JP6206069B2 - Solid preparation - Google Patents

Description

  The present invention relates to a solid preparation containing loxoprofen or a salt thereof and a dry aluminum hydroxide gel. More specifically, the present invention relates to a solid preparation capable of suppressing changes in appearance when blended with loxoprofen or a salt thereof and a dry aluminum hydroxide gel.

Loxoprofen is a phenylpropionic acid anti-inflammatory analgesic whose sodium salt has a proven track record as a pharmaceutical product. This component has a high track record in medical use as an anti-inflammatory analgesic and has features such as relatively light side effects such as gastric disorders.
Loxoprofen has already been studied in combination with various drugs because of its excellent pharmacological action. For example, enhancement of antipyretic action by blending with ketotifen fumarate (Patent Document 1), reduction of gastric disorder by blending thidium bromide (Patent Document 2), prevention of sneezing by blending with pseudoephedrine hydrochloride (Patent Document 3) Etc.

  On the other hand, dry aluminum hydroxide gel has a function as an antacid and is a drug used for antipyretic analgesics and gastrointestinal drugs. Therefore, the case where dry aluminum hydroxide gel was added together with loxoprofen or its salt is already known (patent documents 4 to 6).

It is known that an antipyretic analgesic component causes an interaction when blended with an antacid (Patent Document 7), and it was necessary to design a formulation in consideration of the interaction between these compounds in the formulation.
As an example, after granulating an antacid comprising a divalent or trivalent metal salt using an acid having a PKa = 5 or less or a salt thereof, a method of blending with an antipyretic analgesic component having an acid type carboxy group ( Patent document 7) is known. However, in this method, not only the antipyretic analgesic component and the antacid are isolated, but also the antacid is not granulated using an acid having a PKa = 5 or less or a salt thereof, and the composition change cannot be suppressed and is stable. In order to manufacture a formulation, it was necessary to employ a complicated manufacturing method. As another example, a method for stabilizing components by blending components that cause blending changes in the same granule (Patent Document 8) has been reported, but loxoprofen or a salt thereof and a dry aluminum hydroxide gel are isolated. It is not known to prevent changes in appearance.

Japanese Patent Laid-Open No. 2004-83579 JP 2000-26313 A Japanese Patent Application Laid-Open No. 2004-2362 JP 2006-52210 A JP 2012-51949 A JP 2012-51950 A JP2011-68645A JP 2006-328000 A

  In order to develop a pharmaceutical preparation containing loxoprofen or a salt thereof and a dry aluminum hydroxide gel, the present inventors first formulated these mixtures and examined their storage stability. There was a possibility that a color change to brown was observed due to an interaction, resulting in a decrease in commercial value.

  Accordingly, an object of the present invention is to provide a solid preparation capable of suppressing changes in appearance by a simple method without physically separating between these compounds even when blending loxoprofen or a salt thereof and a dry aluminum hydroxide gel. .

As a result of various investigations, the present inventors have not physically separated these compounds by blending a specific component with a powder containing loxoprofen or a salt thereof and a dry aluminum hydroxide gel. Has also found that the above problems can be solved, and has completed the present invention.
That is, the present invention
(1) (a) loxoprofen or a salt thereof, (b) a dried aluminum hydroxide gel, and (c) one or more inorganic salts selected from the group consisting of calcium lactate, sodium carbonate, sodium bicarbonate and magnesium carbonate A solid preparation characterized by
(2) The solid preparation according to (1), wherein loxoprofen or a salt thereof is loxoprofen sodium hydrate,
(3) With respect to 1 part by mass of component (a), 0.35 to 5.6 parts by mass of component (b) and 0.01 to 2.0 parts by mass of component (c) are characterized. The solid preparation according to (1) or (2),
(4) The solid preparation according to any one of (1) to (3), wherein the dosage form of the solid preparation is a capsule, a pill, a granule, a fine granule, a powder or a tablet,
It is.

  The pharmaceutical preparation of the present invention can suppress the interaction by a simple method without physically separating loxoprofen or a salt thereof and the dry aluminum hydroxide gel. Accordingly, it is possible to provide a solid preparation containing loxoprofen or a salt thereof and a dry aluminum hydroxide gel in which coloring of the preparation is prevented over a long period of time.

It is an external appearance when the tablets of Examples 1 to 4 are stored at 65 ° C. for 2 weeks. It is an external appearance when the tablets of Comparative Examples 1 to 4 are stored at 65 ° C. for 2 weeks.

Loxoprofen or a salt thereof used in the pharmaceutical preparation of the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate with water, alcohol or the like. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, as loxoprofen or a salt thereof,
Loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate) is preferred.

  The content of loxoprofen or a salt thereof in the solid preparation of the present invention is not particularly limited as long as it shows the medicinal effect, but it is 3. in terms of loxoprofen sodium anhydride relative to the total mass of the pharmaceutical composition. 0 to 80.0% by mass is preferable, more preferably 5.0 to 70.0% by mass, particularly preferably 6.0 to 60.0% by mass, and most preferably 7.0 to 50.0% by mass. is there.

  The content of the dry aluminum hydroxide gel in the solid preparation of the present invention is preferably 10.0 to 60.0 mass%, more preferably 15.0 to 50.0 mass%, based on the total mass of the solid preparation. .

  The content of the inorganic salt selected from the group consisting of calcium lactate, sodium carbonate, sodium hydrogen carbonate and magnesium carbonate in the solid preparation of the present invention is preferably 0.3 to 40.0% by mass relative to the total mass of the solid preparation, preferably Is 0.5-35.0 mass%.

  The lower limit of the blending ratio of loxoprofen or a salt thereof and dry aluminum hydroxide gel of the present invention is preferably 0.35 parts by mass with respect to 1 part by mass of loxoprofen or a salt thereof. This is because the appearance changes due to the interaction. The upper limit is preferably 5.6 parts by mass. More preferably, the compounding quantity with dry aluminum hydroxide gel with respect to 1 mass part of loxoprofen or its salt is 0.70-4.0 mass part. Moreover, the compounding ratio of loxoprofen of the present invention or a salt thereof and an inorganic salt selected from the group consisting of calcium lactate, sodium carbonate, sodium bicarbonate and magnesium carbonate is 0.01 to 2 with respect to 1 mass of loxoprofen or a salt thereof. 0.0 part by mass, preferably 0.05 to 1.5 parts by mass is preferred in terms of color suppression.

  The dosage form of the solid preparation of the present invention includes powders, fine granules, granules, pills, tablets (including film-coated tablets, sugar-coated tablets, laminated tablets), capsules, dry syrups, lozenges, etc. Examples include parenteral preparations such as drugs, but capsules, tablets or powders are particularly preferable.

The solid preparation of the present invention can be produced by a conventional method, and the method is not particularly limited, but (a) loxoprofen or a salt thereof, (b) a dried aluminum hydroxide gel, and (c) lactic acid. Even if the inorganic salt selected from the group consisting of calcium, sodium carbonate, sodium hydrogen carbonate and magnesium carbonate is blended so as to contact without being isolated, the interaction is suppressed, so these three components coexist. Such blending is significant in carrying out the present invention.
Specific examples of the solid preparation include the following forms.
1. It was obtained by mixing one or more inorganic salts selected from the group consisting of (a) loxoprofen or a salt thereof, (b) a dried aluminum hydroxide gel, and (c) calcium lactate, sodium carbonate, sodium bicarbonate and magnesium carbonate. Powders, granules, etc. and preparations coated with them.
2. (A) Loxoprofen or a salt thereof, (b) a dried aluminum hydroxide gel, and (c) one or more inorganic salts selected from the group consisting of calcium lactate, sodium carbonate, sodium bicarbonate and magnesium carbonate, and granulated Powders, granules and the like and preparations coated therewith.
3. A tablet containing the preparation of 1 or 2, and a preparation coated therewith.

  As the method for producing the solid preparation of the present invention, specifically, depending on the dosage form, any conventional method such as a direct tableting method, a wet granulation method, a dry granulation method and a melt granulation method can be used. Preferably it is manufactured.

  The pharmaceutical preparation of the present invention impairs the effects of the present invention in addition to loxoprofen or a salt thereof, a dry aluminum hydroxide gel and calcium lactate, sodium carbonate, sodium bicarbonate and magnesium carbonate. In other qualitative and quantitative ranges, other known additives such as excipients, disintegrants, binders, lubricants, antioxidants, coating agents, coloring agents, flavoring agents, surfactants, A plasticizer or the like may be mixed.

Below, this invention is demonstrated further in detail based on an Example and a comparative example. The present invention is not limited to these examples.
(Examples 1-7, Comparative Examples 1-5 and Reference Example 1)

(1) Manufacturing method of formulation (tablet) According to the mixing ratio shown in Table 1 below, various raw materials (excluding magnesium stearate) were mixed with 100 tablets of vinyl, and then passed through a sieve. In the case of wet granulation methods of Examples 1 to 7 and Comparative Examples 1 to 5, purified water is added to the powder after passing through a sieve and kneaded in a mortar, and left at 50 ° C. for 2 hours. After sufficiently drying, granules for tablet production were obtained. After drying, magnesium stearate was added to and mixed with the obtained granules, and tablets with a tablet diameter of 10 mm were obtained using a tabletop simple tablet molding machine (trade name: HANDTAB; Ichihashi Seiki). In the direct tableting method of Reference Example 1, magnesium stearate was added to and mixed with the powder after passing through a sieve, and tablets with a tablet diameter of 10 mm were obtained using a tabletop simple tablet molding machine. The obtained tablets were allowed to stand for 1 day at 25 ° C. and 60% RH, then sealed in a glass bottle, and stored for 2 weeks at 65 ° C., and then the appearance of the preparation was evaluated.

(2) Sensory evaluation About the tablet obtained by the Example, the comparative example, and the reference example, the external appearance evaluation by 2 expert panelists was implemented by sensory evaluation. The evaluation of the appearance of the preparation was performed by a relative comparison between a sample stored for 2 weeks in a 65 ° C. environment and the immediately following product, and evaluated by the following five-step evaluation. The criterion for accepting the appearance change was set to an average value of “2.0” or less.
The sensory evaluation results are shown in Table 1.

<Criteria>
0: No change
1: Slight change
2: Acceptable change but acceptable
3: Acknowledging obvious changes (unacceptable)
4: Recognize significant changes

(3) Color difference measurement About the tablet obtained by the Example, the comparative example, and the reference example, the color difference measurement of the sample preserve | saved for 2 weeks on 65 degreeC conditions was implemented for the tablet immediately after that as a control. For the measurement of the color difference, a spectrocolorimeter (trade name: SE6000; Nippon Denshoku Industries Co., Ltd.) was used. The color difference is measured on the front and back surfaces of 3 tablets at each point, and the lower ΔE ^* (ab) indicates that the color tone does not change.

ΔＬ^*=６５℃２週間保存品のＬ^*値−直後品のＬ^*値（Ｌ^*：明度 ＋は白方向，−は黒方向）
Δａ^*=６５℃２週間保存品のａ^*値−直後品のａ^*値（ａ^*：色度 ＋は赤方向，−は緑方向）
Δｂ^*=６５℃２週間保存品のｂ^*値−直後品のｂ^*値（ｂ^*：色度 ＋は黄方向，−は青方向）

ΔL ^* = 65 ℃ 2 week storage product L ^* value - immediately after product L ^* value (L ^*: lightness + white direction, - the black direction)
Δa ^* = 65 ℃ 2 week storage product of a ^* value - immediately after the goods of a ^* value (a ^*: chromaticity + red direction, - green direction)
Δb ^* = 65 ℃ 2 week storage product of b ^* value - immediately after article b ^* value (b ^*: Chromaticity + Huang direction, - the blue direction)

As is clear from the test results, although the tablet made without blending dry aluminum hydroxide gel with the powder containing loxoprofen sodium was slightly discolored (Reference Example 1), loxoprofen sodium and dry aluminum hydroxide The color difference result and sensory evaluation result of the tablet containing the gel showed high values, and the tablet surface was noticeably discolored to brown (Comparative Example 1). On the other hand, the color difference results and sensory evaluation results of the tablets containing calcium lactate, sodium carbonate, sodium hydrogen carbonate and magnesium carbonate shown in Examples 1 to 7 are low values, and the appearance change is suppressed. It was. In particular, when sodium carbonate and calcium lactate were blended, a remarkable discoloration suppressing effect was observed. On the other hand, about the tablet containing another inorganic salt calcium hydroxide, calcium carbonate, and potassium chloride, the discoloration to brown was not able to be suppressed (Comparative Examples 2-5).

  According to the present invention, the interaction between loxoprofen or a salt thereof and a dry aluminum hydroxide gel can be suppressed. Therefore, it has become possible to provide a solid preparation containing loxoprofen or a salt thereof and a dry aluminum hydroxide gel having excellent storage stability.

Claims (4)

(A) Loxoprofen or a salt thereof, (b) a dried aluminum hydroxide gel, and (c) one or more inorganic salts selected from the group consisting of calcium lactate, sodium carbonate, sodium bicarbonate and magnesium carbonate. A solid preparation. The solid preparation according to claim 1, wherein loxoprofen or a salt thereof is loxoprofen sodium hydrate. (A) 0.35 to 5.6 parts by mass of component (b) and 0.01 to 2.0 parts by mass of component (c) are added to 1 part by mass of component. Item 3. The solid preparation according to Item 1 or 2. The solid formulation in any one of Claims 1-3 whose dosage form of a solid formulation is a capsule, a pill, a granule, a fine granule, a powder, or a tablet.

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