JP4822095B2 - Antipyretic analgesic solid preparation - Google Patents
Antipyretic analgesic solid preparation Download PDFInfo
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- JP4822095B2 JP4822095B2 JP2005136804A JP2005136804A JP4822095B2 JP 4822095 B2 JP4822095 B2 JP 4822095B2 JP 2005136804 A JP2005136804 A JP 2005136804A JP 2005136804 A JP2005136804 A JP 2005136804A JP 4822095 B2 JP4822095 B2 JP 4822095B2
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- average particle
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- ibuprofen
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- etenzamide
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- 238000002360 preparation method Methods 0.000 title claims description 15
- 239000007787 solid Substances 0.000 title claims description 6
- 239000003907 antipyretic analgesic agent Substances 0.000 title description 7
- 239000002245 particle Substances 0.000 claims description 36
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 28
- 229960001680 ibuprofen Drugs 0.000 claims description 28
- SBNKFTQSBPKMBZ-UHFFFAOYSA-N ethenzamide Chemical compound CCOC1=CC=CC=C1C(N)=O SBNKFTQSBPKMBZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000004090 dissolution Methods 0.000 description 20
- 229940079593 drug Drugs 0.000 description 19
- 239000003814 drug Substances 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 230000000202 analgesic effect Effects 0.000 description 6
- 229960000514 ethenzamide Drugs 0.000 description 6
- 239000000843 powder Substances 0.000 description 5
- 230000007423 decrease Effects 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 230000001754 anti-pyretic effect Effects 0.000 description 3
- 239000002221 antipyretic Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- -1 fatty acid ester Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000007561 laser diffraction method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000000790 scattering method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 239000011882 ultra-fine particle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は解熱鎮痛作用を有する薬剤に関する。 The present invention relates to a drug having antipyretic analgesic action.
イブプロフェンは強力な解熱鎮痛作用を有し、以前より解熱鎮痛薬や総合感冒薬の有効成分として用いられる。従来、イブプロフェンと、解熱鎮痛薬の有効成分の１種であるエテンザミドを適切な配合比で投与すると、解熱鎮痛効果が相乗的に増加する事が開示されている（特許文献１）。 Ibuprofen has a strong antipyretic analgesic action and has been used as an active ingredient in antipyretic analgesics and general cold medicines. Conventionally, it has been disclosed that the antipyretic analgesic effect is synergistically increased when ibuprofen and etenzamide, which is one of active ingredients of antipyretic analgesics, are administered at an appropriate blending ratio (Patent Document 1).
解熱鎮痛薬は即効性が求められる薬剤であり、効果の発現時間が短いものが求められている。その様な中、イブプロフェンとエテンザミドを同時投与して即効性と相乗効果を同時に発現するには、イブプロフェンおよびエテンザミドの両薬物共に素早い溶出が求められる。 Antipyretic analgesics are drugs that are required to have immediate effects, and those that have a short onset time are required. Under such circumstances, in order to simultaneously express ibuprofen and etenzamide and to express immediate effects and synergistic effects at the same time, both ebuprofen and etenzamide drugs require rapid dissolution.
難溶性薬物の溶出性を向上するには、粒子径を小さくすることが一般的に行われている。そのため難溶性薬物の溶出性向上を目指してイブプロフェンなどの難溶性薬物の平均粒子径を１〜１５μｍにし、ポリグリセリン脂肪酸エステル等を配合した懸濁剤とする技術（特許文献２）、超難水溶性の薬物の溶出性を向上させるために１μｍ以下の超微粒子にする技術（特許文献３）などが知られている。 In order to improve the dissolution property of a poorly soluble drug, it is a common practice to reduce the particle size. Therefore, aiming to improve the dissolution property of a poorly soluble drug, a technique (Patent Document 2) that makes the average particle diameter of a poorly soluble drug such as ibuprofen 1 to 15 μm and blends a polyglycerin fatty acid ester, etc. In order to improve the dissolution property of the active drug, a technique for making ultrafine particles of 1 μm or less (Patent Document 3) is known.
このように薬物の溶出性向上のために薬物を微細化することは一般的に行われていることである。 Thus, it is common practice to refine a drug in order to improve drug dissolution.
本発明者らはイブプロフェンとエテンザミドを同時配合した製剤において両薬剤の溶出性を向上させるべく成分の微粒子化を行った。しかし、得られた製剤は満足できる溶出性を得ることはできなかった。 The inventors of the present invention made the components finer in order to improve the dissolution properties of both drugs in a preparation containing ibuprofen and etenzamide simultaneously. However, the obtained preparation could not obtain satisfactory dissolution properties.
本発明は、イブプロフェンとエテンザミドを同時配合した製剤において、両薬剤の溶出性を向上させた製剤の提供を目的とする。 An object of the present invention is to provide a preparation in which the dissolution properties of both drugs are improved in a preparation containing ibuprofen and etenzamide simultaneously.
本発明者らは課題を解決するために種々検討した結果、イブプロフェンとエテンザミドをそれぞれ特定の範囲の平均粒子径にすることにより、イブプロフェンとエテンザミド両方の溶出性が向上した即効性に優れた薬剤となることを見出し、本発明を完成した。 As a result of various investigations to solve the problem, the present inventors have determined that ibuprofen and etenzamide each have an average particle diameter in a specific range, thereby improving the dissolution properties of both ibuprofen and etezamide and The present invention was completed.
すなわち、本発明は平均粒子径５〜１００μmのエテンザミドおよび平均粒子径１５〜４０μmのイブプロフェンを含有する固形製剤である。 That is, the present invention is a solid preparation containing etenzamide having an average particle size of 5 to 100 μm and ibuprofen having an average particle size of 15 to 40 μm.
一般的に薬物の溶出性は平均粒子径が小さいほど増加するが、本発明の薬物の組み合わせでは一方の平均粒子径が小さくなりすぎると他方の溶出性を減少させるという驚くべき知見が得られており、それぞれの薬剤の平均粒子径がそれぞれ特定の範囲にはいることにより初めて両薬剤の溶出性が向上する。 In general, the dissolution property of a drug increases as the average particle size decreases. However, in the combination of the drugs of the present invention, a surprising finding has been obtained that if one of the average particle sizes becomes too small, the dissolution property of the other decreases. The dissolution of both drugs is not improved until the average particle size of the drugs is in a specific range.
イブプロフェンとエテンザミドの両薬剤を特定の平均粒子径範囲にすることにより、両薬剤とも溶出性が向上することがわかった。 It was found that by setting both ibuprofen and etezamide to a specific average particle size range, the dissolution of both drugs was improved.
本発明で配合するエテンザミドは平均粒子径５〜１００μmの範囲である必要がある。平均粒子径が大きすぎても小さすぎても、イブプロフェンの溶出性を低下させ、さらにエテンザミドの溶出性も低下させてしまうからである。 The etenzamide blended in the present invention needs to have an average particle size in the range of 5 to 100 μm. This is because, if the average particle size is too large or too small, the dissolution property of ibuprofen is reduced, and further, the dissolution property of etenzamid is also decreased.
本発明で配合するイブプロフェンは平均粒子径１５〜４０μmの範囲である必要がある。平均粒子径が大きすぎるとイブプロフェンの溶出性が低下し、平均粒子径が小さすぎると、イブプロフェンだけではなくエテンザミドの溶出性をも低下させてしまうからである。 The ibuprofen blended in the present invention needs to have an average particle diameter of 15 to 40 μm. This is because if the average particle size is too large, the dissolution property of ibuprofen decreases, and if the average particle size is too small, the dissolution property of not only ibuprofen but also ethenzamide decreases.
本発明で配合する薬物の平均粒子径はレーザー回折・散乱法により測定することができる。 The average particle size of the drug compounded in the present invention can be measured by a laser diffraction / scattering method.
本発明で配合する薬剤はジェットミル法などで粉砕することにより平均粒子径を調節することもできる。 The average particle size of the chemical compounded in the present invention can be adjusted by pulverization by a jet mill method or the like.
本発明でイブプロフェンの配合量は、解熱鎮痛効果の点から１回投与量あたり５０〜１５０mgが好ましい。また、エテンザミドの配合量は、解熱鎮痛効果の点から１回投与量あたり５０〜５００mgが好ましい。それらの配合比は解熱鎮痛作用の相乗効果の点からイブプロフェン１質量部あたりエテンザミドが０．０５〜１０質量部になる範囲が好ましい。 In the present invention, the amount of ibuprofen is preferably 50 to 150 mg per dose in terms of antipyretic analgesic effect. The amount of etenzamide is preferably 50 to 500 mg per dose from the viewpoint of antipyretic analgesic effect. Their blending ratio is preferably in the range of 0.05 to 10 parts by mass of ethenzamide per 1 part by mass of ibuprofen from the viewpoint of the synergistic effect of antipyretic analgesic action.
本発明の固形製剤は、平均粒子径を調整したイブプロフェンとエテンザミドを用いて、賦形剤、滑沢剤などの通常の成分を配合し、一般的な方法で製造することができる。 The solid preparation of the present invention can be produced by a general method by blending ordinary components such as excipients and lubricants using ibuprofen and etenzamide with an adjusted average particle size.
本発明の固形製剤の剤形は、錠剤、顆粒剤、粉剤、カプセル剤などの剤形にすることができる。 The dosage form of the solid preparation of the present invention may be a tablet, granule, powder, capsule or the like.
以下、本発明を実施例および試験例によりさらに詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to examples and test examples.
イブプロフェン（平均粒子径：２３．1μｍ，マイクロトラックにより分散圧０．２０MPaにて測定。以下同様。）１５．１２ｇ、エテンザミド（平均粒子径：２０．２μm）８．８２ｇ、結晶セルロース１．２２ｇ、ステアリン酸マグネシウム０．０７６ｇを秤量し、ポリエチレン製袋内にて均一になるように混合し、粉状製剤を得た。 15.12 g of ibuprofen (average particle size: 23.1 μm, measured with a microtrack at a dispersion pressure of 0.20 MPa, the same applies hereinafter), 15.82 g of etenzaamide (average particle size: 20.2 μm), 1.22 g of crystalline cellulose, 0.076 g of magnesium stearate was weighed and mixed uniformly in a polyethylene bag to obtain a powdery preparation.
比較例１
実施例１のイブプロフェン（平均粒子径２３．1μｍ）を、より粒子径の小さいイブプロフェン（平均粒子径１０．７μｍ）１５．１２ｇに替えて、実施例１と同様にして、比較用粉状製剤を得た。
Comparative Example 1
A powder preparation for comparison was prepared in the same manner as in Example 1, except that ibuprofen (average particle size 23.1 μm) in Example 1 was replaced with 15.12 g of ibuprofen (average particle size 10.7 μm) having a smaller particle size. Obtained.
比較例２
実施例１のイブプロフェン（平均粒子径２３．1μｍ）を、より粒子径の大きいイブプロフェン（平均粒子径５０．２μｍ）１５．１２ｇに替えて、実施例１と同様にして、比較用粉状製剤を得た。
Comparative Example 2
A powder preparation for comparison was prepared in the same manner as in Example 1, except that ibuprofen (average particle size 23.1 μm) of Example 1 was replaced with 15.12 g of ibuprofen (average particle size 50.2 μm) having a larger particle size. Obtained.
比較例３
実施例１のエテンザミド（平均粒子径：２０．２μm）を、より粒子径の小さいエテンザミド（平均粒子径：２．５μm）８．８２ｇに替えて、実施例１と同様にして、比較用粉状製剤を得た。
Comparative Example 3
A powdered powder for comparison was obtained in the same manner as in Example 1, except that ethenzamide (average particle size: 20.2 μm) of Example 1 was replaced with 8.82 g of ethenzamide (average particle size: 2.5 μm) having a smaller particle size. A formulation was obtained.
比較例４
実施例１のエテンザミド（平均粒子径：２０．２μm）を、より粒子径の大きいエテンザミド（平均粒子径：１７２．２μm）８．８２ｇに替えて、実施例１と同様にして、比較用粉状製剤を得た。
Comparative Example 4
A powdered powder for comparison was obtained in the same manner as in Example 1, except that ethenzamide (average particle size: 20.2 μm) of Example 1 was replaced with 8.82 g of ethenzamide (average particle size: 172.2 μm) having a larger particle size. A formulation was obtained.
試験例１（溶出試験）
実施例１、比較例１、比較例２、比較例３および比較例４で得られた製剤を日本薬局方一般試験法溶出試験法第２法（パドル法）に準拠して試験を実施した。試験液は精製水を用い、パドル回転数を毎分５０回転にて試験を行い溶出率（％）を求めた。イブプロフェンの溶出試験結果を表１および図１に、エテンザミドの溶出試験結果を表２および図２に示した。
Test example 1 (dissolution test)
The preparations obtained in Example 1, Comparative Example 1, Comparative Example 2, Comparative Example 3, and Comparative Example 4 were tested according to the Japanese Pharmacopoeia General Test Method Dissolution Test Method Method 2 (Paddle Method). The test solution was purified water and tested at a paddle rotation speed of 50 rotations per minute to determine the dissolution rate (%). The dissolution test results for ibuprofen are shown in Table 1 and FIG. 1, and the dissolution test results for etenzamide are shown in Table 2 and FIG.
表および図から明らかなように、驚くべきことに、一方の薬物の粒子径が他方の薬物の溶出性に大きく影響していることがわかった。 As is clear from the tables and figures, it was surprisingly found that the particle size of one drug greatly affects the dissolution properties of the other drug.
本発明により、イブプロフェンとエテンザミドの溶出性がともに優れた製剤を提供することが可能になったので、医薬品として有用である。 According to the present invention, it is possible to provide a preparation excellent in the dissolution properties of ibuprofen and etenzamide, which is useful as a pharmaceutical product.
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