JP2013043834A - Elution improving solid preparation - Google Patents
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- JP2013043834A JP2013043834A JP2011180486A JP2011180486A JP2013043834A JP 2013043834 A JP2013043834 A JP 2013043834A JP 2011180486 A JP2011180486 A JP 2011180486A JP 2011180486 A JP2011180486 A JP 2011180486A JP 2013043834 A JP2013043834 A JP 2013043834A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000013543 active substance Substances 0.000 claims abstract description 13
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- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 8
- 229960002411 imatinib Drugs 0.000 claims description 8
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、水溶性が極めて高く、水との接触により粒子表面に粘着性のゲル層を形成し、崩壊、溶出が遅延する生理活性物質を含有する製剤であって、その溶出速度が改善された固形製剤に関する。 The present invention is a preparation containing a physiologically active substance that has extremely high water solubility, forms a sticky gel layer on the particle surface upon contact with water, and disintegrates and dissolves slowly, and its dissolution rate is improved. Relates to a solid formulation.
水に極めて溶けやすい薬物は、溶解すると強い粘着性を示すことが多く、その特性が錠剤化した際の崩壊性に大きく影響することがある。たとえば、水に極めて溶けやすい性質を持つイマチニブ（日本医薬品一般名称）もしくは薬学的に許容されるその塩は、水と接触すると、粒子表面が溶解して強い粘着性を示し粒子同士の付着によるゲル膜を形成する。この性質から、錠剤化したものの溶出性を担保するために多量の崩壊剤を必要とする。 Drugs that are extremely soluble in water often exhibit strong tackiness when dissolved, and their properties can greatly affect the disintegration properties when tableted. For example, imatinib (generic name of Japanese pharmaceuticals) or a pharmaceutically acceptable salt thereof, which is very soluble in water, is a gel that adheres to each other due to the adhesion of particles by dissolving the surface of the particles when contacted with water. A film is formed. Because of this property, a large amount of disintegrant is required to ensure dissolution of the tablet.
従来技術の具体例として、特許文献１では流動性に富み、吸湿性が少なく、加工も容易で、140℃以下で熱力学的に安定なβ形結晶を用いて、乳糖、結晶セルロース、クロスポビドン等を配合して直接圧縮による錠剤の製造方法が開示されている。特許文献２では、崩壊性が高いクロスポビドンを錠剤総量に対して１０〜３５％配合し、さらに、吸水性の高い微結晶セルロースを配合し、湿式造粒法による高薬物充填錠剤の製造方法が開示されている。しかし、クロスポビドンや微結晶セルロース等の吸水性が高い添加剤を多量に配合した場合、無包装状態で長期に保存した際に、錠剤の表面が肌荒れを起こし、錠剤硬度が著しく低下する可能性があり、流通過程や調剤薬局での保管における保存安定性を保証するには不十分である。特許文献３では、摂食／絶食での吸収性の変動を解決するために、粒子径が2μm未満のナノ粒子メシル酸イマチニブを用い、HPMC、HPC、PVP等の表面安定化剤を含む組成物が開示されている。更に、特許文献４ではβ形と異なるＶ形、Ｘ形の結晶形を用いてα形、β形へ転移しない製剤処方が記載されている。しかしながら、これらの製造方法は長期保存時の錠剤特性の変化、安定性等について充分に満足できるものではなく、これらの課題を解決し、工業化に適した製造方法の確立が必要とされた。 As a specific example of the prior art, Patent Document 1 uses lactate, crystalline cellulose, crospovidone using β-form crystals that are highly fluid, less hygroscopic, easy to process, and thermodynamically stable at 140 ° C. or lower. And the like, and a method for producing a tablet by direct compression is disclosed. In Patent Document 2, crospovidone having high disintegration is blended in an amount of 10 to 35% based on the total amount of the tablet, and further, microcrystalline cellulose having a high water absorption is blended, and a method for producing a high drug-filled tablet by wet granulation method is disclosed. It is disclosed. However, when a large amount of highly water-absorbing additives such as crospovidone or microcrystalline cellulose is blended, the tablet surface may become rough when stored in a non-packed state for a long time, and the tablet hardness may be significantly reduced. Therefore, it is insufficient to guarantee the storage stability in the distribution process and storage at the dispensing pharmacy. In Patent Document 3, a composition containing a surface stabilizer such as HPMC, HPC, PVP, etc., using nanoparticulate imatinib mesylate having a particle size of less than 2 μm in order to solve the fluctuation in absorbency during feeding / fasting Is disclosed. Further, Patent Document 4 describes a pharmaceutical formulation that does not transfer to α form and β form using crystal forms of V form and X form different from β form. However, these production methods are not fully satisfactory with respect to changes in tablet properties and stability during long-term storage, and it has been necessary to solve these problems and establish a production method suitable for industrialization.
本発明の課題は、水溶性が極めて高く、水との接触により粒子表面に粘着性のゲル層を形成し、崩壊、溶出が遅延する生理活性物質について、製剤操作上簡便な方法により、溶出性が改善された固形製剤を提供することにある。 An object of the present invention is to dissolve a bioactive substance that has extremely high water solubility and forms a sticky gel layer on the particle surface by contact with water, and that disintegrates and dissolves slowly, by a simple method in formulation operation. Is to provide an improved solid preparation.
イマチニブもしくは薬学的に許容されるその塩に、錠剤硬度の低下を改善する目的で、崩壊剤等の配合量を減量して錠剤を製造した。得られた錠剤の溶出試験を行ったところ、錠剤は徐々に膨潤するものの、瞬時には崩壊せず、そのため薬物が溶出するのに大幅な時間を要した。これは、吸水した部分に存在するイマチニブもしくは薬学的に許容されるその塩が溶解すると同時にその強い粘着性によってゲル状の膜を形成し、錠剤内部への水の浸透が阻害され薬物の放出が遅延しているものと考えられた。この知見を基に、発明者らは種々検討した結果、水溶性の糖類又は糖アルコールを配合したイマチニブもしくは薬学的に許容されるその塩の錠剤は、上述のような現象を生じることなく薬物の溶出性が担保されることを見出し、さらに改良を加え、本発明を完成することができた。 In order to improve the decrease in tablet hardness, imatinib or a pharmaceutically acceptable salt thereof was used to reduce the blending amount of disintegrant and the like to produce tablets. When the dissolution test of the obtained tablet was performed, the tablet gradually swelled but did not disintegrate instantaneously, and therefore it took a long time for the drug to dissolve. This is because imatinib or its pharmaceutically acceptable salt present in the water-absorbed part dissolves and at the same time forms a gel-like film due to its strong adhesiveness, which inhibits the penetration of water into the tablet and releases the drug. It was considered delayed. Based on this finding, the inventors have conducted various studies. As a result, imatinib or a pharmaceutically acceptable salt tablet containing a water-soluble saccharide or sugar alcohol does not cause the above phenomenon. It was found that the dissolution property was ensured, and further improvements were made to complete the present invention.
すなわち、本発明によれば、下記（１）〜（５）の発明を提供することができる。
（１）水に極めて溶けやすい生理活性物質及び水溶性の糖類又は糖アルコールを含有することを特長とする、生理活性物質の溶出性が改善された固形製剤。
（２）生理活性物質がイマチニブもしくは薬学的に許容されるその塩である前記（１）に記載の固形製剤。
（３）水溶性の糖類又は糖アルコールが水１ｇに対し１００ｍｇ以上溶解する添加剤である（１）又は（２）に記載の固形製剤。
（４）水溶性の糖類又は糖アルコールが、錠剤の総重量に対して１０〜５０重量％含まれてなる前記（１）又は（３）に記載の固形製剤。
（５）フイルムコーティング錠である前記（１）〜（４）に記載の固形製剤。
That is, according to the present invention, the following inventions (1) to (5) can be provided.
(1) A solid preparation with improved dissolution of a physiologically active substance, characterized by containing a physiologically active substance that is extremely soluble in water and a water-soluble saccharide or sugar alcohol.
(2) The solid preparation according to (1), wherein the physiologically active substance is imatinib or a pharmaceutically acceptable salt thereof.
(3) The solid preparation according to (1) or (2), which is an additive capable of dissolving 100 mg or more of water-soluble saccharide or sugar alcohol with respect to 1 g of water.
(4) The solid preparation according to (1) or (3), wherein the water-soluble saccharide or sugar alcohol is contained in an amount of 10 to 50% by weight based on the total weight of the tablet.
(5) The solid preparation according to (1) to (4), which is a film-coated tablet.
本発明によれば、水溶性が極めて高く、水との接触により粒子表面に粘着性のゲル層を形成し、崩壊、溶出が遅延する生理活性物質の製造において、吸水性添加剤を配合しないことにより、製剤操作上簡便な方法で、生理活性物質粒子表面のゲル化を抑制し、溶出性を改善することが可能である。 According to the present invention, a water-absorbing additive is not blended in the production of a physiologically active substance that is extremely water-soluble and forms a sticky gel layer on the particle surface upon contact with water and delays disintegration and elution. Thus, it is possible to suppress the gelation of the surface of the physiologically active substance particle and improve the dissolution property by a simple method in terms of formulation operation.
本発明における水溶性の糖類又は糖アルコールは、乳糖、トレハロース、Ｄ−マンニトール、ソルビトール、キシリトール、マルチトール、エリスリトール、還元パラチノース、白糖、ショ糖、ブドウ糖、粉糖、デキストリン、粉末還元麦芽糖水あめ、クエン酸、クエン酸ナトリウム、塩化ナトリウム、水酸化ナトリウム等の水に溶解するものであれば良く、各々単味あるいは複数を組み合わせて使用することが可能であり、その配合割合を任意に調節して使用することができる。本発明において使用される結合剤としては、ヒドロキシプロピルセルロース、ヒプロメロース、ポビドン、ポリエチレングリコール、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体又はポリビニルアルコールグラフトコポリマー等の一般的に固形製剤に用いられる結合剤が挙げられる。また、崩壊剤としては、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、カルメロースナトリウム、カルボシキメチルスターチナトリウム、クロスポビドン、部分アルファー化デンプン及びクロスカルメロースナトリウム等の通常に固形製剤用として用いられる崩壊剤が挙げられる。また、本発明の錠剤は、通常の環境下において薬物の露出を保護する目的でフイルムコーティング膜を施すこともあり、コーティング剤としては、ヒプロメロース、酸化チタン、タルク、ポリエチレングリコール等の一般的に用いられるコーティング剤を使用することができ、識別性を目的として着色剤を使用することもある。 The water-soluble saccharide or sugar alcohol in the present invention is lactose, trehalose, D-mannitol, sorbitol, xylitol, maltitol, erythritol, reduced palatinose, sucrose, sucrose, glucose, powdered sugar, dextrin, powdered reduced maltose starch syrup, citrus Any acid, sodium citrate, sodium chloride, sodium hydroxide, or the like that dissolves in water can be used, and each can be used alone or in combination. can do. Examples of the binder used in the present invention include hydroxypropyl cellulose, hypromellose, povidone, polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and polyvinyl alcohol graft copolymer. The binder used is mentioned. In addition, as disintegrants, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, crospovidone, partially pregelatinized starch, croscarmellose sodium, etc. The disintegrant used is mentioned. The tablet of the present invention may be provided with a film coating film for the purpose of protecting the exposure of the drug under a normal environment. As a coating agent, hypromellose, titanium oxide, talc, polyethylene glycol and the like are generally used. Coating agents, and colorants may be used for the purpose of discrimination.
実施例１
イマチニブメシル酸塩２３９ｇ及びＤ−マンニトール１６０ｇを流動層造粒機（パウレック社製：ＭＰ−０１型）に投入し、ヒドロキシプロピルセルロース６ｇを精製水１１４ｇに溶解した液をスプレーし造粒した。得られた造粒物２０２．５ｇをとり、クロスポビドン１０ｇ及びステアリン酸マグネシウム１ｇを配合して打錠し、下記組成の錠剤を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
イマチニブメシル酸塩 １１９．５
Ｄ−マンニトール ８０．０
ヒドロキシプロピルセルロース ３．０
クロスポビドン １０．０
ステアリン酸マグネシウム １．０
Example 1
239 g of imatinib mesylate and 160 g of D-mannitol were put into a fluidized bed granulator (manufactured by Paulek, Inc .: MP-01 type), and a solution obtained by dissolving 6 g of hydroxypropyl cellulose in 114 g of purified water was sprayed and granulated. 202.5 g of the obtained granulated product was taken, 10 g of crospovidone and 1 g of magnesium stearate were blended and tableted to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imatinib mesylate 119.5
D-mannitol 80.0
Hydroxypropyl cellulose 3.0
Crospovidone 10.0
Magnesium stearate 1.0
実施例２
イマチニブメシル酸塩２３９ｇ及び還元パラチノース１００ｇを流動層造粒機（パウレック社製：ＭＰ−０１型）に投入し、ヒプロメロース６ｇを精製水１１４ｇに溶解した液をスプレーし造粒した。得られた造粒物１７２．５ｇをとり、低置換度ヒドロキシプロピルセルロース１０ｇ及びステアリン酸マグネシウム１ｇを配合して打錠し、下記組成の錠剤を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
イマチニブメシル酸塩 １１９．５
還元パラチノース ５０．０
ヒプロメロース ３．０
低置換度ヒドロキシプロピルセルロース ６．０
ステアリン酸マグネシウム １．０
Example 2
239 g of imatinib mesylate and 100 g of reduced palatinose were put into a fluidized bed granulator (manufactured by Paulek, Inc .: MP-01 type), and a solution obtained by dissolving 6 g of hypromellose in 114 g of purified water was sprayed and granulated. 172.5 g of the obtained granulated product was taken, 10 g of low-substituted hydroxypropylcellulose and 1 g of magnesium stearate were blended and tableted to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imatinib mesylate 119.5
Reduced palatinose 50.0
Hypromellose 3.0
Low-substituted hydroxypropylcellulose 6.0
Magnesium stearate 1.0
実施例３
イマチニブメシル酸塩２３９ｇ及びトレハロース２４０ｇを流動層造粒機（パウレック社製：ＭＰ−０１型）に投入し、ヒプロメロース６ｇを精製水１１４ｇに溶解した液をスプレーし造粒した。得られた造粒物２４２．５ｇをとり、カルメロースカルシウム１０ｇ及びステアリン酸マグネシウム１ｇを配合して打錠し、下記組成の錠剤を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
イマチニブメシル酸塩 １１９．５
トレハロース １２０．０
ヒプロメロース ３．０
カルメロースカルシウム １０．０
ステアリン酸マグネシウム １．０
Example 3
239 g of imatinib mesylate and 240 g of trehalose were put into a fluidized bed granulator (manufactured by Paulek, Inc .: MP-01 type), and a solution obtained by dissolving 6 g of hypromellose in 114 g of purified water was sprayed and granulated. 242.5 g of the obtained granulated product was taken, mixed with 10 g of carmellose calcium and 1 g of magnesium stearate, and tableted to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imatinib mesylate 119.5
Trehalose 120.0
Hypromellose 3.0
Carmellose calcium 10.0
Magnesium stearate 1.0
比較例１
イマチニブメシル酸塩２３９ｇを流動層造粒機（パウレック社製：ＭＰ−０１型）に投入し、ヒドロキシプロピルセルロース６ｇを精製水１１４ｇに溶解した液をスプレーし造粒した。得られた造粒物１２２．５ｇをとり、低置換度ヒドロキシプロピルセルロース１０ｇ及びステアリン酸マグネシウムを１ｇ配合して打錠し、下記組成の錠剤を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
イマチニブメシル酸塩 １１９．５
ヒドロキシプロピルセルロース ３．０
低置換度ヒドロキシプロピルセルロース １０．０
ステアリン酸マグネシウム １．０
Comparative Example 1
239 g of imatinib mesylate was charged into a fluidized bed granulator (manufactured by Paulec Co., Ltd .: MP-01 type), and a solution obtained by dissolving 6 g of hydroxypropylcellulose in 114 g of purified water was sprayed and granulated. 122.5 g of the resulting granulated product was taken, 10 g of low-substituted hydroxypropyl cellulose and 1 g of magnesium stearate were blended and tableted to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imatinib mesylate 119.5
Hydroxypropyl cellulose 3.0
Low-substituted hydroxypropylcellulose 10.0
Magnesium stearate 1.0
試験例１
実施例１〜３及び比較例１で得た錠剤について溶出試験（試験液水、パドル回転数５０ｒｐｍ）によりイマチニブの溶出率を測定し、表１の結果を得た。
表１の結果から、本発明に係る実施例１〜３の錠剤は、比較例１の錠剤と比べ、イマチニブの溶出率を極めて効果的に改善し得ることが判った。
Test example 1
For the tablets obtained in Examples 1 to 3 and Comparative Example 1, the dissolution rate of imatinib was measured by a dissolution test (test solution water, paddle rotation speed 50 rpm), and the results shown in Table 1 were obtained.
From the result of Table 1, it turned out that the tablet of Examples 1-3 which concerns on this invention can improve the elution rate of imatinib very effectively compared with the tablet of the comparative example 1.
水溶性が極めて高く、水との接触により粒子表面に粘着性のゲル層を形成し、崩壊、溶出が遅延する生理活性物質の製造において、水溶性の糖類又は糖アルコールを配合することにより、製剤操作上簡便な方法で、生理活性物質粒子表面のゲル化を抑制し、溶出性が改善された固形製剤を提供することができる。
Formulation by blending water-soluble saccharides or sugar alcohols in the production of bioactive substances with extremely high water-solubility, forming a sticky gel layer on the particle surface when contacted with water, and disintegration and elution being delayed By a method that is simple in terms of operation, gelation of the surface of the physiologically active substance particle can be suppressed, and a solid preparation with improved dissolution can be provided.
Claims (5)
It is a film coating tablet, The solid formulation of Claims 1-4.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013145749A1 (en) * | 2012-03-29 | 2013-10-03 | 杏林製薬株式会社 | Capsule preparation |
| WO2013145750A1 (en) * | 2012-03-29 | 2013-10-03 | 杏林製薬株式会社 | Capsule pharmaceutical preparation |
| WO2016063544A1 (en) * | 2014-10-23 | 2016-04-28 | 杏林製薬株式会社 | Solid pharmaceutical composition |
| WO2016063542A1 (en) * | 2014-10-23 | 2016-04-28 | 杏林製薬株式会社 | Solid pharmaceutical composition |
-
2011
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013145749A1 (en) * | 2012-03-29 | 2013-10-03 | 杏林製薬株式会社 | Capsule preparation |
| WO2013145750A1 (en) * | 2012-03-29 | 2013-10-03 | 杏林製薬株式会社 | Capsule pharmaceutical preparation |
| JPWO2013145749A1 (en) * | 2012-03-29 | 2015-12-10 | 杏林製薬株式会社 | Capsule formulation |
| WO2016063544A1 (en) * | 2014-10-23 | 2016-04-28 | 杏林製薬株式会社 | Solid pharmaceutical composition |
| WO2016063542A1 (en) * | 2014-10-23 | 2016-04-28 | 杏林製薬株式会社 | Solid pharmaceutical composition |
| JP6018334B2 (en) * | 2014-10-23 | 2016-11-02 | 杏林製薬株式会社 | Solid pharmaceutical composition |
| US10154993B2 (en) | 2014-10-23 | 2018-12-18 | Kyorin Pharmaceutical Co., Ltd. | Solid pharmaceutical composition |
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