JP2021138689A - Tablet, method for producing the same, and pharmaceutical - Google Patents
Tablet, method for producing the same, and pharmaceutical Download PDFInfo
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- JP2021138689A JP2021138689A JP2021028039A JP2021028039A JP2021138689A JP 2021138689 A JP2021138689 A JP 2021138689A JP 2021028039 A JP2021028039 A JP 2021028039A JP 2021028039 A JP2021028039 A JP 2021028039A JP 2021138689 A JP2021138689 A JP 2021138689A
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- tablet
- granules
- tablets
- granulated
- outside
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- 238000004519 manufacturing process Methods 0.000 title claims description 20
- 239000008187 granular material Substances 0.000 claims abstract description 151
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims abstract description 45
- 229960002373 loxoprofen Drugs 0.000 claims abstract description 43
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Abstract
Description
本発明は、錠剤、その製造方法、および医薬品に関する。より詳しくは、本発明は、ロキソプロフェン又はその塩を含有しつつ、保管時には錠剤の安定性が優れ、服用時には崩壊時間が適切であるとともに薬剤の溶出性に優れた錠剤、その製造方法、および医薬品に関する。 The present invention relates to tablets, methods for producing the same, and pharmaceuticals. More specifically, the present invention describes a tablet containing loxoprofen or a salt thereof, which has excellent tablet stability during storage, an appropriate disintegration time when taken, and an excellent drug dissolution method, a method for producing the same, and a pharmaceutical product. Regarding.
プロピオン酸系非ステロイド性解熱鎮痛消炎剤(以下、NSAIDsと称する)であるロキソプロフェンは、他のNSAIDsと同様なプロスタグランジン生合成の抑制作用を示すものの、強い解熱・鎮痛・抗炎症作用を有することが知られている。ロキソプロフェンは経口投与後に胃粘膜刺激作用の弱い未変化体のまま消化管から吸収され、体内で活性体となるプロドラッグであるため、他のNSAIDsと比較して胃粘膜障害は少ないという特徴を有することでも知られている(例えば、非特許文献1参照)。 Loxoprofen, a propionic acid-based non-steroidal antipyretic analgesic and anti-inflammatory drug (hereinafter referred to as NSAIDs), exhibits the same inhibitory effect on prostaglandin biosynthesis as other NSAIDs, but has strong antipyretic, analgesic, and anti-inflammatory effects. It is known. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract as an unchanged form with a weak gastric mucosal stimulating effect after oral administration and becomes an active substance in the body. It is also known (see, for example, Non-Patent Document 1).
ロキソプロフェン又はその塩と他の有効成分とを併用して経口投与することで胃粘膜障害を更に抑制する技術として、ロキソプロフェンに特定の糖類(乳糖、蔗糖、マルチトール、果糖、キシリトール又はラクチトール)を含有させる技術(特許文献1参照)、制酸剤(酸化マグネシウム)を含有させる技術(特許文献2参照)、抗プラスミン薬のトラネキサム酸を含有させる技術(特許文献3参照)などが開示されている。 Loxoprofen contains specific sugars (lactose, sucrose, maltitol, fructose, xylitol or lactitol) as a technique for further suppressing gastric mucosal damage by oral administration of loxoprofen or a salt thereof in combination with other active ingredients. A technique for containing a sucrose (see Patent Document 1), a technique for containing an antacid (magnesium oxide) (see Patent Document 2), a technique for containing a plasmin drug tranexamic acid (see Patent Document 3), and the like are disclosed.
また、ロキソプロフェンナトリウム又はその水和物は、吸湿性が高く、安定して製剤化すること、及び、製剤化後の保存安定性に優れた製剤とするのが困難であることが開示されている(特許文献4)。 Further, it is disclosed that it is difficult for loxoprofen sodium or its hydrate to be highly hygroscopic, to be stably formulated, and to be a preparation having excellent storage stability after formulation. (Patent Document 4).
また、速崩壊性錠剤としては、セチリジンを含む口腔内崩壊錠(特許文献5参照)が知られている。 Further, as a rapidly disintegrating tablet, an orally disintegrating tablet containing cetirizine (see Patent Document 5) is known.
しかし、ロキソプロフェン又はその塩を含む錠剤において、保管時には錠剤の保存安定性が優れ、服用時には崩壊時間が適切であるとともに薬剤の溶出性に優れた錠剤については知られていない。 However, among tablets containing loxoprofen or a salt thereof, there is no known tablet having excellent storage stability during storage, appropriate disintegration time at the time of administration, and excellent drug dissolution.
本発明の課題は、上述のような課題を解決するためになされたものであり、ロキソプロフェン又はその塩を含む錠剤において、「錠剤の保存安定性が改善されること」、「服用時に錠剤が適切な時間で崩壊・溶解すること」、および「服用時に薬剤の溶出性が改善すること」を実現するために、錠剤の崩壊性・溶解性に及ぼす影響は如何なるものかを明らかにすることである。本発明は、ロキソプロフェン又はその塩を含みつつも、保管時には安定であり、服用時には適切な時間で崩壊・溶解し、かつ、薬剤の溶出性が好適な錠剤を提供することを目的とする。 The problems of the present invention have been made to solve the above-mentioned problems, and in tablets containing loxoprofen or a salt thereof, "improvement of storage stability of tablets" and "tablets are suitable when taken". It is to clarify what kind of effect the tablet has on the disintegration / solubility in order to realize "disintegration / dissolution in a short time" and "improvement of drug dissolution when taken". .. An object of the present invention is to provide a tablet containing loxoprofen or a salt thereof, which is stable during storage, disintegrates and dissolves at an appropriate time when taken, and has suitable drug elution.
本発明者らは上記課題を解決するために鋭意検討した結果、ロキソプロフェン又はその塩を含む錠剤に、特定の組成および構造を設けることによって、ロキソプロフェン又はその塩を含みつつも、保管時には安定であり、服用時には適切な時間で崩壊・溶解し、かつ、薬剤の溶出性が好適な錠剤を見出し、本発明を完成するに至った。 As a result of diligent studies to solve the above problems, the present inventors have provided a tablet containing loxoprofen or a salt thereof with a specific composition and structure so that the tablet contains loxoprofen or a salt thereof but is stable during storage. The present invention has been completed by finding a tablet that disintegrates and dissolves in an appropriate time when taken and has a suitable dissolution property of the drug.
すなわち、本発明の態様は、以下に示す通りである。
(1) ロキソプロフェン又はその塩を含む少なくとも1つの造粒顆粒と、前記造粒顆粒を覆うように構成された顆粒外部とを含む、錠剤であって、
前記顆粒外部は、無水リン酸水素カルシウムと、低置換度ヒドロキシプロピルセルロースと、崩壊剤とを含む、
錠剤。
(2) 前記造粒顆粒および前記顆粒外部のうち少なくとも1つが、制酸剤をさらに含む、(1)に記載の錠剤。
(3) 前記崩壊剤が、クロスカルメロースナトリウムおよびクロスポピドンのうち少なくとも1つを含む、(1)または(2)に記載の錠剤。
(4) 前記造粒顆粒が、無水リン酸水素カルシウム及び低置換度ヒドロキシプロピルセルロースとは異なる第3の賦形剤をさらに含む、(1)から(3)のいずれか一に記載の錠剤。
(5) 前記顆粒外部が、無水リン酸水素カルシウム、低置換度ヒドロキシプロピルセルロース及び第3の賦形剤とは異なる第4の賦形剤をさらに含む、(4)に記載の錠剤。
(6) 前記顆粒外部が、滑沢剤をさらに含む、(1)から(5)のいずれか一に記載の錠剤。
(7) 第17改正日本薬局方の崩壊試験法に従い測定した場合に3分以内に崩壊が開始可能である、(1)から(6)のいずれか一に記載の錠剤。
(8) 造粒顆粒の水分値が5重量%未満である、(1)から(7)のいずれか一に記載の錠剤。
(9) 錠剤の水分値が5重量%未満である、(1)から(8)のいずれか一に記載の錠剤。
(10) ロキソプロフェン又はその塩を含む少なくとも1つの造粒顆粒を製造する工程;及び
前記造粒顆粒と、無水リン酸水素カルシウムと、低置換度ヒドロキシプロピルセルロースと、崩壊剤とを混合して、打錠することにより錠剤を製造する工程;
を含む、(1)から(9)のいずれか一に記載の錠剤の製造方法。
(11) (1)から(9)のいずれか一に記載の錠剤と、前記錠剤を包装する包装材と、を備える医薬品。
(12) 前記包装材が、防湿材料で形成されている、(11)に記載の医薬品。
That is, the aspect of the present invention is as shown below.
(1) A tablet comprising at least one granulated granule containing loxoprofen or a salt thereof and an outer surface of the granule configured to cover the granulated granule.
The outside of the granules contains anhydrous calcium hydrogen phosphate, low-degree-of-substitution hydroxypropyl cellulose, and a disintegrant.
tablet.
(2) The tablet according to (1), wherein at least one of the granulated granules and the outside of the granules further contains an antacid.
(3) The tablet according to (1) or (2), wherein the disintegrant contains at least one of croscarmellose sodium and crospopidone.
(4) The tablet according to any one of (1) to (3), wherein the granulated granules further contain a third excipient different from anhydrous calcium hydrogen phosphate and low-degree-of-substitution hydroxypropyl cellulose.
(5) The tablet according to (4), wherein the outside of the granule further contains anhydrous calcium hydrogen phosphate, low-degree-of-substitution hydroxypropyl cellulose, and a fourth excipient different from the third excipient.
(6) The tablet according to any one of (1) to (5), wherein the outside of the granule further contains a lubricant.
(7) The tablet according to any one of (1) to (6), wherein disintegration can be started within 3 minutes when measured according to the 17th revised Japanese Pharmacopoeia disintegration test method.
(8) The tablet according to any one of (1) to (7), wherein the water content of the granulated granules is less than 5% by weight.
(9) The tablet according to any one of (1) to (8), wherein the water content of the tablet is less than 5% by weight.
(10) A step of producing at least one granulated granule containing loxoprofen or a salt thereof; and the granulated granule, anhydrous calcium hydrogen phosphate, low-degree-of-substitution hydroxypropyl cellulose, and a disintegrant are mixed. The process of producing tablets by tableting;
The method for producing a tablet according to any one of (1) to (9), which comprises.
(11) A pharmaceutical product comprising the tablet according to any one of (1) to (9) and a packaging material for packaging the tablet.
(12) The pharmaceutical product according to (11), wherein the packaging material is made of a moisture-proof material.
本発明の錠剤は、ロキソプロフェン又はその塩を含有し、保存安定性が改善され、服用時における崩壊時間が適切であり、服用時における薬剤の溶出性が改善された優れた品質を有する錠剤として有用である。 The tablet of the present invention contains loxoprofen or a salt thereof, has improved storage stability, has an appropriate disintegration time at the time of administration, and is useful as a tablet having excellent quality with improved dissolution of the drug at the time of administration. Is.
<錠剤>
本発明の錠剤は、ロキソプロフェン又はその塩を含む、少なくとも1つの造粒顆粒と、前記造粒顆粒を覆うように構成された顆粒外部と、を備え、前記顆粒外部は、第1の賦形剤である無水リン酸水素カルシウムと、第2の賦形剤である低置換度ヒドロキシプロピルセルロースと、崩壊剤と、を含む。
なお、本発明における「錠剤が適切な時間で崩壊・溶解すること」とは、特に限定されないが、錠剤の服用後に適切な時間でロキソプロフェン又はその塩が放出されるように錠剤が崩壊・溶解することをいい、例えば、第17改正日本薬局方の「崩壊試験法」に従った錠剤の崩壊試験において、錠剤の崩壊時間が3.4分以内であってよい。また、本発明においては、錠剤の崩壊時間が3.4分以内である場合には、速崩壊性錠剤であると定義される。また、本発明における錠剤の崩壊時間は、上記錠剤の崩壊試験において、3分以内であることが好ましく、2.9分以内であることがより好ましく、2.7分以内であることがさらに好ましい。
<Tablet>
The tablet of the present invention comprises at least one granulated granule containing loxoprofen or a salt thereof and an outer granule configured to cover the granule, wherein the outer granule is a first excipient. Includes anhydrous calcium hydrogen phosphate, a second excipient, low-degree-of-substitution hydroxypropyl cellulose, and a disintegrant.
The term "tablet disintegrates and dissolves in an appropriate time" in the present invention is not particularly limited, but the tablet disintegrates and dissolves so that loxoprofen or a salt thereof is released at an appropriate time after taking the tablet. That is, for example, in the disintegration test of a tablet according to the "disintegration test method" of the 17th revised Japanese Pharmacopoeia, the disintegration time of the tablet may be 3.4 minutes or less. Further, in the present invention, when the disintegration time of the tablet is within 3.4 minutes, it is defined as a rapidly disintegrating tablet. Further, the disintegration time of the tablet in the present invention is preferably 3 minutes or less, more preferably 2.9 minutes or less, and further preferably 2.7 minutes or less in the tablet disintegration test. ..
第17改正日本薬局方の「崩壊試験法」の装置概要を以下に記載する。
1.装置
装置は、高さ138〜160mmで浸漬部の内径が97〜115mmの1000 mL低形ビーカー、37±2℃で温度調節可能な恒温槽、1分間29〜32往復、振幅53〜57mmで上下する試験器及び電動機からなっている。ビーカーに入れる試験液の量は、試験器が最も上がったとき、試験器の網面が液面から下へ少なくとも15 mm以上離れるようにし、試験器が最も下がったとき、網面はビーカーの底から25 mm以上で、試験器が完全に沈むことがあってはならない。電動機の上方及び下方への移動時間は等しくし、また上下の方向転換は、急ではなく滑らかに行われるようにする。試験器は垂直軸に沿って動作するようにし、水平方向に軸が動いたり移動したりしないようにする。
(i) 試験器:試験器には、長さ77.5±2.5 mm、内径20.7〜23 mm、厚さ1.0〜2.8 mmの両端が開口した透明な管6本と、これらの管を上下方向からはさみ垂直に立てておくための直径88〜92mm、厚さ5〜8.5mmの2枚のプラスチック板があり、これらの板には、それぞれ直径22〜26 mmの穴が6個、中心から等距離かつ等間隔で開いている。下のプラスチック板の下面には、網目の開き1.8〜2.2 mm、線径0.57〜0.66 mmの平らなステンレス網を取り付ける。試験器は、2枚のプラスチック板を貫く3本の支柱を用いて、組み立て固定する。試験器は第17改正日本薬局方の図6.09−1に示した構造に合うものである。ガラス管と網が規格に合っている限り、他の部分の多少の変更は可能で、例えば、ガラス管を試験器に固定するため、上のプラスチック板の上面及び下のプラスチック板の下面に、それぞれの穴に当たる部分に直径22〜26 mmの穴を6個開けた直径88〜92mm、厚さ0.5〜1 mmの耐酸性の金属板を取り付けてもよい。試験器はその中心軸に沿って上下運動できるように、電動機に適当な方法で吊るす。
The device outline of the "disintegration test method" of the 17th revision of the Japanese Pharmacopoeia is described below.
1. 1. Equipment The equipment is a 1000 mL low-profile beaker with a height of 138 to 160 mm and an inner diameter of 97 to 115 mm, a constant temperature bath with temperature control at 37 ± 2 ° C, 29 to 32 reciprocations per minute, and an amplitude of 53 to 57 mm. It consists of a tester and an electric motor. The amount of test solution to be placed in the beaker should be at least 15 mm below the liquid level when the tester is at its highest position, and when the tester is at its lowest level, the net surface is at the bottom of the beaker. The tester must not sink completely above 25 mm. The upward and downward travel times of the motor should be equal and the up and down turn should be smooth rather than abrupt. The tester should operate along a vertical axis so that the axis does not move or move horizontally.
(i) Tester: The tester includes six transparent tubes with a length of 77.5 ± 2.5 mm, an inner diameter of 20.7 to 23 mm, and a thickness of 1.0 to 2.8 mm with both ends open, and these tubes are sandwiched from above and below. There are two plastic plates with a diameter of 88-92 mm and a thickness of 5-8.5 mm for standing vertically, each of which has six holes 22-26 mm in diameter, equidistant from the center. It is open at regular intervals. A flat stainless steel mesh with a mesh opening of 1.8 to 2.2 mm and a wire diameter of 0.57 to 0.66 mm is attached to the underside of the lower plastic plate. The tester is assembled and fixed using three columns that penetrate two plastic plates. The tester conforms to the structure shown in Figure 6.091-1 of the 17th revised Japanese Pharmacopoeia. As long as the glass tube and mesh meet the specifications, some other parts can be changed, for example, on the upper surface of the upper plastic plate and the lower surface of the lower plastic plate to fix the glass tube to the tester. An acid-resistant metal plate having a diameter of 88 to 92 mm and a thickness of 0.5 to 1 mm may be attached to the portion corresponding to each hole with six holes having a diameter of 22 to 26 mm. The tester is hung on the motor in an appropriate manner so that it can move up and down along its central axis.
2.操作法
錠剤は、試験器の6本のガラス管にそれぞれに試料1個ずつを入れ、試験液に水を用いて、37±2℃で試験器を作動させる。適宜試験器を試験液から引き上げ、試料の崩壊の様子を観察する。試料の残留物をガラス管内に全く認めないとき試料は崩壊したものとし、6個の試料の崩壊時間を測定する。
2. Operation method For tablets, put one sample in each of the six glass tubes of the tester, use water as the test solution, and operate the tester at 37 ± 2 ° C. As appropriate, pull up the tester from the test solution and observe the state of sample disintegration. When no residue of the sample is found in the glass tube, the sample is assumed to have collapsed, and the decay time of 6 samples is measured.
[錠剤の硬度]
本発明の錠剤の硬度は、特に限定されないが、10kgf以上であることが好ましく、17〜20kgfであることがより好ましい。
[Hardness of tablets]
The hardness of the tablet of the present invention is not particularly limited, but is preferably 10 kgf or more, and more preferably 17 to 20 kgf.
[造粒顆粒]
本発明における造粒顆粒は、ロキソプロフェン又はその塩を含む。
本発明において「ロキソプロフェン又はその塩」とは、ロキソプロフェン又はその塩(含水塩を含む)であり、好適には、ロキソプロフェンナトリウムであり、さらに好適には、ロキソプロフェンナトリウム・2水和物である。
本発明で用いるロキソプロフェン又はその塩は、ロキソプロフェンナトリウム水和物として第17改正日本薬局方に収載されている。
[Granulated granules]
The granulated granules in the present invention contain loxoprofen or a salt thereof.
In the present invention, the "loxoprofen or a salt thereof" is loxoprofen or a salt thereof (including a hydrous salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.
Loxoprofen or a salt thereof used in the present invention is listed in the 17th revised Japanese Pharmacopoeia as loxoprofen sodium hydrate.
本発明の錠剤中に含まれるロキソプロフェン又はその塩の含有量としては、制限はされないが、成人1投与単位(1回投与量)あたりの錠剤に含まれる成分の量として、無水物換算量として好ましくは10〜180mg、より好ましくは30〜120mg、さらに好ましくは60〜90mgであり、投与回数は1日1〜3回である。 The content of loxoprofen or a salt thereof contained in the tablet of the present invention is not limited, but is preferably an anhydride-equivalent amount as the amount of the component contained in the tablet per adult 1 administration unit (single dose). Is 10 to 180 mg, more preferably 30 to 120 mg, still more preferably 60 to 90 mg, and the number of administrations is 1 to 3 times a day.
なお、本発明の錠剤において、造粒顆粒内に含まれるロキソプロフェン又はその塩の含有量としては、特に制限はされないが、成人1投与単位(1回投与量)あたりの錠剤に含まれる成分の量として、無水物換算量として好ましくは10〜180mg、より好ましくは30〜120mg、さらに好ましくは60〜90mgである。 In the tablet of the present invention, the content of loxoprofen or a salt thereof contained in the granulated granules is not particularly limited, but the amount of the component contained in the tablet per adult 1 administration unit (single dose). As an anhydride equivalent amount, it is preferably 10 to 180 mg, more preferably 30 to 120 mg, and further preferably 60 to 90 mg.
なお、造粒顆粒に含まれるロキソプロフェン又はその塩は、特に限定されないが、造粒顆粒100重量部当たり、1〜80重量部であり、20〜75重量部であることが好ましく、35.1〜70重量部であることがより好ましく、40〜60重量部であってもよい。 The amount of loxoprofen or a salt thereof contained in the granulated granules is not particularly limited, but is 1 to 80 parts by weight, preferably 20 to 75 parts by weight, preferably 35.1 to 100 parts by weight per 100 parts by weight of the granulated granules. It is more preferably 70 parts by weight, and may be 40 to 60 parts by weight.
[顆粒外部(造粒顆粒外部)]
本発明における顆粒外部(造粒顆粒外部)は、錠剤において造粒顆粒の外部を構成する部位である。
例えば、顆粒外部(造粒顆粒外部)は、錠剤において1つの造粒顆粒を覆うように構成された部位であってもよく、複数の造粒顆粒を覆うように構成された部位であってもよい。
[Outside of granules (outside of granulated granules)]
The outside of the granule (outside of the granulated granule) in the present invention is a portion constituting the outside of the granulated granule in the tablet.
For example, the outside of the granule (outside of the granulated granule) may be a site configured to cover one granulated granule in the tablet, or may be a site configured to cover a plurality of granulated granules. good.
例えば、顆粒外部は、錠剤において少なくとも1つの造粒顆粒を覆う部位であるとともに、錠剤の外面を構成する部位であってよい。
また、顆粒外部は、第1の賦形剤である無水リン酸水素カルシウムと、第2の賦形剤である低置換度ヒドロキシプロピルセルロースと、崩壊剤と、を含む。
なお、第1の賦形剤および第2の賦形剤と、崩壊剤と、は異なる化合物である。
ここで、「第1の賦形剤および第2の賦形剤と、崩壊剤と、は異なる化合物である」とは、顆粒外部の形成には、第1の賦形剤(無水リン酸水素カルシウム)と、第2の賦形剤(低置換度ヒドロキシプロピルセルロース)と、崩壊剤とで、3種類の異なる化合物を用いることを意味する。
互いに異なる3種類の化合物である、第1の賦形剤(無水リン酸水素カルシウム)と、第2の賦形剤(低置換度ヒドロキシプロピルセルロース)と、崩壊剤と、を含むことにより、「錠剤の保存安定性」、「服用時に錠剤が適切な時間で崩壊・溶解すること」、「服用時における薬剤の溶出性」といった錠剤の特性の改善を行うことができる。
For example, the outer surface of the granule may be a site covering at least one granulated granule in the tablet and a site constituting the outer surface of the tablet.
The outer surface of the granule contains anhydrous calcium hydrogen phosphate as a first excipient, low-degree-of-substitution hydroxypropyl cellulose as a second excipient, and a disintegrant.
The first and second excipients and the disintegrant are different compounds.
Here, "the first excipient, the second excipient, and the disintegrant are different compounds" means that the first excipient (hydroxic anhydride) is used for forming the outside of the granules. It means that three different compounds are used for calcium), a second excipient (low degree of substitution hydroxypropyl cellulose), and a disintegrant.
By containing a first excipient (anhydrous calcium hydrogen phosphate), a second excipient (low-degree-of-substitution hydroxypropyl cellulose), and a disintegrant, which are three different compounds, " It is possible to improve the characteristics of tablets such as "storage stability of tablets", "disintegration and dissolution of tablets at an appropriate time when taken", and "dissolution of drugs when taken".
顆粒外部に含まれる第1の賦形剤は、無水リン酸水素カルシウムである。
また、顆粒外部に含まれる第1の賦形剤としては、見掛け比容積が1.2〜5mL/gである無水リン酸水素カルシウムが好ましく、見掛け比容積が1.5〜4mL/gである無水リン酸水素カルシウムがより好ましい。
顆粒外部に含まれる第1の賦形剤が無水リン酸水素カルシウムであれば、錠剤の保管時における錠剤割れを防げるとともに、錠剤の服用時における導水作用により崩壊性に寄与しつつ、錠剤成型後(錠剤の保存の際、錠剤の服用前)に吸湿膨張することによる錠剤の割れのリスクが低く、保存安定性に優れた錠剤を得ることができる。
なお、顆粒外部に含まれる第1の賦形剤である無水リン酸水素カルシウムの含有量は、特に限定されないが、顆粒外部100重量部当たり、0.1〜30重量部であり、1〜25重量部であることが好ましく、2〜20重量部であることがより好ましく、3〜15重量部であってもよく、5〜10重量部であってもよい。
また、第1の賦形剤としての無水リン酸水素カルシウムは、例えば、医薬品添加物事典に収載されているものを用いてもよく、例えば、協和化学工業株式会社製、無水リン酸水素カルシウム(重質)を用いてもよい。
The first excipient contained outside the granules is anhydrous calcium hydrogen phosphate.
Further, as the first excipient contained outside the granules, anhydrous calcium hydrogen phosphate having an apparent specific volume of 1.2 to 5 mL / g is preferable, and the apparent specific volume is 1.5 to 4 mL / g. Anhydrous calcium hydrogen phosphate is more preferred.
If the first excipient contained on the outside of the granule is anhydrous calcium hydrogen phosphate, the tablet can be prevented from cracking during storage of the tablet, and the water-conducting action during the administration of the tablet contributes to disintegration, and after tablet molding. It is possible to obtain a tablet having excellent storage stability with a low risk of cracking of the tablet due to moisture absorption and expansion (when storing the tablet, before taking the tablet).
The content of anhydrous calcium hydrogen phosphate, which is the first excipient contained outside the granules, is not particularly limited, but is 0.1 to 30 parts by weight per 100 parts by weight outside the granules, and is 1 to 25 parts by weight. It is preferably 2 to 20 parts by weight, more preferably 3 to 15 parts by weight, or 5 to 10 parts by weight.
Further, as the anhydrous calcium hydrogen phosphate as the first excipient, for example, those listed in the Encyclopedia of Pharmaceutical Additives may be used, for example, anhydrous calcium hydrogen phosphate manufactured by Kyowa Chemical Industry Co., Ltd. ( Heavy) may be used.
顆粒外部に含まれる第2の賦形剤は、低置換度ヒドロキシプロピルセルロースである。
「低置換度ヒドロキシプロピルセルロース」とは、少量のヒドロキシプロポキシ基をグルコース環に導入したヒドロキシプロピルセルロース(ヒドロキシプロポキシ基が5.0〜16.0%であり、ブドウ糖1残基当たりの置換モル数が0.11〜0.39であるヒドロキシプロピルセルロース)である。
なお、市販の低置換度ヒドロキシプロピルセルロースは、第17改正日本薬局方に収載されているものを用いてもよく、医薬品添加物事典に収載されているものを用いてもよく、例えば、L−HPC(信越化学工業製)が挙げられる。
顆粒外部に含まれる第2の賦形剤が低置換度ヒドロキシプロピルセルロースであれば、錠剤成型後(錠剤の保存の際、錠剤の服用前)に吸湿膨張することによる錠剤の割れのリスクが低く、保存安定性に優れた錠剤を得ることができる。
なお、顆粒外部に含まれる第2の賦形剤である低置換度ヒドロキシプロピルセルロースの含有量は、特に限定されないが、顆粒外部100重量部当たり、0.1〜50重量部であり、1〜40重量部であることが好ましく、5〜35重量部であることがより好ましく、10〜35重量部であることがさらに好ましく、12〜20重量部であってもよい。
The second excipient contained outside the granules is low-substituted hydroxypropyl cellulose.
"Low-substituted hydroxypropyl cellulose" means hydroxypropyl cellulose in which a small amount of hydroxypropoxy groups are introduced into the glucose ring (hydroxypropoxy groups are 5.0 to 16.0%, and the number of moles substituted per glucose residue). (Hydroxypropyl cellulose) having a value of 0.11 to 0.39.
As the commercially available low-substituted hydroxypropyl cellulose, those listed in the 17th revised Japanese Pharmacopoeia may be used, or those listed in the Encyclopedia of Pharmaceutical Additives may be used, for example, L-. HPC (manufactured by Shin-Etsu Chemical Co., Ltd.) can be mentioned.
If the second excipient contained outside the granules is low-substituted hydroxypropyl cellulose, the risk of tablet cracking due to moisture absorption and expansion after tablet molding (during tablet storage, before taking tablets) is low. , A tablet having excellent storage stability can be obtained.
The content of low-substituted hydroxypropyl cellulose, which is a second excipient contained outside the granules, is not particularly limited, but is 0.1 to 50 parts by weight per 100 parts by weight outside the granules, and is 1 to 1 by weight. It is preferably 40 parts by weight, more preferably 5 to 35 parts by weight, further preferably 10 to 35 parts by weight, and may be 12 to 20 parts by weight.
顆粒外部に含まれる崩壊剤は、例えば、クロスカルメロースナトリウムまたはクロスポビドンであることが好ましい。
また、顆粒外部に含まれる崩壊剤は、クロスカルメロースナトリウムであることがより好ましい。
顆粒外部に含まれる崩壊剤がクロスポビドンであれば、錠剤の服用の際における錠剤の崩壊時間が適切であるとともに、錠剤成型後(錠剤の保存の際、錠剤の服用前)に吸湿膨張することによる錠剤の割れが防止される。
なお、本発明で用いるクロスカルメロースナトリウムまたはクロスポビドンは、例えば、医薬品添加物事典に収載されているものを用いることができる。
The disintegrant contained outside the granules is preferably, for example, croscarmellose sodium or crospovidone.
Further, the disintegrant contained outside the granules is more preferably croscarmellose sodium.
If the disintegrant contained outside the granules is crospovidone, the disintegration time of the tablet when taking the tablet is appropriate, and the tablet absorbs and expands after molding (when storing the tablet, before taking the tablet). The tablet is prevented from cracking due to.
As the croscarmellose sodium or crospovidone used in the present invention, for example, those listed in the Encyclopedia of Pharmaceutical Additives can be used.
顆粒外部に含まれる崩壊剤がクロスカルメロースナトリウムであれば、錠剤の服用の際における錠剤の崩壊時間が適切であるとともに、錠剤成型後(錠剤の保存の際、錠剤の服用前)に吸湿膨張することによる錠剤の割れが防止され、ロキソプロフェン又はその塩が溶出遅延することなく良好な安定性(良好な溶出安定性、例えば、錠剤保存後における薬剤の良好な溶出安定性)を達成することができる。
なお、顆粒外部に含まれる崩壊剤の含有量は、特に限定されないが、顆粒外部100重量部当たり、0.1〜65重量部であり、1〜60重量部であることが好ましく、10〜60重量部であることがより好ましく、15〜60重量部であることがさらに好ましく、15〜50重量部であってもよく、15〜40重量部であってもよく、15〜30重量部であってもよい。
If the disintegrant contained outside the granules is croscarmellose sodium, the disintegration time of the tablet during tablet administration is appropriate, and the tablet absorbs and expands after tablet molding (during tablet storage, before tablet administration). The tablet can be prevented from cracking and good stability (good elution stability, for example, good elution stability of the drug after tablet storage) can be achieved without delaying elution of loxoprofen or a salt thereof. can.
The content of the disintegrant contained in the outside of the granule is not particularly limited, but is 0.1 to 65 parts by weight, preferably 1 to 60 parts by weight, and 10 to 60 parts by weight per 100 parts by weight of the outside of the granule. It is more preferably parts by weight, more preferably 15 to 60 parts by weight, and may be 15 to 50 parts by weight, 15 to 40 parts by weight, or 15 to 30 parts by weight. You may.
[造粒顆粒および/または顆粒外部における任意成分]
本発明における造粒顆粒は、賦形剤(第3の賦形剤)を含んでいてもよい。
造粒顆粒に含まれる賦形剤(第3の賦形剤)は、例えば、結晶セルロース、粉末セルロース、バレイショデンプン、トウモロコシデンプン、軽質無水ケイ酸、含水二酸化ケイ素、二酸化ケイ素、沈降炭酸カルシウム、無水リン酸水素カルシウム、酸化マグネシウム、乳酸カルシウム、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウム、合成ヒドロタルサイト、合成ケイ酸アルミニウム、乳糖、白糖、D−マンニトール、エリスリトール、ブドウ糖、果糖等から選ばれる1種又は2種以上の成分を配合することができる。
この中でも、造粒顆粒に含まれる賦形剤(第3の賦形剤)は、無水リン酸水素カルシウムであることが好ましく、見掛け比容積が1.2mL/g未満である無水リン酸水素カルシウムであることがより好ましく、見掛け比容積が1.15mL/g以下である無水リン酸水素カルシウムであることがさらに好ましい。
造粒顆粒に含まれる賦形剤(第3の賦形剤)が無水リン酸水素カルシウムであれば、錠剤の服用時における水の導入による造粒顆粒の崩壊が容易となる。
なお、造粒顆粒に含まれる第3の賦形剤の含有量は、特に限定されないが、造粒顆粒100重量部当たり、0.1〜30重量部であり、1〜20重量部であることが好ましく、5〜15重量部であることがより好ましい。
また、第3の賦形剤としての無水リン酸水素カルシウムは、例えば、医薬品添加物事典に収載されているものを用いることができる。
[Granulated granules and / or optional components outside the granules]
The granulated granules in the present invention may contain an excipient (third excipient).
Excipients contained in the granulated granules (third excipient) are, for example, crystalline cellulose, powdered cellulose, potato starch, corn starch, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous. One selected from calcium hydrogen phosphate, magnesium oxide, calcium lactate, calcium silicate, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose, etc. Alternatively, two or more kinds of components can be blended.
Among these, the excipient (third excipient) contained in the granulated granules is preferably anhydrous calcium hydrogen phosphate, and has an apparent specific volume of less than 1.2 mL / g. Is more preferable, and anhydrous calcium hydrogen phosphate having an apparent specific volume of 1.15 mL / g or less is further preferable.
If the excipient (third excipient) contained in the granulated granules is anhydrous calcium hydrogen phosphate, the granulated granules can be easily disintegrated by the introduction of water when taking tablets.
The content of the third excipient contained in the granulated granules is not particularly limited, but is 0.1 to 30 parts by weight and 1 to 20 parts by weight per 100 parts by weight of the granulated granules. Is preferable, and 5 to 15 parts by weight is more preferable.
Further, as the anhydrous calcium hydrogen phosphate as the third excipient, for example, those listed in the Encyclopedia of Pharmaceutical Additives can be used.
造粒顆粒、および、顆粒外部のうち少なくとも1つは、制酸剤を含んでいてもよい。
換言すれば、造粒顆粒および顆粒外部のうちいずれか一方が制酸剤を含んでいてもよく、造粒顆粒および顆粒外部の両方が制酸剤を含んでいてもよい。
錠剤における造粒顆粒、および、顆粒外部のうち少なくとも1つに制酸剤が含まれていれば、好適に胃粘膜障害を抑制することができる。
造粒顆粒、および、顆粒外部のうち少なくとも1つに含まれる制酸剤は、例えば、グリシン(アミノ酢酸とも呼ばれる)、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウムアルミニウム、酸化マグネシウム、水酸化マグネシウム、水酸化マグネシウム・硫酸アルミニウムカリウムの共沈生成物、炭酸マグネシウム、合成ヒドロタルサイト、メタケイ酸アルミン酸マグネシウム、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、水酸化アルミナマグネシウム、水酸化アルミニウムゲル、水酸化アルミニウム・炭酸水素ナトリウム共沈生成物、水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲル、水酸化アルミニウム・炭酸マグネシウム・炭酸カルシウム共沈生成物、ベントナイト、ケイ酸カルシウム、炭酸カルシウム、沈降炭酸カルシウム、リン酸水素カルシウム、無水リン酸水素カルシウム等のマグネシウム、アルミニウム及びカルシウム塩、乾燥炭酸ナトリウム、水酸化ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム水和物、リン酸水素ナトリウム水和物、無水リン酸一水素ナトリウム、水酸化カリウム、炭酸水素カリウム、炭酸カリウム等のナトリウム及びカリウムから選ばれる塩等の胃酸のpHをあげる成分が挙げられる。
At least one of the granulated granules and the outside of the granules may contain an antacid.
In other words, either one of the granulated granules and the outside of the granules may contain an antacid, and both the granulated granules and the outside of the granules may contain an antacid.
If at least one of the granulated granules in the tablet and the outside of the granules contains an antacid, gastric mucosal damage can be suitably suppressed.
The acid-forming agent contained in the granulated granules and at least one of the outside of the granules includes, for example, glycine (also called aminoacetic acid), magnesium silicate, magnesium silicate aluminate, magnesium aluminum silicate, magnesium oxide, and water. Magnesium oxide, co-precipitated products of magnesium hydroxide and potassium aluminum hydroxide, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium hydroxide, aluminum hydroxide gel , Aluminum hydroxide / sodium hydrogen carbonate co-precipitated product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate co-precipitated product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, Magnesium hydrogen phosphate, anhydrous calcium hydrogen phosphate and other magnesium, aluminum and calcium salts, dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous monohydrogen phosphate Examples thereof include components that raise the pH of stomach acids such as sodium and salts selected from potassium such as sodium, potassium hydroxide, potassium hydrogencarbonate, and potassium carbonate.
この中でも、錠剤における造粒顆粒、および、顆粒外部のうち少なくとも1つに含まれる制酸剤は、メタケイ酸アルミン酸マグネシウムであることが好ましい。
錠剤における造粒顆粒に、メタケイ酸アルミン酸マグネシウムが含まれていれば、胃粘膜障害抑制効果が得られることに加えて、造粒顆粒の硬度が向上する。
錠剤における顆粒外部に、メタケイ酸アルミン酸マグネシウムが含まれていれば、胃粘膜障害抑制効果が得られることに加えて、崩壊時間を短縮することができる。
造粒顆粒の硬度の向上の観点、および、錠剤の崩壊時間の短縮の観点から、本発明の錠剤においては、造粒顆粒および顆粒外部の両方に、メタケイ酸アルミン酸マグネシウムを含むことがより好ましい。
なお、本発明で用いるメタケイ酸アルミン酸マグネシウムは、例えば、医薬品添加物事典に収載されているものを用いることができる。
Among these, the antacid contained in at least one of the granulated granules in the tablet and the outside of the granules is preferably magnesium aluminometasilicate.
If magnesium aluminometasilicate is contained in the granulated granules in the tablet, the hardness of the granulated granules is improved in addition to the effect of suppressing gastric mucosal damage.
If magnesium aluminometasilicate is contained outside the granules in the tablet, the effect of suppressing gastric mucosal damage can be obtained and the disintegration time can be shortened.
From the viewpoint of improving the hardness of the granulated granules and shortening the disintegration time of the tablets, it is more preferable that the tablets of the present invention contain magnesium aluminometasilicate in both the granulated granules and the outside of the granules. ..
As the magnesium aluminate metasilicate used in the present invention, for example, those listed in the Encyclopedia of Pharmaceutical Additives can be used.
なお、造粒顆粒に含まれる制酸剤の含有量は、特に限定されないが、造粒顆粒100重量部当たり、0.1〜80重量部であり、15〜70重量部であることが好ましく、30〜60重量部であることがより好ましい。
なお、顆粒外部に含まれる制酸剤の含有量は、特に限定されないが、顆粒外部100重量部当たり、0.1〜70重量部であり、1〜65重量部であることが好ましく、10〜60重量部であることがより好ましく、20〜60重量部であることがさらに好ましく、30〜50重量部であることが特に好ましく、35〜50重量部であってもよく、40〜50重量部であってもよい。
The content of the antacid contained in the granulated granules is not particularly limited, but is 0.1 to 80 parts by weight, preferably 15 to 70 parts by weight, per 100 parts by weight of the granulated granules. More preferably, it is 30 to 60 parts by weight.
The content of the antioxidant contained in the outside of the granule is not particularly limited, but is 0.1 to 70 parts by weight, preferably 1 to 65 parts by weight, preferably 10 to 65 parts by weight per 100 parts by weight of the outside of the granule. It is more preferably 60 parts by weight, further preferably 20 to 60 parts by weight, particularly preferably 30 to 50 parts by weight, and may be 35 to 50 parts by weight, 40 to 50 parts by weight. It may be.
造粒顆粒、および、顆粒外部のうち少なくとも1つは、胃腸薬成分を含んでいてもよい。
胃腸薬成分としては、ゲファルナート、セトラキサート塩酸塩、レバミピド、ソファルコン、テプレノン、メチルメチオニンスルホニウムクロリド等があげられる。
At least one of the granulated granules and the outside of the granules may contain a gastrointestinal drug component.
Examples of the gastrointestinal drug component include gefarnate, cetraxate hydrochloride, rebamipide, sofalcone, teprenone, methylmethionine sulfonium chloride and the like.
造粒顆粒の水分値は、特に限定されないが、5重量%未満であることが好ましく、4重量%以下であることがより好ましく、3重量%以下であることがさらに好ましく、2重量%以下であることが特に好ましい。また、造粒顆粒の水分値が2重量%以下であれば、ロキソプロフェンの含量低下を抑制することができるとともに、長期安定性に優れた錠剤が得られる。
また、錠剤(素錠)の水分値は、特に限定されないが、5重量%未満であることが好ましく、4重量%以下であることがより好ましく、3重量%以下であることがさらに好ましく、2重量%以下であることが特に好ましい。また、錠剤(素錠)の水分値が3重量%以下であれば、ロキソプロフェンの含量低下を抑制することができるとともに、長期安定性に優れた錠剤が得られる。
The water content of the granulated granules is not particularly limited, but is preferably less than 5% by weight, more preferably 4% by weight or less, further preferably 3% by weight or less, and 2% by weight or less. It is particularly preferable to have. Further, when the water content of the granulated granules is 2% by weight or less, a decrease in the content of loxoprofen can be suppressed, and a tablet having excellent long-term stability can be obtained.
The water content of the tablet (uncoated tablet) is not particularly limited, but is preferably less than 5% by weight, more preferably 4% by weight or less, and further preferably 3% by weight or less. It is particularly preferable that the weight is% by weight or less. Further, when the water content of the tablet (uncoated tablet) is 3% by weight or less, a decrease in the content of loxoprofen can be suppressed, and a tablet having excellent long-term stability can be obtained.
顆粒外部は、「任意の賦形剤(第4の賦形剤)」を含んでいてもよい。
任意の賦形剤(第4の賦形剤)とは、例えば、結晶セルロース、粉末セルロース、バレイショデンプン、トウモロコシデンプン、軽質無水ケイ酸、含水二酸化ケイ素、二酸化ケイ素、沈降炭酸カルシウム、無水リン酸水素カルシウム、酸化マグネシウム、乳酸カルシウム、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウム、合成ヒドロタルサイト、合成ケイ酸アルミニウム、乳糖、白糖、D−マンニトール、エリスリトール、ブドウ糖、果糖等から選ばれる1種又は2種以上の成分を配合することができる。
顆粒外部に含まれる任意の賦形剤(第4の賦形剤)は、乳糖であることが好ましい。
顆粒外部に含まれる任意の賦形剤(第4の賦形剤)が乳糖であれば、「錠剤の保存安定性の改善」、「服用時に錠剤が適切な時間で崩壊・溶解すること」、「服用時における薬剤の溶出性および安定性が改善すること」といった3つの効果がより好適に得られる。
なお、顆粒外部に含まれる第4の賦形剤の含有量は、特に限定されないが、顆粒外部100重量部当たり、0.1〜70重量部であり、1〜50重量部であることが好ましく、2〜40重量部であることがより好ましく、3〜30重量部であることがさらに好ましく、5〜20重量部であることが特に好ましい。
なお、本発明で用いる第4の賦形剤としての乳糖は、例えば、医薬品添加物事典に収載されているものを用いることができる。
The outside of the granule may contain "any excipient (fourth excipient)".
The optional excipient (fourth excipient) is, for example, crystalline cellulose, powdered cellulose, potato starch, corn starch, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous hydrogen phosphate. One or two selected from calcium, magnesium oxide, calcium lactate, calcium silicate, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose, etc. The above ingredients can be blended.
Any excipient (fourth excipient) contained outside the granules is preferably lactose.
If any excipient (fourth excipient) contained outside the granules is lactose, "improvement of tablet storage stability", "tablet disintegrates and dissolves in an appropriate time when taken", Three effects such as "improvement of elution and stability of the drug at the time of administration" can be more preferably obtained.
The content of the fourth excipient contained outside the granules is not particularly limited, but is 0.1 to 70 parts by weight, preferably 1 to 50 parts by weight, per 100 parts by weight outside the granules. , 2 to 40 parts by weight, more preferably 3 to 30 parts by weight, and particularly preferably 5 to 20 parts by weight.
As the lactose as the fourth excipient used in the present invention, for example, those listed in the Encyclopedia of Pharmaceutical Additives can be used.
顆粒外部は、滑沢剤を含んでいてもよい。
滑沢剤とは、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、ポリエチレングリコール、硬化油等から選ばれる1種又は2種以上の成分を配合することができる。
顆粒外部に含まれる滑沢剤は、ステアリン酸マグネシウムであることが好ましい。
なお、顆粒外部に含まれる滑沢剤の含有量は、特に限定されないが、顆粒外部100重量部当たり、0.1〜10重量部であってよい。
The outside of the granules may contain a lubricant.
The lubricant may contain one or more components selected from, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, hydrogenated oil and the like.
The lubricant contained outside the granules is preferably magnesium stearate.
The content of the lubricant contained outside the granules is not particularly limited, but may be 0.1 to 10 parts by weight per 100 parts by weight outside the granules.
本発明の錠剤は、好適には発熱、痛み、炎症を抑制する目的で使用することができる。有効成分であるロキソプロフェン又はその塩は、解熱鎮痛抗炎症作用を有していることから、鎮痛剤及び解熱剤として、特に、頭痛、月経痛(生理痛)、歯痛、抜歯後疼痛、咽喉痛、腰痛、関節痛、筋肉痛、肩こり痛、耳痛、打撲痛、骨折痛、ねんざ痛、外傷痛等の鎮痛、悪寒・発熱時の解熱に好適に使用され、又、感冒治療剤として、かぜの諸症状(鼻水、鼻づまり、せき、たん、のどの痛み、発熱、悪寒、頭痛、くしゃみ、関節の痛み、筋肉の痛み)の緩和を目的として好適に使用することができる。 The tablets of the present invention can be preferably used for the purpose of suppressing fever, pain and inflammation. Since the active ingredient, loxoprofen or a salt thereof, has an analgesic and anti-inflammatory effect, it is used as an analgesic and an analgesic, especially headache, menstrual pain (physiological pain), toothache, post-extraction pain, sore throat, and lower back pain. , Joint pain, muscle pain, stiff shoulder pain, ear pain, bruising pain, fracture pain, numbness pain, traumatic pain, etc. It can be suitably used for the purpose of alleviating various symptoms (nasal discharge, stuffy nose, cough, tan, sore throat, fever, cold, headache, squeezing, joint pain, muscle pain).
本発明の錠剤は、例えば、錠剤(口腔内崩壊錠、チュアブル錠、発泡錠、分散錠、溶解錠などを含む)、口腔用錠剤(トローチ剤、舌下錠、バッカル錠、付着錠などを含む)などの、第十七改正日本薬局方 製剤総則等に記載の剤形とすることができる。
これらの組成物には、更に、必要に応じてその他の有効成分、例えば、鎮咳・去痰剤、抗ヒスタミン剤、抗炎症剤、抗コリン剤、その他のビタミン類、キサンチン誘導体、鎮静剤を、本発明を損なわない範囲内で適宜配合してもよく、それらに配合禁忌があれば、適宜顆粒分け等を行い製剤化すればよい。
顆粒分けとしては、例えば、配合禁忌があれば、配合禁忌を避けるように、造粒顆粒と、顆粒外部と、で異なる有効成分が含まれるように顆粒分けを行えばよい。
The tablets of the present invention include, for example, tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolving tablets, etc.), oral tablets (troche agents, sublingual tablets, buccal tablets, adhesive tablets, etc.). ), Etc., can be the dosage form described in the 17th revised Japanese Pharmacopoeia General Regulations for Formulations, etc.
Further, if necessary, other active ingredients such as antitussive / expectorant, antihistamine, anti-inflammatory agent, anticholinergic agent, other vitamins, xanthine derivative, and sedative are added to these compositions. It may be appropriately blended within a range that does not impair it, and if there are any contraindications to blending, it may be formulated by appropriately granulating or the like.
As the granule division, for example, if there is a contraindication for compounding, the granules may be segmented so that different active ingredients are contained in the granulated granules and the outside of the granules so as to avoid the contraindications for compounding.
鎮咳・去痰剤としては、例えば、コデイン、コデインリン酸塩水和物、ジヒドロコデイン、ジヒドロコデインリン酸塩、ジブナートナトリウム、ジメモルファンリン酸塩、チペピジンクエン酸塩、チペピジンヒベンズ酸塩、デキストロメトルファン、デキストロメトルファン臭化水素酸塩水和物、デキストロメトルファンフェノールフタリン塩、ノスカピン塩酸塩、トリメトキノール塩酸塩、フェニレフリン塩酸塩、プソイドエフェドリン塩酸塩、プソイドエフェドリン硫酸塩、l−メチルエフェドリン塩酸塩、dl−メチルエフェドリン塩酸塩、アンブロキソール塩酸塩、ブロムヘキシン塩酸塩等があげられる。 Antitussive / sputum preparations include, for example, codeine, codeine phosphate hydrate, dihydrocodein, dihydrocodein phosphate, dibunato sodium, dimemorphan phosphate, tipepidin citrate, tipepidin hibenzate, dextromethorphan, dextromethorphan. Lomethorphan hydrobromide hydrate, dextromethorphanphenol phthalin salt, noscapine hydrochloride, trimetokinol hydrochloride, phenilefurin hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methyl Examples thereof include efedrin hydrochloride, ambroxol hydrochloride, bromhexin hydrochloride and the like.
抗ヒスタミン剤としては、例えば、アゼラスチン塩酸塩、アリメマジン酒石酸塩、エバスチン、エピナスチン塩酸塩、エメダスチンフマル酸塩、オキサトミド、オロパタジン塩酸塩、カルビノキサミン、クレマスチンフマル酸塩、ジフェニルジスルホン酸塩、カルビノキサミンマレイン酸塩、d−クロルフェニラミンマレイン酸塩、dl−クロルフェニラミンマレイン酸塩、ケトチフェンフマル酸塩、ジフェニルピラリン塩酸塩、ジフェニルピラリンテオクル酸塩、ジフェンヒドラミン塩酸塩、ジフェンヒドラミンサリチル酸塩、ジフェンヒドラミンタンニン酸塩、トリプロリジン塩酸塩、トリペレナミン塩酸塩、トンジルアミン塩酸塩、フェキソフェナジン、フェネタジン塩酸塩、プロメタジン塩酸塩、プロメタジン、メキタジン、メトジラジン塩酸塩、ロラタジン等が挙げられる。 Examples of antihistamines include azerastin hydrochloride, alimemazine tartrate, evastin, epinastine hydrochloride, emedastin fumarate, oxatomide, olopatazine hydrochloride, carbinoxamine, cremastine fumarate, diphenyldisulfonate, carbinoxamine maleic acid. Salt, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotiphenfumarate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydraminetannate, Examples thereof include triprolidine hydrochloride, tryperenamine hydrochloride, tonsylamine hydrochloride, fexophenazine, phenetazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, metodylazine hydrochloride, loratazine and the like.
抗炎症剤としては、グリチルリチン酸及びその誘導体並びにそれらの塩類(例えば、グリチルリチン酸二カリウム、グリチルリチン酸モノアンモニウム等)、トラネキサム酸等が挙げられる。 Examples of the anti-inflammatory agent include glycyrrhizic acid and its derivatives, salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid and the like.
抗コリン剤としては、スコポラミン臭化水素酸塩、ダツラエキス、メチルスコポラミン臭化物、メチル−l−ヒヨスチアミン臭化物、ピレンゼピン塩酸塩、ブチルスコポラミン臭化物、ベラドンナアルカロイド、ベラドンナエキス、ベラドンナ総アルカロイド、ヨウ化イソプロパミド、ヨウ化ジフェニルピペリジノメチルジオキソラン、ロートエキス、ロート根、ロート根総アルカロイドクエン酸塩等が挙げられる。 Anticholinergic agents include scopolamine hydrobromide, dazzling extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pyrenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, isopropamide iodide, yo. Examples thereof include diphenylpiperidinomethyldioxolane, scopolia extract, scopolia root, and scopolia total alkaloid citrate.
ビタミン類としては、ビタミンA、ビタミンC、ビタミンB1、ビタミンB2、ビタミンB5、ビタミンB6、ビタミンB12、ビタミンP、ビタミンE、ニコチン酸、ニコチン酸アミド、パンテノール、パントテン酸カルシウム、パントテン酸ナトリウム、ビオチン、アスパラギン酸カリウム・マグネシウム等等量混合物、イノシトールヘキサニコチネート、ウルソデオキシコール酸、L−システイン、L−塩酸システイン、オロチン、ガンマーオリザノール、グリセロリン酸カルシウム、グルコン酸カルシウム、グルクノラクトン、グルクロン酸アミド、コンドロイチン硫酸ナトリウム、ニンジン、ヨクイニン、ヨウ酸があげられる。 Vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, nicotinic acid, nicotinic acid amide, pantenol, calcium pantothenate, sodium pantothenate, etc. Equal mixture of biotin, potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, glucnolactone, glucuronic acid amide , Chondroitin sodium sulfate, carrots, yoquinin, iodine.
キサンチン誘導体としては、カフェイン水和物、無水カフェイン、安息香酸ナトリウムカフェイン、クエン酸カフェインがあげられる。
鎮静剤としては、アリルイソプロピルアセチル尿素、ブロムワレリル尿素があげられる。
Examples of the xanthine derivative include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate.
Examples of the sedative include allyl isopropyl acetyl urea and bromvalerylurea.
本発明の錠剤は、常法に従って製剤化することができる。
本発明においては、ロキソプロフェン又はその塩を含む造粒顆粒を製造し、得られた造粒顆粒に、顆粒外部を形成するように、後末として第1の賦形剤である無水リン酸水素カルシウムと、第2の賦形剤である低置換度ヒドロキシプロピルセルロースと、崩壊剤と、滑沢剤を加え、打錠することにより、錠剤を製造してよい。即ち、本発明の錠剤は、ロキソプロフェン又はその塩を含む少なくとも1つの造粒顆粒を製造する工程;及び前記造粒顆粒と、無水リン酸水素カルシウムと、低置換度ヒドロキシプロピルセルロースと、崩壊剤と、所望によりその他の添加剤を混合して、打錠することにより錠剤を製造する工程により製造することができる。
また、上述の「錠剤」の項に示すように、任意で造粒顆粒および、顆粒外部に添加物(制酸剤、胃腸薬成分、第3の賦形剤、第4の賦形剤などの任意成分)を加えて、製造すればよい。
なお、顆粒外部に配置する成分は、任意で顆粒状としてもよい。
The tablet of the present invention can be formulated according to a conventional method.
In the present invention, granulated granules containing loxoprofen or a salt thereof are produced, and anhydrous calcium hydrogen phosphate, which is a first excipient as a terminal, is formed on the obtained granulated granules so as to form the outside of the granules. A tablet may be produced by adding a second excipient, low-substituted hydroxypropyl cellulose, a disintegrant, and a lubricant, and tableting. That is, the tablet of the present invention is a step of producing at least one granulated granule containing loxoprofen or a salt thereof; and the granulated granule, anhydrous calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose, and a disintegrant. , If desired, it can be produced by a step of producing a tablet by mixing other additives and tableting.
In addition, as shown in the above-mentioned "tablet" section, optionally granulated granules and additives (antacids, gastrointestinal drug components, third excipients, fourth excipients, etc.) on the outside of the granules, etc. Any component) may be added to produce the product.
The component arranged outside the granule may be optionally in the form of granules.
製剤化にあたっては、公知の方法と添加剤を適宜用いて製剤化することができる。添加剤は、本発明の効果を損なわない範囲で適宜加えればよい。
添加剤としては、任意のコーティング剤、結合剤、流動化剤、可塑剤、糖衣剤、光沢化剤、溶剤、pH調節剤、着色剤、矯味剤、甘味剤、香料、着香剤・香料等をあげることができる。
In the formulation, a known method and additives can be appropriately used for the formulation. Additives may be appropriately added as long as the effects of the present invention are not impaired.
Additives include arbitrary coating agents, binders, fluidizers, plasticizers, sugar coating agents, brighteners, solvents, pH adjusters, colorants, flavoring agents, sweeteners, fragrances, flavoring agents / fragrances, etc. Can be given.
任意のコーティング剤としては、例えば、アミノアルキルメタクリレートコポリマー、アラビアゴム、エチルセルロース、カルナウバロウ、カルボキシビニルポリマー、ステアリン酸マグネシウム、タルク、セラック、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、プルラン、ポビドン、ポリビニルアルコール、マクロゴール等から選ばれる1種又は2種以上の成分を配合することができる。 Optional coatings include, for example, aminoalkyl methacrylate copolymers, gum arabic, ethyl cellulose, carnauba wax, carboxyvinyl polymers, magnesium stearate, talc, cellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pullulan, povidone, polyvinyl alcohol, macrogol. One kind or two or more kinds of ingredients selected from the above can be blended.
結合剤としては、例えば、アラビアゴム、アラビアゴム末、カンテン、カンテン末、寒梅粉、ゼラチン、セラック、ヒドロキシプロピルスターチ、ヒドロキシプロピルセルロース、ヒプロメロース、プルラン、ポビドン、ポリビニルアルコール、メタクリル酸コポリマーL、メタクリル酸コポリマー、メタクリル酸ブチル・メタクリル酸メチルコポリマー、メチルセルロース等から選ばれる1種又は2種以上の成分を配合することができる。 Examples of the binder include arabic rubber, arabic rubber powder, canten, canten powder, cold plum powder, gelatin, cellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol, methacrylic acid copolymer L, and methacrylic acid. One or more components selected from copolymers, butyl methacrylate / methyl methacrylate copolymers, methyl cellulose and the like can be blended.
流動化剤としては、例えば、含水二酸化ケイ素、軽質無水ケイ酸、合成ケイ酸アルミニウム、重質無水ケイ酸、水酸化アルミナマグネシウム、第三リン酸カルシウム、タルク、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム造粒物等から選ばれる1種又は2種以上の成分を配合することができる。 Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium hydroxide hydroxide, calcium tertiary phosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate. One kind or two or more kinds of components selected from granules and the like can be blended.
可塑剤としては、クエン酸トリエチル、グリセリン、グリセリン脂肪酸エステル、中鎖脂肪酸トリグリセリド、トリアセチン、濃グリセリン、ヒマシ油、プロピレングリコール、ポリオキシエチレン(105)ポリオキシプロピレン(5)グリコール、ポリソルベート80、マクロゴール400、マクロゴール600、マクロゴール1500、マクロゴール4000、マクロゴール6000、マクロゴール6000NF、モノステアリン酸グリセリン、リノール酸イソプロピル、流動パラフィン等から選ばれる1種又は2種以上の成分を配合することができる。 Plastic agents include triethyl citrate, glycerin, glycerin fatty acid ester, medium chain fatty acid triglyceride, triacetin, concentrated glycerin, castor oil, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol. One or more components selected from 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glycerin monostearate, isopropyl linoleate, liquid paraffin, etc. may be blended. can.
糖衣剤としては、アラビアゴム、アラビアゴム末、エチルセルロース、カルナウバロウ、カルメロースナトリウム、酸化チタン、ステアリン酸、ステアリン酸ポリオキシル40、精製ゼラチン、精製セラック、精製白糖、ゼラチン、セラック、タルク、沈降炭酸カルシウム、白色セラック、白糖、ヒドロキシプロピルセルロース、ヒプロメロース、プルラン、ポビドン、ポリオキシエチレン、ポリビニルアルコール、マクロゴール等から選ばれる1種又は2種以上の成分を配合することができる。 As sugar coating agents, arabic rubber, arabic rubber powder, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl stearate 40, refined gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, One or more components selected from white shellac, sucrose, hydroxypropyl cellulose, hypromellose, purulan, povidone, polyoxyethylene, polyvinyl alcohol, macrogol and the like can be blended.
光沢化剤としては、カルナウバロウ、精製セラック、マクロゴール、ミツロウ等から選ばれる1種又は2種以上の成分を配合することができる。 As the brightener, one or more components selected from carnauba wax, purified shellac, macrogol, beeswax and the like can be blended.
溶剤としては、イソプロパノール、エタノール、グリセリン、1,3−ブチレングリコール、プロピレングリコール、マクロゴール等から選ばれる1種又は2種以上の成分を配合することができる。 As the solvent, one or more components selected from isopropanol, ethanol, glycerin, 1,3-butylene glycol, propylene glycol, macrogol and the like can be blended.
pH調節剤としては、塩酸、酢酸、リン酸、乳酸、クエン酸、コハク酸、酒石酸、炭酸水素ナトリウム、炭酸ナトリウム、水酸化ナトリウム、水酸化カリウム、トリエタノールアミン等から選ばれる1種又は2種以上の成分を配合することができる。 As the pH adjuster, one or two selected from hydrochloric acid, acetic acid, phosphoric acid, lactic acid, citric acid, succinic acid, tartaric acid, sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine and the like. The above ingredients can be blended.
着色剤としては、黄酸化鉄、褐色酸化鉄、カーボンブラック、カラメル、β―カロテン、カンゾウエキス、黒酸化鉄、酸化チタン、黄色三二酸化鉄、三二酸化鉄、三二酸化鉄・グリセリン懸濁液、食用青色2号アルミニウムレーキ、食用黄色4号アルミニウムレーキ、銅クロロフィリンナトリウム、リボフラビン、リボフラビン酪酸エステル、リボフラビンリン酸エステルナトリウム、緑茶末、ローズ油等から選ばれる1種又は2種以上の成分を配合することができる。 Coloring agents include yellow iron oxide, brown iron oxide, carbon black, caramel, β-carotene, citrus extract, black iron oxide, titanium oxide, yellow iron sesquioxide, iron sesquioxide, iron sesquioxide / glycerin suspension, Contains one or more ingredients selected from edible blue No. 2 aluminum lake, edible yellow No. 4 aluminum lake, sodium copper chlorophyllin, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc. be able to.
矯味剤としては、塩化ナトリウム、オウバク末、オウヒエキス、オウレン、オウレン末、オレンジ、オレンジ油、カカオ末、果糖、カラメル、カンゾウ、カンゾウエキス、カンゾウ末、キシリトール、クエン酸カルシウム、クエン酸水和物、クエン酸ナトリウム水和物、L−グルタミン酸、L−グルタミン酸ナトリウム、グレープフルーツエキス、黒砂糖、ケイヒ末、ケイヒ油、サッカリン、サッカリンナトリウム水和物、サンショウ末、酒石酸、D−酒石酸、酒石酸水素カリウム、DL−酒石酸ナトリウム、ショウキョウ末、スクラロース、ステビアエキス、ステビア抽出精製物、センブリ、D−ソルビトール、タンニン酸、チョウジ油、チンピチンキ、トウガラシ、トウガラシ末、トウヒ末、トレハロース水和物、ニガキ末、梅肉エキス、フラクトオリゴ糖、粉糖、ペパーミントパウダー、D−マンニトール、dl−メントール、l−メントール、メントールパウダー、リュウノウ、リュウノウ末、緑茶末、DL−リンゴ酸、DL−リンゴ酸ナトリウム、レモン油、ローズ油等から選ばれる1種又は2種以上の成分を配合することができる。 As a flavoring agent, sodium chloride, powdered pearl oyster, powdered pearl oyster extract, oleum powder, powdered aulen powder, orange, orange oil, powdered cacao, fructose, caramel, citrus fruit, citrus extract, citrus powder, xylitol, calcium citrate, tartaric acid hydrate, Sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, kei powder, kei oil, saccharin, saccharin sodium hydrate, sansho powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL -Sodium tartaric acid, powdered ginger, sclerose, stevia extract, purified stevia extract, sembly, D-sorbitol, tannic acid, chow oil, chimpi tincture, capsicum, powdered pepper, powdered pepper, trehalose hydrate, powdered nigaki, plum meat Extract, fructo-oligosaccharide, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, ryunou, ryunou powder, green tea powder, DL-citric acid, DL-sodium malate, lemon oil, rose oil One kind or two or more kinds of ingredients selected from the above can be blended.
甘味剤としては、アスパルテーム、アセスルファムカリウム、アマチャ、アマチャ末、還元麦芽糖水アメ、カンゾウ、カンゾウエキス、カンゾウ末、キシリトール、グリチルリチン酸二カリウム、グリチルリチン酸二ナトリウム、サッカリン、サッカリンナトリウム水和物、スクラロース、ステビアエキス、ステビア抽出精製物、精製白糖、果糖、白糖、マルチトール、D−マンニトール、エリスリトール等から選ばれる1種又は2種以上の成分を配合することができる。 As sweeteners, aspartame, acesulfame potassium, amacha, amacha powder, reduced malt sugar water candy, kanzo, kanzo extract, kanzo powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, sucralose, sodium saccharin hydrate, sucralose, stevia One or more components selected from extracts, stevia extract purified products, purified sucralose, fructose, sucralose, maltitol, D-mannitol, erythritol and the like can be blended.
香料としては、オレンジフレーバー、ガラナエキス、スイートオレンジ、ストロベリー、黒糖フレーバー、ストロベリーフレーバー、チェリーフレーバー、バナナパウダーフレーバー、ピーチエッセンス、フルーツエッセンス、ペパーミント、メロンパウダーフレーバー、l−メントール、ハッカ油等から選ばれる1種又は2種以上の成分を配合することができる。 The flavor is selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, peppermint oil, etc. One kind or two or more kinds of ingredients can be blended.
着香剤・香料としては、ウイキョウ末、ウイキョウ油、エチルバニリン、オレンジ、オレンジエキス、オレンジエッセンス、オレンジ油、カミツレ油、カラメル、カンゾウ末、d−カンフル、dl−カンフル、ケイヒ末、ケイヒ油、シトロネラー油、シュガーフレーバー、スペアミント油、チェリーフレーバー、チョウジ油、チリフレーバー、トウヒチンキ、トウヒ油、パインオイル、ハッカ油、バニラフレーバー、バニリン、ビターエッセンス、ビタベース、ヒマラヤスギ油、フルーツフレーバー、フレーバーG1、ヘスペリジンペパーミントエッセンス、ベルガモット油、ベルモットフレーバー、d−ボルネオール、dl−ボルネオール、マッチャ、ミックスフレーバー、ミントフレーバー、dl−メントール、l−メントール、ユーカリ油、ラベンダー油、リュウノウ、リュウノウ末、レモンパウダー、レモン油、ローズ水、ローズ油、ハッカ油等から選ばれる1種又は2種以上の成分を配合することができる。 As flavoring agents and fragrances, uikyo powder, uikyo oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, kanzo powder, d-campul, dl-campul, keihi powder, keihi oil, Citronella oil, sugar flavor, spare mint oil, cherry flavor, chow oil, chili flavor, tohi tincture, touhi oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, bita base, Himalayan cedar oil, fruit flavor, flavor G1, hesperidin Peppermint Essence, Bergamot Oil, Belmot Flavor, d-Borneol, dl-Borneol, Matcher, Mixed Flavor, Mint Flavor, dl-Mentor, l-Mentor, Eucalyptus Oil, Lavender Oil, Ryunou, Ryunou Powder, Lemon Powder, Lemon Oil, One or more components selected from rose water, rose oil, peppermint oil and the like can be blended.
これら添加物は、上記に挙げたものに限定されるものではなく、また、これらのうち1種を用いてもよいし、2種以上を組み合わせて用いてもよい。 These additives are not limited to those listed above, and one of them may be used, or two or more of them may be used in combination.
本発明の錠剤を、SP包装、PTP包装、スティック包装、瓶包装等により一旦包装して気密保存してもよい。さらにそれらをピロー包装してもよく、それらを箱等に格納してもよい。
換言すれば、本発明の一実施形態に係る医薬品は、上記実施形態に係る錠剤と、前記錠剤を包装する包装材と、を備えていてもよい。
SP包装、PTP包装、スティック包装、ピロー包装に用いられる材料としては、特に限定されず、例えば、ポリエチレン、ポリプロピレンフィルム、ポリエチレンテレフタレートフィルム、ポリエチレンフィルム等の樹脂フィルムやこれら樹脂フィルムにアルミニウム箔を付着させたものを用いることができる。
The tablet of the present invention may be once packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, or the like and stored in an airtight manner. Further, they may be pillow-wrapped, or they may be stored in a box or the like.
In other words, the pharmaceutical product according to the embodiment of the present invention may include the tablet according to the embodiment and the packaging material for packaging the tablet.
The material used for SP packaging, PTP packaging, stick packaging, and pillow packaging is not particularly limited, and for example, a resin film such as polyethylene, polypropylene film, polyethylene terephthalate film, or polyethylene film, or an aluminum foil is attached to these resin films. Can be used.
本発明の錠剤の包装材料は、例えば、水分の影響を受けにくい材質の包装(防湿材料により形成された包装)が好ましい。
例えば、水分の影響が低い材質の包装(防湿材料)として、PTP(ポリプロピレン)+ポリエチレンアルミニウムピロー包装(PTPとポリエチレンアルミニウムピローとの組み合わせ包装)としてもよい。また、錠剤における水分値の上昇抑制、錠剤の保存安定性、開封後の錠剤安定性などを考慮し、水分の影響を受けにくい材質の包装(防湿材料)として、両面にアルミウムを使用したPTP包装(Al−Al包装)を用いてもよい。
なお、吸湿性が懸念される場合には乾燥剤等を瓶包装内やピロー包装内に同時に保存してもよい。
As the packaging material for the tablets of the present invention, for example, packaging made of a material that is not easily affected by moisture (packaging formed of a moisture-proof material) is preferable.
For example, as a packaging (moisture-proof material) made of a material that is less affected by moisture, PTP (polypropylene) + polyethylene aluminum pillow packaging (combination packaging of PTP and polyethylene aluminum pillow) may be used. In addition, in consideration of suppression of increase in water content in tablets, storage stability of tablets, tablet stability after opening, etc., PTP packaging using aluminum on both sides as packaging (moisture-proof material) made of a material that is not easily affected by moisture. (Al—Al packaging) may be used.
If hygroscopicity is a concern, a desiccant or the like may be stored in a bottle package or a pillow package at the same time.
以下に、実施例をあげて本発明を更に具体的に説明するが、これらの例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
<実施例1の錠剤の製造>
ロキソプロフェンナトリウム・2水和物(KOLON LIFE SCIENCE,INC.製)、メタケイ酸アルミン酸マグネシウム(富士化学工業株式会社製、ノイシリン)と、乳糖水和物(フロイント産業株式会社製、ダイラクトーズF)と、無水リン酸水素カルシウム(協和化学工業株式会社製、無水リン酸水素カルシウム(重質))と、三二酸化鉄(チタン工業株式会社製)と、を混合し、造粒顆粒を形成した。
造粒顆粒に対して、後末として、無水リン酸水素カルシウム(富士化学工業株式会社製、フジカリンSG)と、クロスカルメロースナトリウム(FMC International製、AcDiSol Croscarmellose Sodium)と、低置換度ヒドロキシプロピルセルロース(信越化学工業株式会社製、L−HPC LH−11)と、ステアリン酸マグネシウム(太平化学産業株式会社製、ステアリン酸マグネシウム(植物性))と、を添加した。
その後、造粒顆粒と後末との混合物を、打錠して顆粒外部を形成することにより、錠剤を得た。
実施例1の組成を表1に示す。
<Manufacturing of Tablets of Example 1>
Loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), Magnesium aluminometasilicate (Fuji Chemical Industries, Ltd., Neucillin), lactose hydrate (Freund Sangyo Co., Ltd., Dilactos F), Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industries, Ltd., anhydrous calcium hydrogen phosphate (heavy)) and iron sesquioxide (manufactured by Titanium Industries, Ltd.) were mixed to form granulated granules.
For the granulated granules, anhydrous calcium hydrogen phosphate (Fuji Chemical Industries, Ltd., Fujikarin SG), croscarmellose sodium (FMC International, AcDiSol Croscarmellose Sodium), and low-substituted hydroxypropyl cellulose are used as the final powders. (L-HPC LH-11 manufactured by Shinetsu Chemical Industries, Ltd.) and magnesium stearate (manufactured by Taihei Chemical Industries, Ltd., magnesium stearate (vegetable)) were added.
Then, the mixture of the granulated granules and the powder was tableted to form the outside of the granules to obtain tablets.
The composition of Example 1 is shown in Table 1.
<実施例1の錠剤の特性評価>
(1)錠剤の崩壊時間の測定、および、(2)錠剤の吸湿膨張による割れの有無の確認を行った。
条件を以下に示す。
(1)錠剤の崩壊時間は、第17改正日本薬局方の「崩壊試験法」に従い測定した。
(2)錠剤をシャーレに入れ、開放状態で25℃60%RH環境下に3日間静置し、割れが発生するか確認した。
<Characteristic evaluation of tablet of Example 1>
(1) The disintegration time of the tablet was measured, and (2) the presence or absence of cracking due to moisture absorption and expansion of the tablet was confirmed.
The conditions are shown below.
(1) The disintegration time of the tablet was measured according to the "disintegration test method" of the 17th revised Japanese Pharmacopoeia.
(2) The tablets were placed in a petri dish and allowed to stand in an open state in a 25 ° C. 60% RH environment for 3 days, and it was confirmed whether cracks occurred.
実施例1の錠剤の特性評価結果を表1に示す。
なお、表1および以下の表において、「錠剤割れ」の項の対応は以下のとおりである。
○:上記(2)の試験で錠剤の割れが生じなかった。
×:上記(2)の試験で錠剤が吸湿膨張し、割れが生じた。
また、表1および以下の表において、「−」は、錠剤に成分を添加していないことを意味し、「N/A」とは評価を行っていない場合を意味する。
Table 1 shows the characteristics evaluation results of the tablets of Example 1.
In Table 1 and the following tables, the correspondence of the item of "tablet cracking" is as follows.
◯: No cracking occurred in the tablet in the test (2) above.
X: In the test of (2) above, the tablet absorbed moisture and expanded, causing cracks.
Further, in Table 1 and the following tables, "-" means that no ingredient is added to the tablet, and "N / A" means that the evaluation has not been performed.
なお、錠剤の硬度と、造粒顆粒の水分値、および素錠(錠剤)の水分値の測定も行った。
錠剤の硬度は、硬度計 型式:KHT−20(メーカー:株式会社 藤原製作所)を用いて測定した。
また、造粒顆粒の水分値、および、素錠(錠剤)の水分値については、ハロゲン水分計 型式:HB43(メーカー:メトラー・トレド株式会社)を用いて、80℃で15分間加熱したときの乾燥減量を水分値として測定した。
なお、以下の実施例、比較例においても、実施例1と同様の手法により、錠剤の硬度と、造粒顆粒の水分値、および素錠(錠剤)の水分値を行った。
The hardness of the tablets, the water content of the granulated granules, and the water content of the uncoated tablets (tablets) were also measured.
The hardness of the tablets was measured using a hardness tester model: KHT-20 (manufacturer: Fujiwara Seisakusho Co., Ltd.).
Regarding the water content of the granulated granules and the water content of the uncoated tablets (tablets), when heated at 80 ° C. for 15 minutes using a halogen moisture meter model: HB43 (manufacturer: METTLER TOLEDO Co., Ltd.). The dry weight loss was measured as the water content.
In the following Examples and Comparative Examples, the hardness of the tablets, the water content of the granulated granules, and the water content of the uncoated tablets (tablets) were measured by the same method as in Example 1.
<比較例1の錠剤の製造>
低置換度ヒドロキシプロピルセルロースを後末に加えなかったほかは、実施例1と同様の方法により、比較例1の錠剤を作製した。
比較例1の組成を表1に示す。
<Manufacturing of Tablets of Comparative Example 1>
A tablet of Comparative Example 1 was prepared by the same method as in Example 1 except that low-substituted hydroxypropyl cellulose was not added to the powder.
The composition of Comparative Example 1 is shown in Table 1.
<比較例1の特性評価>
実施例1と同様の方法により、(1)錠剤の崩壊時間の測定、および、(2)錠剤の吸湿膨張による割れの有無の確認を行った。
比較例1の特性評価結果を表1に示す。
<Characteristic evaluation of Comparative Example 1>
By the same method as in Example 1, (1) the disintegration time of the tablet was measured, and (2) the presence or absence of cracking due to moisture absorption and expansion of the tablet was confirmed.
The characteristic evaluation results of Comparative Example 1 are shown in Table 1.
実施例1および比較例1の結果によれば、低置換度ヒドロキシプロピルセルロース(L−HPC)を錠剤に配合することにより、錠剤の吸湿膨張による割れを抑制できる傾向が確認された。 According to the results of Example 1 and Comparative Example 1, it was confirmed that by blending low-substituted hydroxypropyl cellulose (L-HPC) into tablets, cracking due to hygroscopic expansion of tablets can be suppressed.
<実施例2の錠剤の製造>
ロキソプロフェンナトリウム水和物、制酸剤としてノイシリン(メタケイ酸アルミン酸マグネシウム)と、賦形剤として乳糖水和物と、賦形剤として無水リン酸水素カルシウムと、着色剤として三二酸化鉄と、を混合し、造粒顆粒を形成した。
造粒顆粒に対して、後末として、無水リン酸水素カルシウムと、クロスカルメロースナトリウムと、低置換度ヒドロキシプロピルセルロースと、を添加した。
その後、造粒顆粒と後末との混合物を、打錠して顆粒外部を形成することにより、錠剤を得た。
実施例2の組成を表2に示す。
<Manufacturing of Tablets of Example 2>
Loxoprofen sodium hydrate, Neucillin (magnesium aluminometasilicate) as an acid suppressant, lactose hydrate as an excipient, anhydrous calcium hydrogen phosphate as an excipient, and iron sesquioxide as a colorant. It was mixed to form granulated granules.
Anhydrous calcium hydrogen phosphate, sodium croscarmellose, and low-degree-of-substitution hydroxypropyl cellulose were added to the granulated granules as the latter powder.
Then, a mixture of the granulated granules and the powder was tableted to form the outside of the granules to obtain tablets.
The composition of Example 2 is shown in Table 2.
<実施例2の錠剤の特性評価>
実施例1と同様の方法により、(1)錠剤の崩壊時間の測定、および、(2)錠剤の吸湿膨張による割れの有無の確認を行った。
実施例2の錠剤の特性評価結果を表2に示す。
<Characteristic evaluation of tablets of Example 2>
By the same method as in Example 1, (1) the disintegration time of the tablet was measured, and (2) the presence or absence of cracking due to moisture absorption and expansion of the tablet was confirmed.
Table 2 shows the characteristics evaluation results of the tablets of Example 2.
<比較例2の錠剤の製造>
「賦形剤」である無水リン酸水素カルシウムに代えて、「崩壊剤」であるカルメロースを後末に加えたほかは、実施例2と同様の方法により、比較例2の錠剤を作製した。
比較例2の組成を表2に示す。
<Manufacturing of Tablets of Comparative Example 2>
A tablet of Comparative Example 2 was prepared by the same method as in Example 2 except that carmellose, which is a “disintegrant”, was added to the powder instead of the “excipient”, anhydrous calcium hydrogen phosphate.
The composition of Comparative Example 2 is shown in Table 2.
<比較例2の特性評価>
実施例2と同様の方法により、(1)錠剤の崩壊時間の測定、および、(2)錠剤の吸湿膨張による割れの有無の確認を行った。
比較例2の特性評価結果を表2に示す。
<Characteristic evaluation of Comparative Example 2>
By the same method as in Example 2, (1) the disintegration time of the tablet was measured, and (2) the presence or absence of cracking due to moisture absorption and expansion of the tablet was confirmed.
Table 2 shows the characteristic evaluation results of Comparative Example 2.
実施例2に示すように、賦形剤として無水リン酸水素カルシウムおよび低置換度ヒドロキシプロピルセルロース、崩壊剤としてクロスカルメロースナトリウムを顆粒外部に加えた場合には、錠剤の崩壊時間が3.3分以内であり、上記(2)の特性評価試験において錠剤の吸湿膨張による割れが生じなかった。
比較例2に示すように、錠剤において、賦形剤であり、かつ、導水型崩壊助剤である無水リン酸水素カルシウムに代えて、導水型の崩壊剤であるカルメロースを添加することによっては、錠剤の崩壊時間が短くなったものの、上記(2)の特性評価試験における錠剤割れのリスクが上昇してしまった。
As shown in Example 2, when anhydrous calcium hydrogen phosphate and low-degree-of-substitution hydroxypropyl cellulose were added as excipients and croscarmellose sodium as a disintegrant was added to the outside of the granules, the disintegration time of the tablets was 3.3. Within minutes, cracks did not occur due to moisture absorption and expansion of the tablets in the characteristic evaluation test of (2) above.
As shown in Comparative Example 2, by adding carmellose, which is a water-conducting disintegrant, in place of anhydrous calcium hydrogen phosphate, which is an excipient and a water-conducting disintegration aid, in tablets, Although the disintegration time of the tablet was shortened, the risk of tablet cracking in the characteristic evaluation test of (2) above was increased.
<実施例3の錠剤の製造>
ロキソプロフェンナトリウム水和物、制酸剤としてノイシリン(メタケイ酸アルミン酸マグネシウム)と、賦形剤として乳糖水和物と、賦形剤として無水リン酸水素カルシウムと、着色剤として三二酸化鉄と、を混合し、造粒顆粒を形成した。
造粒顆粒に対して、後末として、無水リン酸水素カルシウムと、クロスカルメロースナトリウムと、低置換度ヒドロキシプロピルセルロースと、を添加した。
その後、造粒顆粒と後末との混合物を、打錠して顆粒外部を形成することにより、錠剤を得た。
実施例3の組成を表3に示す。
<Manufacturing of Tablets of Example 3>
Loxoprofen sodium hydrate, Neucillin (magnesium aluminometasilicate) as an acid suppressant, lactose hydrate as an excipient, anhydrous calcium hydrogen phosphate as an excipient, and iron sesquioxide as a colorant. It was mixed to form granulated granules.
Anhydrous calcium hydrogen phosphate, sodium croscarmellose, and low-degree-of-substitution hydroxypropyl cellulose were added to the granulated granules as the latter powder.
Then, a mixture of the granulated granules and the powder was tableted to form the outside of the granules to obtain tablets.
The composition of Example 3 is shown in Table 3.
<実施例3の錠剤の特性評価>
実施例1と同様の方法により、(1)錠剤の崩壊時間の測定、および、(2)錠剤の吸湿膨張による割れの有無の確認を行った。
実施例3の錠剤の特性評価結果を表3に示す。
<Characteristic evaluation of tablets of Example 3>
By the same method as in Example 1, (1) the disintegration time of the tablet was measured, and (2) the presence or absence of cracking due to moisture absorption and expansion of the tablet was confirmed.
Table 3 shows the characteristics evaluation results of the tablets of Example 3.
<実施例4の錠剤の製造>
着色剤としての三二酸化鉄を含まないように造粒顆粒を作製したほかは、実施例3と同様の方法により、実施例4の錠剤を作製した。
実施例4の組成を表3に示す。
<Manufacturing of Tablets of Example 4>
The tablets of Example 4 were prepared by the same method as in Example 3 except that the granulated granules were prepared so as not to contain iron sesquioxide as a colorant.
The composition of Example 4 is shown in Table 3.
<実施例4の特性評価>
実施例3と同様の方法により、(1)錠剤の崩壊時間の測定、および、(2)錠剤の吸湿膨張による割れの有無の確認を行った。
また、実施例4においては、(3)「薬剤の溶出性および錠剤の安定性(溶出安定性)を確認する試験」を行った。
「薬剤の溶出性、および、錠剤の安定性(溶出安定性)を確認する試験」としては、以下の実験を行った。
<Characteristic evaluation of Example 4>
By the same method as in Example 3, (1) the disintegration time of the tablet was measured, and (2) the presence or absence of cracking due to moisture absorption and expansion of the tablet was confirmed.
Further, in Example 4, (3) "a test for confirming the dissolution property of the drug and the stability (dissolution stability) of the tablet" was carried out.
The following experiment was conducted as a "test for confirming drug dissolution and tablet stability (dissolution stability)".
溶出試験としては、第17改正日本薬局方の「ロキソプロフェンナトリウム錠」の以下の規格試験法を採用した。
試験液に水900mLを用い、パドル法により、毎分50回転(50rpm)で試験を行うとき、30分間の溶出率が85%以上である場合には、錠剤の溶出性が良好であると判断した。
また、錠剤を60℃1箇月おいた際の溶出試験における30分時点での溶出率が、製造直後の錠剤の溶出試験における30分時点での溶出率と比較して差が2%以内であった場合、安定であると判断した。
As the dissolution test, the following standard test method of "Loxoprofen sodium tablet" of the 17th revised Japanese Pharmacopoeia was adopted.
When 900 mL of water is used as the test solution and the test is performed at 50 rpm (50 rpm) by the paddle method, if the dissolution rate for 30 minutes is 85% or more, it is judged that the dissolution property of the tablet is good. bottom.
In addition, the dissolution rate at 30 minutes in the dissolution test when the tablets were placed at 60 ° C. for 1 month was within 2% of the dissolution rate at 30 minutes in the dissolution test of the tablets immediately after production. If so, it was judged to be stable.
本実施例および以下の実施例においては、以下の指標を用いた。
なお、表中の「溶出性 安定性」の項は、「薬剤の溶出性、および、錠剤の安定性(溶出安定性)を確認する試験」の結果に対応しており、表中の記号は以下の意味を有する。
○:製造直後、および、経時品の試験において薬剤の溶出性が優れており、錠剤の安定性も優れていた(換言すれば、上記溶出性試験でパドル法50rpm、試験液が水の場合に30分以内に85%以上薬剤を溶出し、かつ、錠剤を60℃1箇月おいた際にも、溶出試験における30分時点での溶出率が、製造直後の錠剤の溶出試験における30分時点での溶出率と比較して差が2%以内であった場合である)。
△:製造直後には薬剤の溶出性が優れた結果を示したが、経時品の試験では若干溶出遅延が生じる場合があり、錠剤の安定性(溶出安定性)を確認する試験の結果が上記「○」の場合と比較して、若干劣る結果となった(換言すれば、上記溶出性試験でパドル法50rpm、試験液が水の場合に30分以内に85%以上薬剤を溶出したものの、錠剤を60℃1箇月おいた際にも、溶出試験における30分時点での溶出率が、製造直後の錠剤の溶出試験における30分時点での溶出率と比較して差が2%を超えてしまった場合である)。
×:薬剤の溶出性、および、錠剤の安定性(溶出安定性)を確認する試験の結果が、良好ではなかった。
実施例4の特性評価結果を表3に示す。
In this example and the following examples, the following indicators were used.
In addition, the item of "dissolution stability" in the table corresponds to the result of "test to confirm the dissolution of the drug and the stability of the tablet (dissolution stability)", and the symbols in the table correspond to the results. It has the following meanings.
◯: The drug was excellently eluted immediately after production and in the test of the product over time, and the tablet stability was also excellent (in other words, when the paddle method was 50 rpm and the test solution was water in the above dissolution test). Even when 85% or more of the drug was eluted within 30 minutes and the tablet was left at 60 ° C for 1 month, the dissolution rate at 30 minutes in the dissolution test was 30 minutes in the tablet dissolution test immediately after production. When the difference is within 2% as compared with the dissolution rate of).
Δ: The result of excellent dissolution of the drug was shown immediately after production, but there may be a slight delay in dissolution in the test of the product over time, and the result of the test to confirm the stability (dissolution stability) of the tablet is as described above. The result was slightly inferior to that of "○" (in other words, in the above dissolution test, when the paddle method was 50 rpm and the test solution was water, 85% or more of the drug was eluted within 30 minutes. Even when the tablets were left at 60 ° C. for 1 month, the difference between the dissolution rate at 30 minutes in the dissolution test and the dissolution rate at 30 minutes in the dissolution test of the tablets immediately after production exceeded 2%. If it does).
X: The results of the test for confirming the dissolution of the drug and the stability of the tablet (dissolution stability) were not good.
The characteristic evaluation results of Example 4 are shown in Table 3.
<実施例5の錠剤の製造>
崩壊剤として、クロスカルメロースナトリウムの代わりに、クロスポピドン(BASF社製コリドンCL)を含むように顆粒外部を作製したほかは、実施例4と同様の方法により、実施例5の錠剤を作製した。
実施例5の組成を表3に示す。
<Manufacturing of Tablets of Example 5>
The tablets of Example 5 were prepared by the same method as in Example 4 except that the outside of the granules was prepared so as to contain crospopidone (Corridon CL manufactured by BASF) instead of sodium croscarmellose as a disintegrant. ..
The composition of Example 5 is shown in Table 3.
<実施例5の特性評価>
実施例4と同様の方法により、(1)錠剤の崩壊時間の測定、(2)錠剤の吸湿膨張による割れの有無の確認、および、(3)「薬剤の溶出性および錠剤の安定性(溶出安定性)を確認する試験」を行った。
<Characteristic evaluation of Example 5>
By the same method as in Example 4, (1) measurement of the disintegration time of the tablet, (2) confirmation of the presence or absence of cracking due to hygroscopic expansion of the tablet, and (3) “drug elution and tablet stability (elution)). A test to confirm (stability) ”was conducted.
<実施例6の錠剤の製造>
崩壊剤として、クロスカルメロースナトリウムの代わりに、クロスポピドン(BASF社製コリドンCL-F)を含むように顆粒外部を作製したほかは、実施例4と同様の方法により、実施例6の錠剤を作製した。
実施例6の組成を表3に示す。
<Manufacturing of Tablets of Example 6>
The tablets of Example 6 were prepared by the same method as in Example 4 except that the outside of the granules was prepared so as to contain crospopidone (Coridone CL-F manufactured by BASF) instead of sodium croscarmellose as a disintegrant. Made.
The composition of Example 6 is shown in Table 3.
<実施例6の特性評価>
実施例4と同様の方法により、(1)錠剤の崩壊時間の測定、(2)錠剤の吸湿膨張による割れの有無の確認、および、(3)「薬剤の溶出性および錠剤の安定性(溶出安定性)を確認する試験」を行った。
<Characteristic evaluation of Example 6>
By the same method as in Example 4, (1) measurement of the disintegration time of the tablet, (2) confirmation of the presence or absence of cracking due to hygroscopic expansion of the tablet, and (3) “drug elution and tablet stability (elution)). A test to confirm (stability) ”was conducted.
<実施例7の錠剤の製造>
メタケイ酸アルミン酸マグネシウムの一部および乳糖を、造粒顆粒に含める代わりに、顆粒外部に含めるように錠剤を作製したほかは、実施例6と同様の方法により、実施例7の錠剤を作製した。
実施例7の組成を表3に示す。
<Manufacturing of Tablets of Example 7>
The tablets of Example 7 were prepared by the same method as in Example 6 except that a part of magnesium aluminometasilicate and lactose were contained outside the granules instead of being included in the granulated granules. ..
The composition of Example 7 is shown in Table 3.
<実施例7の特性評価>
実施例6と同様の方法により、(1)錠剤の崩壊時間の測定、(2)錠剤の吸湿膨張による割れの有無の確認、および、(3)「薬剤の溶出性および錠剤の安定性(溶出安定性)を確認する試験」を行った。
<Characteristic evaluation of Example 7>
By the same method as in Example 6, (1) measurement of the disintegration time of the tablet, (2) confirmation of the presence or absence of cracking due to hygroscopic expansion of the tablet, and (3) “drug elution and tablet stability (elution)). A test to confirm (stability) ”was conducted.
<実施例8の錠剤の製造>
顆粒外部におけるクロスポピドン(BASF社製コリドンCL-F)に代えて、クロスカルメロースナトリウム(FMC International社製Ac−Di−Sol)を用いて錠剤を作製したほかは、実施例7と同様の方法により、実施例8の錠剤を作製した。
実施例8の組成を表3に示す。
<Production of Tablets of Example 8>
The same method as in Example 7 except that tablets were prepared using croscarmellose sodium (Ac-Di-Sol manufactured by FMC International) instead of crospopidone (Corridon CL-F manufactured by BASF) outside the granules. To prepare the tablets of Example 8.
The composition of Example 8 is shown in Table 3.
<実施例8の特性評価>
実施例7と同様の方法により、(1)錠剤の崩壊時間の測定、(2)錠剤の吸湿膨張による割れの有無の確認、および、(3)「薬剤の溶出性および錠剤の安定性(溶出安定性)を確認する試験」を行った。
<Characteristic evaluation of Example 8>
By the same method as in Example 7, (1) measurement of the disintegration time of the tablet, (2) confirmation of the presence or absence of cracking due to hygroscopic expansion of the tablet, and (3) “drug elution and tablet stability (elution)). A test to confirm (stability) ”was conducted.
実施例3と実施例4との結果より、着色剤としての三二酸化鉄を含まない場合にも、特性に大きな変化は観察されなかった。
また、実施例4の錠剤によれば、薬剤の溶出性および錠剤の安定性(溶出安定性)も優れていた。
From the results of Example 3 and Example 4, no significant change was observed in the characteristics even when iron sesquioxide as a colorant was not contained.
Further, according to the tablet of Example 4, the dissolution property of the drug and the stability of the tablet (dissolution stability) were also excellent.
また、実施例6と実施例7との比較により、造粒顆粒に添加したノイシリンの一部と、乳糖と、を顆粒外部(後末)に添加することによって、崩壊時間が短縮される傾向にあった。
実施例4と、実施例5及び実施例6との比較により、顆粒外部に添加した崩壊剤がクロスポピドンの場合、顆粒外部に添加した崩壊剤がクロスカルメロースナトリウムの場合と比較して、崩壊時間は短くなる傾向にあった。
一方、実施例4と実施例5及び実施例6との比較により、顆粒外部に添加した崩壊剤がクロスポピドンの場合よりも、顆粒外部に添加した崩壊剤がクロスカルメロースナトリウムを用いた場合のほうが、薬剤の溶出性および錠剤の安定性(溶出安定性)が優れる傾向にあった。
本実験の結果から、顆粒外部(後末)に、ノイシリンの一部と、賦形剤としての乳糖と、崩壊剤としてのクロスカルメロースナトリウムと、を添加することによって、(1)錠剤の崩壊時間が3分以内となり、(2)錠剤の割れが防止され、(3)薬剤の溶出性が優れるとともに、錠剤の安定性(溶出安定性)が優れる傾向にあることを確認できた。
Further, as a comparison between Example 6 and Example 7, the disintegration time tends to be shortened by adding a part of noicillin added to the granulated granules and lactose to the outside (posterior powder) of the granules. there were.
By comparing Example 4 with Examples 5 and 6, when the disintegrant added to the outside of the granules was crospopidone, the disintegrant added to the outside of the granules was disintegrated as compared with the case of sodium croscarmellose. The time tended to be shorter.
On the other hand, by comparing Example 4 with Examples 5 and 6, the disintegrant added to the outside of the granules used croscarmellose sodium rather than the disintegrant added to the outside of the granules using crospopidone. The drug tended to be more excellent in drug dissolution and tablet stability (dissolution stability).
From the results of this experiment, (1) Disintegration of tablets by adding a part of Neucillin, lactose as an excipient, and croscarmellose sodium as a disintegrant to the outside of the granules (posterior powder). It was confirmed that the time was less than 3 minutes, (2) cracking of the tablet was prevented, (3) the dissolution property of the drug was excellent, and the stability (dissolution stability) of the tablet tended to be excellent.
実施例9および10については、さらに過酷な条件における錠剤の保存安定性について検証するため、水分値が異なるほかは、実施例8と同様の組成を有する錠剤を作製し、以下の検討を行なった。
<実施例9および10の錠剤の製造>
実施例8と同様の手法により、表4に示すような組成となるように、実施例9および10の錠剤を作製した。
なお、実施例9と実施例10の錠剤は、水分値が異なるほかは、実施例8と同様の組成を有する錠剤であり、上記実施例1〜8で示したような(1)〜(3)の評価の観点においては、保存安定性が改善され、服用時における崩壊時間が適切であり、服用時における薬剤の溶出性が改善された錠剤である。
For Examples 9 and 10, in order to verify the storage stability of the tablets under more severe conditions, tablets having the same composition as in Example 8 except that the water values were different were prepared, and the following studies were conducted. ..
<Production of Tablets of Examples 9 and 10>
The tablets of Examples 9 and 10 were prepared by the same method as in Example 8 so as to have the composition shown in Table 4.
The tablets of Examples 9 and 10 have the same composition as that of Example 8 except that the water values are different, and are (1) to (3) as shown in Examples 1 to 8 above. ), The tablet has improved storage stability, an appropriate disintegration time at the time of administration, and an improved dissolution property of the drug at the time of administration.
<実施例9および10の特性評価>
錠剤をPTP包装(Al−Al包装)し、40℃75%RHの条件で6箇月放置した。このように40℃75%RHの条件で6箇月間保管した後、HPLC法により、この条件で保管した錠剤中のロキソプロフェンナトリウム含量を測定し、保管前からの残存率(保管前の錠剤中のロキソプロフェンナトリウム含量(100%)に対する40℃75%RHの条件で6箇月間保管後の錠剤中のロキソプロフェンナトリウム含量の比)を算出した。
<Characteristic evaluation of Examples 9 and 10>
The tablets were packed in PTP (Al-Al packaging) and left at 40 ° C. and 75% RH for 6 months. After storing for 6 months under the condition of 40 ° C. and 75% RH, the loxoprofen sodium content in the tablets stored under these conditions was measured by the HPLC method, and the residual rate from before storage (in the tablets before storage). The ratio of the loxoprofen sodium content in the tablets after storage for 6 months under the condition of 40 ° C. and 75% RH to the loxoprofen sodium content (100%)) was calculated.
また、実施例9と実施例10との比較により、素錠水分値が低いほうが、より過酷な条件(40℃75%RHの条件で6箇月間保管)においても保存安定性(ロキソプロフェンナトリウム残存率)が優れる傾向にあることがわかった。
本実験の結果から、製剤水分値を下げることにより、過酷な条件においても錠剤の保存安定性(ロキソプロフェンナトリウム残存率)がより優れる傾向にあることを確認できた。
In addition, as a comparison between Example 9 and Example 10, the lower the uncoated tablet water content, the more storage stability (loxoprofen sodium residual rate) even under more severe conditions (storage for 6 months under the condition of 40 ° C. and 75% RH). ) Tends to be superior.
From the results of this experiment, it was confirmed that the storage stability (loxoprofen sodium residual rate) of tablets tends to be more excellent even under harsh conditions by lowering the water content of the pharmaceutical product.
(製剤例1〜4)
実施例1と同様の手法により、表5に示すような組成となるように、製剤例1〜4の錠剤を作製した。
(Formulation Examples 1 to 4)
The tablets of Pharmaceutical Examples 1 to 4 were prepared by the same method as in Example 1 so as to have the composition shown in Table 5.
以上、本発明の好ましい実施形態および実施例を説明したが、本発明はこれらに限定されることはない。本発明の趣旨を逸脱しない範囲で、構成の付加、省略、置換、およびその他の変更が可能である。 Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Configurations can be added, omitted, replaced, and other modifications without departing from the spirit of the present invention.
本発明の錠剤は、ロキソプロフェン又はその塩を含みつつも、保管時には錠剤の安定性(溶出安定性)が優れ、服用時には崩壊時間が適切であるとともに、薬剤の溶出性が優れることから、品質上極めて有用である。
本発明の錠剤は、解熱剤、鎮痛剤として、特に、頭痛、月経痛(生理痛)、歯痛、抜歯後疼痛、咽喉痛、腰痛、関節痛、筋肉痛、肩こり痛、耳痛、打撲痛、骨折痛、ねんざ痛、外傷痛等の鎮痛、悪寒・発熱時の解熱に好適に用いられ、又、感冒治療剤として、かぜの諸症状(鼻水、鼻づまり、せき、たん、のどの痛み、発熱、悪寒、頭痛、くしゃみ、関節の痛み、筋肉の痛み)の緩和に好適に用いられる。
Although the tablet of the present invention contains loxoprofen or a salt thereof, it has excellent tablet stability (dissolution stability) during storage, an appropriate disintegration time when taken, and excellent drug dissolution. Extremely useful.
The tablets of the present invention are used as antipyretic and analgesic agents, especially headache, menstrual pain (physiological pain), toothache, post-extraction pain, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, ear pain, bruising pain, and fracture. It is preferably used to relieve pain, numbness, traumatic pain, etc., and to relieve fever during cold and fever, and as a cold remedy, various symptoms of cold (nasal discharge, stuffy nose, cough, tan, sore throat, fever. , Cold, headache, squeeze, joint pain, muscle pain).
Claims (12)
前記顆粒外部は、無水リン酸水素カルシウムと、低置換度ヒドロキシプロピルセルロースと、崩壊剤とを含む、
錠剤。 A tablet comprising at least one granulated granule containing loxoprofen or a salt thereof and an outer granule configured to cover the granulated granule.
The outside of the granules contains anhydrous calcium hydrogen phosphate, low-degree-of-substitution hydroxypropyl cellulose, and a disintegrant.
tablet.
前記造粒顆粒と、無水リン酸水素カルシウムと、低置換度ヒドロキシプロピルセルロースと、崩壊剤とを混合して、打錠することにより錠剤を製造する工程;
を含む、請求項1から9のいずれか一項に記載の錠剤の製造方法。 The step of producing at least one granulated granule containing loxoprofen or a salt thereof; and the granulated granule, anhydrous calcium hydrogen phosphate, low-degree-of-substitution hydroxypropyl cellulose, and a disintegrant are mixed and tableted. The process of producing tablets by
The method for producing a tablet according to any one of claims 1 to 9, which comprises.
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