JP2016145203A - Excipient for improving shock-tolerance of tablet - Google Patents
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本発明は、粒子の形状、特性の異なるマンニトールを混合した賦形剤に関する。また当該賦形剤を使用することで、錠剤の割れやカケなど、包装時や輸送段階で錠剤に発生する損傷を低減させることができる方法及びその方法を用いた錠剤に関する。 The present invention relates to an excipient mixed with mannitol having different particle shapes and characteristics. In addition, the present invention relates to a method that can reduce damage to the tablet during packaging or in the transportation stage, such as cracking or chipping of the tablet, and a tablet using the method.
マンニトールは、その安定性、カロリーの低さ、医薬成分との反応性の低さから錠剤の賦形剤として広く使用されている。しかしながら飽和水溶液から晶出したマンニトールは、粒子同士の結合性が低く、マンニトールを賦形剤として使用した錠剤は、硬度が低いと言われており、実用的な硬度を得るためには高成形圧での打錠や、他の結合剤の配合が必要であった。さらに、高成形圧での打錠では打錠機の杵臼の消耗につながるし、結合剤を多く配合すると、特に錠剤の中でも口腔内崩壊錠では、崩壊性に影響を及ぼし、好ましくなかった。 Mannitol is widely used as an excipient for tablets because of its stability, low calories, and low reactivity with pharmaceutical ingredients. However, mannitol crystallized from a saturated aqueous solution has a low bonding property between particles, and tablets using mannitol as an excipient are said to have low hardness. To obtain practical hardness, high molding pressure is required. Tableting and other binders were required. Furthermore, tableting at a high molding pressure leads to consumption of the milling tool of the tableting machine, and blending a large amount of binders is not preferable, especially in the orally disintegrating tablet among tablets.
そこで従来、高い硬度を得ることができる直接打錠用のマンニトールが開発されてきたが、硬度が高い錠剤であっても、錠剤分包機などの使用に伴い、割れやカケなどの問題は多くなっていた。 Thus, mannitol for direct tableting that can obtain high hardness has been developed, but problems such as cracking and chipping increase with the use of tablet packaging machines, even for tablets with high hardness. It was.
さらに本出願人は、このような状況を鑑み、国際公開第２００８／１４６５９０号（特許文献１）や国際公開第２０１０／０２１３００号（特許文献２）に開示されるような、高い錠剤硬度の得られる特殊な物性のマンニトールの球形結晶粒子を開発していた。 Furthermore, in view of such circumstances, the present applicant has obtained high tablet hardness as disclosed in International Publication No. 2008/146590 (Patent Document 1) and International Publication No. 2010/021300 (Patent Document 2). We have been developing spherical crystal particles of mannitol with special properties.
しかしながら、依然として、低成形圧で高硬度かつ割れやカケなどが発生しづらいという課題の解決法が望まれており、一般的に求められる錠剤硬度を得るために、特許文献１や特許文献２のような特殊な物性の粒子が大量に必要となることは、コストの面からも問題となっていた。 However, there is still a demand for a solution to the problem that high hardness and low cracking and chipping are difficult to occur at a low molding pressure, and in order to obtain generally required tablet hardness, Patent Document 1 and Patent Document 2 The necessity of a large amount of particles having such special physical properties has been a problem from the viewpoint of cost.
そこで、本発明者らは、直接打錠用に開発されたマンニトールではない、一般的な晶出法で得られる、従来のマンニトールの結晶粉砕粒子を主成分として用いつつ、硬度が高く、かつ、錠剤の割れやカケなどを防止できる賦形剤を得るよう、各種物性のマンニトール粒子を配合し、特定の製法で得られるマンニトールを、従来のマンニトールの結晶粉砕粒子に特定の割合混合した賦形剤により、課題を解決できることを見出し、本発明を完成させた。 Therefore, the present inventors are not mannitol developed for direct tableting, and are obtained by a general crystallization method, using conventional pulverized mannitol crystallized particles as a main component, have high hardness, and In order to obtain excipients that can prevent tablet breakage and chipping, mannitol particles with various physical properties are blended, and mannitol obtained by a specific manufacturing method is mixed in a specific proportion with conventional crushed particles of mannitol. Thus, the present inventors have found that the problem can be solved and completed the present invention.
すなわち、本発明の解決手段は下記の通りである。
第一に、マンニトールからなる打錠用賦形剤であって、該マンニトールが、安息角が３５〜５０度であることを特徴とする球形結晶粒子と、結晶粉砕粒子とを、５：９５から５０：５０の割合で混合したものであることを特徴とする打錠用賦形剤である。
第二に、前記球形結晶粒子が、アスペクト比が１．０〜１．２、試験法Ａによる吸油率１が２５〜４０％、吸油率２が１５〜３０％、ゆるみかさ密度が０．４〜０．６ｇ／ｍｌ、平均粒径が３０〜５０μｍであることを特徴とする、上記第一に記載の打錠用賦形剤である。
第三に、前記結晶粉砕粒子が、安息角が４５〜７０度、平均粒径が１５〜５５μｍであることを特徴とする、上記第一または第二に記載の打錠用賦形剤である。
第四に、上記第一から第三のいずれか一つに記載の打錠用賦形剤を使用した錠剤落下破損率改善方法である。
第五に、上記第一から第三のいずれか一つに記載の打錠用賦形剤を用いた落下破損率が改善した口腔内崩壊錠剤である。
That is, the solution of the present invention is as follows.
First, a tableting excipient comprising mannitol, wherein the mannitol has spherical crystal particles characterized by an angle of repose of 35 to 50 degrees, and crystal ground particles from 5:95 A tableting excipient characterized by being mixed at a ratio of 50:50.
Second, the spherical crystal particles have an aspect ratio of 1.0 to 1.2, an oil absorption rate 1 according to Test Method A of 25 to 40%, an oil absorption rate 2 of 15 to 30%, and a loose bulk density of 0.4. The excipient for tableting according to the first aspect, characterized in that it has a particle size of ˜0.6 g / ml and an average particle size of 30-50 μm.
Thirdly, the tableting excipient according to the first or second aspect, wherein the crystal pulverized particles have an angle of repose of 45 to 70 degrees and an average particle diameter of 15 to 55 μm. .
Fourthly, there is provided a tablet drop breakage rate improving method using the tableting excipient according to any one of the first to third.
Fifth, it is an orally disintegrating tablet with improved drop breakage rate using the tableting excipient according to any one of the first to third.
以下に本発明の詳細を説明する。 Details of the present invention will be described below.
本発明において、マンニトールの球形結晶粒子は噴霧乾燥によって得られたものであり、噴霧乾燥とは乾燥塔内の熱風気流中にマンニトールの溶液や懸濁液を微細噴霧し、溶媒を蒸発させて粒子を得る方法である。この方法で得られた粒子は、溶媒の蒸発によって、粒子内に空隙を有することを特徴とし、また乾燥塔内に噴霧された液滴が空中で乾燥し粒子化することで、球形の粒子構造を有するために、流動性の良い粒子を得ることが出来る。 In the present invention, the spherical crystal particles of mannitol are obtained by spray drying, and spray drying is a particle obtained by finely spraying a solution or suspension of mannitol in a hot air stream in a drying tower and evaporating the solvent. Is the way to get. The particles obtained by this method are characterized by having voids in the particles due to the evaporation of the solvent, and the droplets sprayed in the drying tower are dried in the air to form particles, thereby forming a spherical particle structure. Therefore, particles having good fluidity can be obtained.
ここで、本発明においては、球形結晶粒子とは、噴霧乾燥によって得られた球状の構造を内包する粒子のことを意味する。粒子そのものの形状が球状であってもいいし、球状の構造がいくつか寄り集まったような粒子の形状であってもよい。 Here, in the present invention, the spherical crystal particle means a particle containing a spherical structure obtained by spray drying. The shape of the particle itself may be spherical, or may be a particle shape in which several spherical structures are gathered.
また、流動性は安息角で表すことが出来る。安息角は、粉体を円盤上に自然落下させた状態で形成される山の角度であり、以下のように設定したパウダーテスタＰＴ−Ｘ（ホソカワミクロン株式会社製）により測定する。試料用ホッパーは振動幅１ｍｍの設定でホッパーを振動させ、目開き７１０μｍの網、排出ロート、ノズル（内径７．８ｍｍ）を通し、安息角試料台の円板上に落下させ粉体の山を作る。この条件により形成された粉体の山の角度が、パウダーテスタＰＴ−Ｘによる画像解析の結果、測定値としてあらわされる。 In addition, fluidity can be expressed in terms of angle of repose. The angle of repose is an angle of a mountain formed when the powder is naturally dropped on the disk, and is measured by a powder tester PT-X (manufactured by Hosokawa Micron Corporation) set as follows. The sample hopper is vibrated with a vibration width of 1 mm, passed through a mesh with a mesh opening of 710 μm, a discharge funnel, and a nozzle (inner diameter 7.8 mm), dropped onto the disc of the angle of repose sample table, and piled up powder. create. The angle of the peak of the powder formed under these conditions is expressed as a measured value as a result of image analysis by the powder tester PT-X.
本発明においては、マンニトールの球形結晶粒子と結晶粉砕粒子を混合することから、２種の粒子を混合した際に結晶粉砕粒子中に球形結晶粒子を均一にいきわたらせるために、球形結晶粒子の流動性は重要である。このような理由から本発明に係る球形結晶粒子において、安息角は３５〜５０度であることが好ましい。より低い安息角であると好ましく、具体的には３５〜４５度の安息角であるとさらに好ましい。 In the present invention, since the spherical crystal particles of mannitol and the crystal pulverized particles are mixed, in order to uniformly distribute the spherical crystal particles in the crystal pulverized particles when the two kinds of particles are mixed, Liquidity is important. For these reasons, the angle of repose is preferably 35 to 50 degrees in the spherical crystal particle according to the present invention. A lower angle of repose is preferable, and specifically, an angle of repose of 35 to 45 degrees is more preferable.
また、球形結晶粒子がより真球度が高く、空隙を多く有する中空構造でありながら、微細な粒子であるほうが、本発明の効果を顕著に得ることが出来る。これは、中空構造であるほうが塑性変形しやすいことから、打錠時に、粒子表面における隣接粒子間のみならず、中空構造の内部においても粒子間の接着面が付与されるため、打錠性が良くなることに起因すると考えられる。また、微細粒子であるほど、比表面積が広くなるため、この特性も粒子間の接着面の増加に寄与し、錠剤硬度が上がりやすい。 In addition, the spherical crystal particles have a higher sphericity and a hollow structure having many voids, but the finer particles can achieve the effect of the present invention more remarkably. This is because the hollow structure is more likely to be plastically deformed, so that at the time of tableting, not only between adjacent particles on the particle surface, but also an inside surface of the hollow structure gives an adhesive surface between the particles, so that tabletability is improved. This is thought to be due to improvement. Further, the finer the particles, the larger the specific surface area. This characteristic also contributes to an increase in the adhesion surface between the particles, and the tablet hardness tends to increase.
したがって、球形結晶粒子の真球度を表すアスペクト比が１．０〜１．２であることが好ましく、粒子の空隙を表す吸油率について、以下に表す方法で測定した吸油率１が２５〜４０％、吸油率２が１５〜３０％であることが好ましい。 Therefore, the aspect ratio representing the sphericity of the spherical crystal particles is preferably 1.0 to 1.2, and the oil absorption 1 representing the voids of the particles is 25 to 40 as measured by the method described below. %, And the oil absorption 2 is preferably 15 to 30%.
本発明におけるアスペクト比とは、粒子の長軸と短軸との比であり、真球度を示す目安となるものである。長軸、短軸の比は、試料粒子を電子顕微鏡（ＴＭ−３０００、株式会社日立ハイテクノロジーズ製）を用いて拡大倍率２００倍程度で写真撮影し、３０個の球形結晶粒子について長軸の長さ（長径）と長軸の中点から垂直に引いた短軸の長さ（短径）を各々測定し、各々について短径に対する長径の比を求め、３０個の平均値で示したものである。 The aspect ratio in the present invention is a ratio between the major axis and the minor axis of a particle and serves as a standard indicating sphericity. The ratio of the major axis to the minor axis is determined by taking a photograph of the sample particles with an electron microscope (TM-3000, manufactured by Hitachi High-Technologies Corporation) at an enlargement ratio of about 200 times. Measure the length (major axis) and the length (minor axis) of the minor axis perpendicularly drawn from the midpoint of the major axis, find the ratio of the major axis to the minor axis for each, and show the average value of 30 is there.
アスペクト比が１．０〜１．２であれば、球形結晶粒子の流動性はさらに好ましいものとなり、結晶粉砕粒子との混合が均一になるし、真球度の高い粒子を結晶粉砕粒子と混合した賦形剤は、他成分との均一混合が可能となり、含量均一性に優れる。 If the aspect ratio is 1.0 to 1.2, the flowability of the spherical crystal particles is more preferable, the mixing with the crystal pulverized particles becomes uniform, and the particles with high sphericity are mixed with the crystal pulverized particles. The obtained excipient can be uniformly mixed with other components and is excellent in content uniformity.
なお、本発明における試験法Ａによる吸油率とは以下の通りである。中鎖脂肪酸トリグリセライド（花王株式会社製、ココナードＭＴ）３０ｇと試料マンニトール１５ｇを１００ｍｌのガラス製ビーカーに入れ、粉体を破砕しないように穏やかにスパチュラで油と粉末試料とをかき混ぜたのち、真空定温乾燥機（ＶＯＳ−３００Ｄ、ＥＹＥＬＡ社製）に入れ、室温で０．６７Ｐａまで減圧して３時間油を含浸させる。 In addition, the oil absorption rate by the test method A in this invention is as follows. Place 30g of medium chain fatty acid triglyceride (Coconard MT, manufactured by Kao Corporation) and 15g of mannitol sample into a 100ml glass beaker, gently mix the oil and powder sample with a spatula so as not to crush the powder, It puts into drying machine (VOS-300D, the product made by EYELA), and decompresses to 0.67 Pa at room temperature, and impregnates oil for 3 hours.
次に、目開き４５μｍ（３２５メッシュ）のろ布を敷いた遠沈管（底に孔のあるもの）に移し、遠心分離機（株式会社コクサン製、Ｈ−５００Ｒ）を用いて１３００Ｇに設定し１０分間遠心分離する。遠心分離後の試料入り遠沈管重量と遠沈管風袋重量の測定値から遠心分離後に遠沈管内に残った粉末試料の重量（重量ａ）を求め、下記式１により計算された値を吸油率１とする。 Next, the sample is transferred to a centrifuge tube (having a hole in the bottom) covered with a filter cloth having an opening of 45 μm (325 mesh), and set to 1300 G using a centrifuge (Hokusan Co., Ltd., H-500R). Centrifuge for minutes. The weight (weight a) of the powder sample remaining in the centrifuge tube after centrifugation is obtained from the measured value of the centrifuge tube containing the sample after centrifugation and the weight of the centrifuge tube tare, and the value calculated by the following equation 1 is the oil absorption rate 1 And
吸油率１（％）＝［（重量ａ−１５）／１５］×１００ （式１） Oil absorption 1 (%) = [(weight a-15) / 15] × 100 (formula 1)
更に、１００ｍｌのガラス製ビーカーに遠心分離後の試料入り遠沈管を入れ、ｎ−ヘキサン２０ｇを粉末試料の上から加え、遠心分離機を用いて１３００Ｇに設定し１０分間遠心分離する。次に、遠心分離後の試料入り遠沈管重量と遠沈管風袋重量の測定値から遠心分離後に遠沈管内に残った粉末試料の重量（重量ｂ）を求め、下記式２により計算された値を吸油率２とする。 Further, the centrifuge tube containing the sample after centrifugation is placed in a 100 ml glass beaker, 20 g of n-hexane is added from above the powder sample, and the mixture is centrifuged at 1300 G using a centrifuge for 10 minutes. Next, the weight (weight b) of the powder sample remaining in the centrifuge tube after centrifugation is obtained from the measured value of the centrifuge tube containing the sample after centrifugation and the centrifuge tube tare weight, and the value calculated by the following equation 2 is obtained. Oil absorption rate is 2.
吸油率２（％）＝［（重量ｂ−１５）／１５］×１００ （式２） Oil absorption 2 (%) = [(weight b−15) / 15] × 100 (Formula 2)
また、球形結晶粒子の平均粒径は３０〜５０μｍであることが好ましい。平均粒径が３０μｍより小さくなると、混合物を得る際に偏析が起こりやすくなるし、また混合物をそのまま打錠した際に、微細な粒子が打錠機内で杵臼間のクリアランスに入りこみ、打錠障害がおこりやすい。一方、平均粒径が５０μｍより大きくなると、得られる錠剤の硬度はわずかに下がる。これは粒子同士の接点が多いほど、結着点が増えることに起因すると考えられる。 Moreover, it is preferable that the average particle diameter of a spherical crystal particle is 30-50 micrometers. When the average particle size is smaller than 30 μm, segregation is likely to occur when the mixture is obtained, and when the mixture is tableted as it is, fine particles enter the clearance between the millstones in the tableting machine, and the tableting trouble is disturbed. Easy to happen. On the other hand, when the average particle size is larger than 50 μm, the hardness of the resulting tablet slightly decreases. This is considered to be caused by the fact that the number of contact points between the particles increases the number of binding points.
ここで、上記の平均粒径は粉体のメジアン径を表し、レーザー回折式の粒度分布計で知ることが出来る。レーザー回折式の粒度分布計としてはマイクロトラック・ベル株式会社のＭｉｃｒｏｔｒａｃ ＭＴ３０００を好適な例として使用することが出来、水溶性のマンニトールを測定する方法として、イソプロパノールを溶媒として、溶媒中で分散した湿式状態で測定を行うことがよい。 Here, the above average particle diameter represents the median diameter of the powder, and can be known with a laser diffraction particle size distribution meter. As a laser diffraction particle size distribution analyzer, Microtrac MT3000 manufactured by Microtrac Bell Co., Ltd. can be used as a suitable example. As a method for measuring water-soluble mannitol, wet method in which isopropanol is used as a solvent and dispersed in the solvent. It is better to measure in the state.
また、本発明の球形結晶粒子は、ゆるみかさ密度が０．４〜０．６ｇ／ｍｌとなるものが好ましい。本発明の球形結晶粒子は、空隙を多く有する構造であるが、ゆるみかさ密度が０．４より低いものは得難いし、０．６より高いものは、空隙が少なく本発明の効果を奏さない。 The spherical crystal particles of the present invention preferably have a loose bulk density of 0.4 to 0.6 g / ml. The spherical crystal particles of the present invention have a structure having many voids, but it is difficult to obtain particles having a loose bulk density lower than 0.4, and particles having a loose bulk density of less than 0.6 do not have the effects of the present invention because there are few voids.
本発明におけるゆるみかさ密度とは、粉体を所定の容器内に自然落下させた状態の充填密度であり、パウダーテスタＰＴ−Ｘを用いて以下の方法で測定する。 The loose bulk density in the present invention is a packing density in a state where powder is naturally dropped into a predetermined container, and is measured by the following method using a powder tester PT-X.
測定円台に試料容器（容積１００ｍｌ）を置き、試料用ホッパーは振動幅１ｍｍの設定でホッパーを振動させ、目開き７１０μｍの網を通して試料を落下させ試料容器に山盛りに充填し、試料容器の上部においてすり切りヘラですり切りし、その重量を測定する。一種類の試料について同じ操作を３度繰り返し、その平均値をゆるみかさ密度とする。 Place the sample container (volume 100ml) on the measurement platform, and the sample hopper vibrates with the setting of the vibration width of 1mm, drop the sample through the net of 710μm mesh, fill the sample container in the heap, and the upper part of the sample container In, cut with a spatula and measure the weight. The same operation is repeated three times for one type of sample, and the average value is defined as the loose bulk density.
次に、本発明の結晶粉砕粒子は、当業者によって従来知られている飽和水溶液からの結晶化方法で得ることが出来る結晶を、やはり従来知られている各種粉砕方法により、微細化したものである。 Next, the crystal pulverized particles of the present invention are obtained by refining crystals that can be obtained by a crystallization method from a saturated aqueous solution conventionally known by those skilled in the art by various conventionally known pulverization methods. is there.
つまり、マンニトールの飽和溶液を、加熱状態または冷却状態にすることにより過飽和をもたらし、結晶を析出させたのちに、濾過や遠心分離などで結晶体のみを分離することで回収し、回収した結晶体を乾燥し結晶粒子が得られる。さらに得られた結晶粒子を、湿式粉砕や乾式粉砕などの方法で、物理的に破砕させ、結晶粒子を微細化することで、粉砕粒子を得ることが出来る。 In other words, a saturated solution of mannitol is brought into supersaturation by bringing it into a heated state or a cooled state, and after the crystals are precipitated, it is recovered by separating only the crystals by filtration or centrifugation, and the recovered crystals Is dried to obtain crystal particles. Further, the obtained crystal particles are physically crushed by a method such as wet pulverization or dry pulverization, and the crystal particles are refined to obtain pulverized particles.
結晶粉砕粒子の平均粒径は１５〜５５μｍであることが好ましい。平均粒径が１５μｍより小さいものは、特殊な粉砕方法をとっているものも多く、一般的に得難いし、球形結晶粒子同様、混合物を得る際に偏析が起こりやすくなる。また、平均粒径が５５μｍより大きくなると、球形結晶粒子同様、得られる錠剤の硬度が下がる。 The average particle size of the pulverized crystal particles is preferably 15 to 55 μm. Those having an average particle size of less than 15 μm often take a special pulverization method and are generally difficult to obtain, and as with spherical crystal particles, segregation tends to occur when a mixture is obtained. On the other hand, when the average particle size is larger than 55 μm, the hardness of the resulting tablet is lowered as in the case of spherical crystal particles.
また、安息角は４５〜７０度であることが好ましい。溶液から析出させたマンニトールの結晶は針状の形状であり、結晶粉砕粒子も、もともとの針状結晶の形状に起因した多面体をしていることが多い。したがって流動性は非常に悪いが、７０度より大きくなると混合の際、粒子が偏析するため好ましくない。さらに、４５〜６０度であると、混合の際の偏析の心配が少ないので特に好ましい。 The angle of repose is preferably 45 to 70 degrees. The mannitol crystals precipitated from the solution have an acicular shape, and the crystal pulverized particles often have a polyhedron resulting from the original acicular crystal shape. Accordingly, the fluidity is very poor, but if it exceeds 70 degrees, the particles are segregated during mixing, which is not preferable. Furthermore, it is particularly preferable that the angle is 45 to 60 degrees because there is little fear of segregation during mixing.
また、上記のような結晶粉砕粒子のなかでも、ゆるみかさ密度が０．２５〜０．６０ｇ／ｍｌとなるものが好ましい。 Among the above-mentioned crystal pulverized particles, those having a loose bulk density of 0.25 to 0.60 g / ml are preferable.
本発明は、これまで説明したような球形結晶粒子と結晶粉砕粒子を特定の割合で混合し賦形剤とする。その混合割合は、球形結晶粒子：結晶粉砕粒子が質量比で５：９５から５０：５０である。５：９５の割合よりも球形結晶粒子が少ない場合は、本発明の効果である、錠剤の割れやカケを低減することが出来ない。 In the present invention, spherical crystal particles and crystal pulverized particles as described above are mixed at a specific ratio to obtain an excipient. The mixing ratio of spherical crystal particles: crystal pulverized particles is 5:95 to 50:50 by mass ratio. When the amount of spherical crystal particles is less than the ratio of 5:95, it is not possible to reduce tablet breakage and chipping, which are the effects of the present invention.
また、球形結晶粒子：結晶粉砕粒子の混合比率において、５０：５０の割合よりも球形結晶粒子が多い場合は、球形結晶粒子の特性により、錠剤の割れやカケを低減することはできるが、賦形剤中に結晶粉砕粒子が多い場合に、球形結晶粒子を少量添加するだけで、錠剤の割れやカケを顕著に低減できることは、驚くべきことであった。 In addition, when the spherical crystal particle: crystal pulverized particle mixing ratio has more spherical crystal particles than the ratio of 50:50, tablet breakage and chipping can be reduced depending on the characteristics of the spherical crystal particles. It was surprising that when there are many pulverized crystal grains in the form, it is possible to remarkably reduce tablet breakage and chipping by adding a small amount of spherical crystal particles.
また、本発明の賦形剤の使用態様としては、球形結晶粒子と結晶粉砕粒子を混合したものを、そのまま賦形剤として、他の錠剤の原料である、薬理活性成分や他の賦形剤、崩壊剤、滑沢剤などと混合して直接打錠する態様、または、球形結晶粒子と結晶粉砕粒子を混合したあとに造粒してから、錠剤用賦形剤として使用する態様である。 In addition, as the usage mode of the excipient of the present invention, a mixture of spherical crystal particles and crystal pulverized particles is used as it is as an excipient, and a pharmacologically active ingredient or other excipient which is a raw material for other tablets. It is an aspect of mixing directly with a disintegrating agent, a lubricant, etc., or an aspect of using it as a tablet excipient after granulating after mixing spherical crystal particles and crystal pulverized particles.
なお、球形結晶粒子と結晶粉砕粒子の混合は、粉体を均一に混合できる方法であれば、任意の方法でよく、タンブラー型混合機やＶ型混合機などを用いることが出来る。また、球形結晶粒子と結晶粉砕粒子の造粒は、撹拌造粒機、流動層造粒乾燥機や押出し造粒機など従来知られた方法で良いが、流動層造粒乾燥機で任意の結着剤をバインダーとして噴霧しながら造粒することが、球形結晶粒子が結晶粉砕粒子の粒子間に均一に分散した状態で固定され、適度な凝集をもたらすことから好ましい。 The spherical crystal particles and the crystal pulverized particles can be mixed by any method as long as the powder can be uniformly mixed, and a tumbler mixer, a V mixer, or the like can be used. In addition, the spherical crystal particles and the crystal pulverized particles may be granulated by a conventionally known method such as a stirring granulator, a fluidized bed granulating dryer, or an extrusion granulator. Granulation while spraying the adhesive as a binder is preferable because the spherical crystal particles are fixed in a state of being uniformly dispersed between the particles of the crystal pulverized particles, thereby causing appropriate aggregation.
以下に、実施例に基づいて本発明の内容を詳細に説明するが、本発明の技術的範囲は以下の例に限定されるものではない。 Hereinafter, the contents of the present invention will be described in detail based on examples, but the technical scope of the present invention is not limited to the following examples.
噴霧乾燥によって得られるマンニトール球形結晶粒子として、三菱商事フードテック社製のマンニットＱを使用した。 As a mannitol spherical crystal particle obtained by spray drying, Mannit Q manufactured by Mitsubishi Corporation Foodtech was used.
またマンニトール結晶粉砕粒子として、三菱商事フードテック社製のマンニットＰまたは同社製のマンニットＣを使用した。 Further, as the mannitol crystal pulverized particles, Mannit P manufactured by Mitsubishi Corporation Foodtech or Mannit C manufactured by the same company was used.
いずれの粒子も複数の製造ロットの製品を使用し、物性については測定された数値の範囲を表１および表２にまとめた。 For each particle, products of a plurality of production lots were used, and the ranges of measured numerical values were summarized in Tables 1 and 2 for physical properties.
なお、本願において錠剤の割れやカケは、落下破損率として示した。落下破損率は、錠剤を一定の高さから大理石平面へ落下させ、目視で検品し、割れやカケが発生した錠剤の数を、試験に供した錠剤の全数で除した値とした。さらに、対照となる粉砕粒子のみを賦形剤として用いた場合の錠剤の落下破損率を求め、同目標硬度の試験区で比較し、球形結晶粒子と結晶粉砕粒子を混合した場合、どの程度落下破損率が改善されたかを以下の式で求めた。 In addition, in this application, the crack and chip of a tablet were shown as a fall breakage rate. The drop breakage rate was defined as a value obtained by dropping a tablet onto a marble plane from a certain height, inspecting it visually, and dividing the number of tablets with cracks or chipping by the total number of tablets used in the test. In addition, the drop breakage rate of the tablet when only the control pulverized particles are used as an excipient is obtained, compared in the test group of the same target hardness, and how much drops when spherical crystal particles and crystal pulverized particles are mixed. It was calculated | required with the following formula | equation whether the breakage rate was improved.
落下破損改善率（％）＝［１−（実施例落下破損率／対照例落下破損率）］×１００ Drop breakage improvement rate (%) = [1- (Example drop breakage rate / Control drop drop breakage rate)] × 100
［対照例１］
結晶粉砕粒子として、マンニットＰを用い、この結晶粉砕粒子のみを賦形剤として使用して錠剤を作成した。錠剤は、賦形剤を流動層造粒機によってヒドロキシプロピルセルロース（日本曹達社製「ＨＰＣ−ＳＳＬ」）８％溶液をバインダーとして、賦形剤となる粉体仕込み重量に対してヒドロキシプロピルセルロースの固形量を１％となるように噴霧して造粒した賦形剤造粒物を９８．５質量部、崩壊剤（ＢＡＳＦジャパン社製「コリドンＣＬ−Ｆ」）を１質量部、導水剤として二酸化ケイ素（日本アエロジル社製「アエロジル２００」）０．５質量部を均一に混合したのちに、この混合物と滑沢剤としてのステアリン酸マグネシウム１質量部とを混合し、φ８ｍｍ隅丸の形状で重量１８０ｍｇとなるよう単発式打錠機（ナノシーズ社製「ＮＳ−Ｔ１００」）を用いて打錠した。打錠圧は、硬度が６ｋｇｆとなるよう打錠時の荷重・厚みを適宜変更して錠剤を製造する打錠条件とした。なお、錠剤硬度は、硬度計（富山産業社製「ＴＨ−３０３ＭＰ」）を用いて、打錠して得られた錠剤から５錠について測定し、平均値を採用した。
[Control Example 1]
Mannitol P was used as the crystal pulverized particles, and tablets were prepared using only the crystal pulverized particles as an excipient. Tablets were prepared by using a fluidized bed granulator with a hydroxypropylcellulose (“HPC-SSL” manufactured by Nippon Soda Co., Ltd.) 8% solution as a binder, 98.5 parts by mass of an excipient granulated product granulated by spraying so that the solid content is 1%, 1 part by mass of a disintegrant (“Collidon CL-F” manufactured by BASF Japan Ltd.) After uniformly mixing 0.5 parts by mass of silicon dioxide (“Aerosil 200” manufactured by Nippon Aerosil Co., Ltd.), this mixture is mixed with 1 part by mass of magnesium stearate as a lubricant, and in the shape of a φ8 mm corner Tableting was performed using a single-type tableting machine (“NS-T100” manufactured by Nano Seeds) so that the weight was 180 mg. The tableting pressure was set to the tableting conditions for producing tablets by appropriately changing the load and thickness at the time of tableting so that the hardness was 6 kgf. The tablet hardness was measured for 5 tablets from tablets obtained by tableting using a hardness meter (“TH-303MP” manufactured by Toyama Sangyo Co., Ltd.), and an average value was adopted.
得られた錠剤について、硬度と落下破損率を表３に示す。なお、落下破損率を算出する際には、１．５ｍの高さから落下させる条件とした。 Table 3 shows the hardness and drop breakage rate of the obtained tablets. In addition, when calculating a fall breakage rate, it was set as the conditions made to drop from the height of 1.5 m.
球形結晶粒子としてマンニットＱを、結晶粉砕粒子としてマンニットＰを用い、５：９５の比率で混合して賦形剤として用いた。錠剤は、対照例１と同様に、賦形剤を造粒したのち、他の錠剤原料と混合して打錠して得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率、落下破損改善率を表３に示す。 Mannite Q was used as spherical crystal particles, and Mannite P was used as crystal pulverized particles, and they were mixed at a ratio of 5:95 and used as an excipient. Tablets were obtained in the same manner as in Control Example 1, after granulating the excipient, and then mixing with other tablet materials to make tablets. Table 3 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 1 for the obtained tablets.
球形結晶粒子と結晶粉砕粒子の比率を、１０：９０とした以外は、実施例１と同様にして、錠剤を得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率、落下破損改善率を表３に示す。 A tablet was obtained in the same manner as in Example 1 except that the ratio of the spherical crystal particles to the crystal pulverized particles was 10:90. Table 3 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 1 for the obtained tablets.
球形結晶粒子と結晶粉砕粒子の比率を、３０：７０とした以外は、実施例１と同様にして、錠剤を得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率、落下破損改善率を表３に示す。 A tablet was obtained in the same manner as in Example 1 except that the ratio of the spherical crystal particles to the crystal pulverized particles was 30:70. Table 3 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 1 for the obtained tablets.
球形結晶粒子と結晶粉砕粒子の比率を、５０：５０とした以外は、実施例１と同様にして、錠剤を得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率、落下破損改善率を表３に示す。 A tablet was obtained in the same manner as in Example 1 except that the ratio of the spherical crystal particles to the crystal pulverized particles was 50:50. Table 3 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 1 for the obtained tablets.
［比較例１］
球形結晶粒子と結晶粉砕粒子の比率を、１：９９とした以外は、実施例１と同様にして、錠剤を得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率、落下破損改善率を表３に示す。
[Comparative Example 1]
A tablet was obtained in the same manner as in Example 1 except that the ratio of the spherical crystal particles to the crystal pulverized particles was 1:99. Table 3 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 1 for the obtained tablets.
表３の結果から、本発明に係る特定の混合割合のマンニトールの打錠用賦形剤を用いた錠剤は、対照である結晶粉砕粒子のみからなる賦形剤を用いた錠剤に比べて、顕著に落下破損改善率が向上することが分かる。 From the results of Table 3, the tablets using the mannitol tableting excipient of a specific mixing ratio according to the present invention are more prominent than the tablets using the excipient consisting only of crystal crushed particles as a control. It can be seen that the drop breakage improvement rate is improved.
［対照例２］
結晶粉砕粒子として、マンニットＣを用い、この結晶粉砕粒子のみを賦形剤として使用して錠剤を作成した。錠剤は対照例１と同様に賦形剤を造粒したのち、打錠圧を、硬度８ｋｇｆとなるような打錠条件とした以外は対照例１と同様に他の錠剤原料と混合して打錠して得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率を表４に示す。
[Control Example 2]
Mannit C was used as crystal ground particles, and tablets were prepared using only the crystal ground particles as excipients. Tablets were granulated in the same manner as in Control Example 1 and then mixed with other tablet raw materials in the same manner as in Control Example 1 except that the tableting pressure was changed to a tableting condition with a hardness of 8 kgf. Obtained by locking. Table 4 shows the hardness and the drop damage rate measured in the same manner as in Control Example 1 for the obtained tablets.
球形結晶粒子としてマンニットＱを、結晶粉砕粒子としてマンニットＣを用い、５：９５の比率で混合して賦形剤として用いた。錠剤は、対照例２と同様に、賦形剤を造粒したのち、他の錠剤原料と混合して打錠して得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率、落下破損改善率を表４に示す。 Mannite Q was used as spherical crystal particles, and Mannite C was used as crystal pulverized particles, and they were mixed at a ratio of 5:95 and used as an excipient. The tablets were obtained in the same manner as in Control Example 2, after granulating the excipient, and then mixing with other tablet materials to make tablets. Table 4 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 1 for the obtained tablets.
球形結晶粒子と結晶粉砕粒子の比率を、１０：９０とした以外は、実施例５と同様にして、錠剤を得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率、落下破損改善率を表４に示す。 A tablet was obtained in the same manner as in Example 5 except that the ratio of the spherical crystal particles to the crystal pulverized particles was 10:90. Table 4 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 1 for the obtained tablets.
球形結晶粒子と結晶粉砕粒子の比率を、３０：７０とした以外は、実施例５と同様にして、錠剤を得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率、落下破損改善率を表４に示す。 A tablet was obtained in the same manner as in Example 5 except that the ratio of the spherical crystal particles to the crystal pulverized particles was 30:70. Table 4 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 1 for the obtained tablets.
球形結晶粒子と結晶粉砕粒子の比率を、５０：５０とした以外は、実施例５と同様にして、錠剤を得た。得られた錠剤について、硬度と、対照例１と同様に測定した落下破損率、落下破損率改善率を表４に示す。 A tablet was obtained in the same manner as in Example 5 except that the ratio of spherical crystal particles to crystal pulverized particles was 50:50. Table 4 shows the hardness, the drop breakage rate, and the drop breakage rate improvement rate measured for the obtained tablets in the same manner as in Control Example 1.
表４の結果から、本発明に係る特定の混合割合のマンニトールの打錠用賦形剤を用いた錠剤は、対照である結晶粉砕粒子のみからなる賦形剤を用いた錠剤に比べて、顕著に落下破改善率が向上することが分かる。 From the results in Table 4, the tablets using the specific mixing ratio of mannitol tableting excipients according to the present invention are more prominent than the tablets using excipients consisting only of crystal crushed particles as a control. It can be seen that the fall break improvement rate is improved.
［対照例３］
結晶粉砕粒子として、マンニットＰを用い、この結晶粉砕粒子のみを賦形剤として使用して錠剤を作成した。錠剤は、賦形剤６０質量部、他の錠剤原料には、成形助剤として「顆粒コンス」（日本コーンスターチ社製）を３８質量部、崩壊剤として「コリドンＣＬ−Ｆ」を１質量部、導水剤として二酸化ケイ素（日本アエロジル社製「アエロジル２００」）１質量部を均一に混合したのちに、この混合物と滑沢剤としてのステアリン酸マグネシウム１質量部とを混合し、打錠圧を、硬度６ｋｇｆまたは８ｋｇｆとなるような打錠条件とした以外は対照例１と同様に打錠して、錠剤を得た。得られた錠剤について、硬度と落下破損率を表５に示す。なお、落下破損率を算出する際には、２．０ｍの高さから落下させる条件とした。
[Control 3]
Mannitol P was used as the crystal pulverized particles, and tablets were prepared using only the crystal pulverized particles as an excipient. 60 parts by weight of excipients for tablets, 38 parts by weight of “granule cons” (manufactured by Nippon Corn Starch Co., Ltd.) as a molding aid, and 1 part by weight of “Kollidon CL-F” as disintegrants, After uniformly mixing 1 part by mass of silicon dioxide (“Aerosil 200” manufactured by Nippon Aerosil Co., Ltd.) as a water-conducting agent, this mixture and 1 part by mass of magnesium stearate as a lubricant are mixed, and the tableting pressure is determined. Tablets were obtained in the same manner as in Control Example 1 except that the tableting conditions were such that the hardness was 6 kgf or 8 kgf. Table 5 shows the hardness and drop breakage rate of the obtained tablets. In addition, when calculating the fall breakage rate, it was set as the conditions for dropping from a height of 2.0 m.
球形結晶粒子としてマンニットＱを、結晶粉砕粒子としてマンニットＰを用い、１０：９０の比率で混合して賦形剤として用いた。錠剤は対照例３と同様に、賦形剤と他の錠剤原料と混合して打錠して得た。得られた錠剤について、硬度と、対照例３と同様に測定した落下破損率、落下破損改善率を表５に示す。 Mannite Q was used as spherical crystal particles, and Mannite P was used as crystal pulverized particles, which were mixed at a ratio of 10:90 and used as an excipient. Tablets were obtained by mixing with excipients and other tablet raw materials in the same manner as in Control Example 3. Table 5 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 3 for the obtained tablets.
球形結晶粒子と結晶粉砕粒子の比率を、３０：７０とした以外は、実施例９と同様にして、錠剤を得た。得られた錠剤について、硬度と、対照例３と同様に測定した落下破損率、落下破損改善率を表５に示す。 A tablet was obtained in the same manner as in Example 9 except that the ratio of spherical crystal particles to crystal pulverized particles was 30:70. Table 5 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 3 for the obtained tablets.
球形結晶粒子と結晶粉砕粒子の比率を、５０：５０とした以外は、実施例９と同様にして、錠剤を得た。得られた錠剤について、硬度と、対照例３と同様に測定した落下破損率、落下破損改善率を表５に示す。 A tablet was obtained in the same manner as in Example 9 except that the ratio of the spherical crystal particles to the crystal pulverized particles was 50:50. Table 5 shows the hardness, the drop breakage rate, and the drop breakage improvement rate measured in the same manner as in Control Example 3 for the obtained tablets.
表５の結果から、本発明に係る特定の混合割合のマンニトールの打錠用賦形剤を用いた錠剤は、対照である結晶粉砕粒子のみからなる賦形剤を用いた錠剤に比べて、顕著に落下破損改善率が向上することが分かる。 From the results of Table 5, the tablets using the mannitol tableting excipient of a specific mixing ratio according to the present invention are more prominent than the tablets using the excipient consisting only of crystal crushed particles as a control. It can be seen that the drop breakage improvement rate is improved.
Claims (5)
An orally disintegrating tablet with improved drop breakage rate using the excipient for tableting according to any one of claims 1 to 3.
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| JP2009114113A (en) * | 2007-11-06 | 2009-05-28 | Nipro Corp | Intraorally disintegrable tablet and method for producing the same |
| WO2010021300A1 (en) * | 2008-08-18 | 2010-02-25 | 三菱商事フードテック株式会社 | Novel excipient for mannitol tableting |
| JP2017071558A (en) * | 2015-10-05 | 2017-04-13 | 三菱商事フードテック株式会社 | Shock resistance-improving excipient for tablet |
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| JP2009114113A (en) * | 2007-11-06 | 2009-05-28 | Nipro Corp | Intraorally disintegrable tablet and method for producing the same |
| WO2010021300A1 (en) * | 2008-08-18 | 2010-02-25 | 三菱商事フードテック株式会社 | Novel excipient for mannitol tableting |
| JP2017071558A (en) * | 2015-10-05 | 2017-04-13 | 三菱商事フードテック株式会社 | Shock resistance-improving excipient for tablet |
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