, and ibuprofen, polyoxyethylene hydrogenated castor oil was emulsified sugar esters, beta-cyclodextrin, and one or more surfactants selected from mono-oleate walk polyoxyethylene sorbitan after heated and melted An oral liquid containing ibuprofen in which xanthan gum dispersed in a base is added to a liquid and dissolved in warm purified water, and dispersed as fine crystal crystals. The internal use liquid according to claim 1, wherein the base is concentrated glycerin. Furthermore, the internal use liquid of Claim 1 or 2 containing a hydroxypropyl methylcellulose. The content of the surfactant according to claim 1 is 100-300 mg / 90 ml in the total amount of the liquid agent, the content of hydroxypropylmethylcellulose is 300-500 mg / 90 ml in the total amount of the liquid agent, and the content of xanthan gum The internal use liquid according to claim 3, wherein the total amount of the liquid is 150 to 300 mg / ml. The internal use liquid of any one selected from Claims 1-4 whose median diameter of ibuprofen is 40 micrometers or less. The oral solution according to any one of claims 1 to 4, wherein the median diameter of ibuprofen is 20 µm or less. The ratio of the median diameter of ibuprofen after storage and immediately after production when the particle size distribution after storage at 40 ° C. for 3 months is measured by laser diffraction is 2.0 or less. The internal use liquid of any one of the above.