JP6660139B2 - Excipient for improving impact resistance of tablets - 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 in which mannitol having different shapes and characteristics of particles is mixed. In addition, the present invention relates to a method capable of reducing damage to a tablet at the time of packaging or transportation, such as cracking or chipping of a tablet, by using the excipient, 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。しかしながら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 calorie, and low reactivity with pharmaceutical ingredients. However, mannitol crystallized from a saturated aqueous solution has low binding properties between particles, and tablets using mannitol as an excipient are said to have low hardness. Tableting and blending of other binders were required. However, tableting at a high molding pressure leads to consumption of the punch and die of the tableting machine, and when a large amount of binder is incorporated, disintegrating properties are affected particularly for orally disintegrating tablets among tablets, which is not preferable.
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。 Therefore, conventionally, mannitol for direct compression which can obtain high hardness has been developed.However, even with a tablet having high hardness, problems such as cracking and chipping increase with the use of a tablet packaging machine. I 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 a situation, the present applicant has obtained a high tablet hardness as disclosed in WO 2008/146590 (Patent Document 1) and WO 2010/021300 (Patent Document 2). Have developed mannitol spherical crystal particles with special physical 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 need for a solution to the problem of high hardness and low occurrence of cracks and chips at low molding pressure, and in order to obtain a 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 in terms 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析出結晶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析出結晶粒子に特定の割合で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, obtained by a general crystallization method, using the conventional precipitated crystal particles of mannitol as a main component, high hardness, and, Mannitol particles of various physical properties are blended so as to obtain an excipient that can prevent cracking and chipping of tablets, and mannitol obtained by a specific manufacturing method is mixed with conventional mannitol precipitated crystal particles at a specific ratio It has been found that the problem can be solved by the agent, and the present invention has been completed.
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、噴霧乾燥によって得られた安息角が３０〜５０度であることを特徴とする球形結晶粒子と、析出結晶粒子とを、１：９９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、前記析出結晶粒子が、平均粒径が７０〜２００μｍ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低下方法である。
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低下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 in that the angle of repose obtained by spray drying is 30 to 50 degrees, and precipitated crystal particles. Are mixed in the ratio of 1:99 to 50:50.
Secondly, the spherical crystal particles have an aspect ratio of 1.0 to 1.2, an oil absorption ratio 1 of 25 to 40%, an oil absorption ratio 2 of 15 to 30%, and a loose bulk density of 0.4 according to Test Method A. The tableting excipient according to the above-mentioned 1, wherein the tableting excipient is characterized in that the tableting excipient has an average particle size of 30 to 50 μm.
Third, the tableting excipient according to the first or second aspect, wherein the precipitated crystal particles have an average particle size of 70 to 200 µm.
Fourthly, there is provided a method for lowering the tablet drop breakage rate using the tableting excipient according to any one of the first to third aspects.
Fifthly, there is provided an orally disintegrating tablet having a reduced drop breakage rate using the tableting excipient according to any one of the first to third aspects.
以下に本発明の詳細を説明する。 The 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、粒子内に空洞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ため、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 method in which a solution or suspension of mannitol is finely sprayed into a stream of hot air in a drying tower, and the solvent is evaporated. Is a way to get The particles obtained by this method are characterized by having cavities in the particles due to evaporation of the solvent, and since the droplets sprayed in the drying tower dry in the air and become particles, a spherical particle structure is formed. As a result, 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 particles mean particles containing a spherical structure obtained by spray drying. The shape of the particle itself may be spherical, or the particle may be such that some spherical structures are gathered together.
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、安息角試料台の円盤上に落下させ山を作る。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。 The fluidity can be represented by the angle of repose. The angle of repose is the angle of a mountain formed when the powder is naturally dropped on a disk, and is measured with a powder tester PT-X (manufactured by Hosokawa Micron Corporation) set as follows. The sample hopper vibrates the hopper at a setting of a vibration width of 1 mm, passes through a net having an opening of 710 μm, a discharge funnel, and a nozzle (inner diameter: 7.8 mm), and falls on a disk of a repose angle sample table to form a mountain. The angle of the peak of the powder formed under these conditions is expressed as a measured value as a result of image analysis using 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析出結晶粒子を混合することから、２種の粒子を混合した際に析出結晶粒子中に球形結晶粒子が均一にいきわたるために、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３０〜５０度が好ましく、より好ましくは３５〜４５度である。 In the present invention, since the spherical crystal particles of mannitol and the precipitated crystal particles are mixed, the spherical crystal particles are uniformly distributed in the precipitated crystal particles when the two types of particles are mixed. Is important. For this reason, in the spherical crystal particles according to the present invention, the angle of repose is preferably 30 to 50 degrees, more preferably 35 to 45 degrees.
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 having higher sphericity and a hollow structure having many voids, but having fine particles, can significantly obtain the effects of the present invention. 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 between the particles inside the hollow structure, an adhesive surface between the particles is provided, so that the tableting property is improved. It is thought to be due to improvement. Further, since the specific surface area increases as the size of the fine particles increases, this property also contributes to an increase in the bonding 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 representing the void of the particles is 25 to 40 as measured by the method described below. % And an oil absorption 2 of 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 measure of sphericity. The ratio of the long axis to the short axis was determined by taking a photograph of the sample particles using an electron microscope (TM-3000, manufactured by Hitachi High-Technologies Corporation) at a magnification of about 200 times, and measuring the length of the long axis for 30 spherical crystal particles. The length (minor axis) and the length of the minor axis (minor axis) perpendicularly drawn from the midpoint of the major axis were measured, and the ratio of the major axis to the minor axis was determined for each of them. 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、析出結晶粒子との混合が均一になるし、真球度の高い粒子を析出結晶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。 When the aspect ratio is 1.0 to 1.2, the fluidity of the spherical crystal particles becomes more preferable, and the mixing with the precipitated crystal particles becomes uniform, and the particles with high sphericity are mixed with the precipitated crystal particles. The excipient thus obtained 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。 The oil absorption according to the test method A in the present invention is as follows. 30 g of medium-chain fatty acid triglyceride (Coconad MT, manufactured by Kao Corporation) and 15 g of sample mannitol are placed in a 100 mL glass beaker, and the oil and the powder sample are gently stirred with a spatula so as not to break the powder. It is put in a dryer (VOS-300D, manufactured by EYELA) and impregnated with oil for 3 hours by reducing the pressure to 0.67 Pa at room temperature.
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１３００Ｇに設定して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 mixture was transferred to a centrifuge tube (having a hole at the bottom) covered with a filter cloth having a mesh size of 45 μm (325 mesh), and the centrifugal separator (H-500R manufactured by Kokusan Co., Ltd.) was set to 1300 G for 10 minutes. Centrifuge. The weight (weight a) of the powder sample remaining in the centrifuge tube after centrifugation was determined from the measured values of the centrifuge tube containing the sample after centrifugation and the weight of the centrifuge tube tare. And
吸油率１（％）＝［（重量ａ−１５）／１５］×１００ （式１） Oil absorption rate 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１３００Ｇに設定して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, a centrifuge tube containing the sample after centrifugation is put into a 100 mL glass beaker, 20 g of n-hexane is added from above the powder sample, and the centrifuge is set to 1300 G and centrifuged for 10 minutes. Next, the weight (weight b) of the powder sample remaining in the centrifuge tube after centrifugation was determined from the measured centrifuge tube weight containing the sample after centrifugation and the measured value of the centrifuge tube tare weight, and the value calculated by the following equation 2 was calculated. The oil absorption ratio is set to 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。 Further, the average particle diameter of the spherical crystal particles is preferably 30 to 50 μm. If the average particle size is smaller than 30 μm, segregation is likely to occur when the mixture is obtained, and when the mixture is compressed as it is, fine particles enter the clearance between the punches and dies in the tableting machine, resulting in a tableting failure. Easy to get offended. On the other hand, when the average particle size is larger than 50 μm, the hardness of the obtained tablet is slightly reduced. This is considered to be due to the fact that as the number of contact points between particles increases, the number of binding points increases.
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 by a laser diffraction type particle size distribution meter. As a laser diffraction type particle size distribution analyzer, Microtrac MT3000 manufactured by Microtrac Bell Co., Ltd. can be used as a preferable example. As a method for measuring water-soluble mannitol, a wet method in which isopropanol is used as a solvent and dispersed in a solvent is used. It is good 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 those having a loose bulk density lower than 0.4 are difficult to obtain, and those having a loose bulk density higher than 0.6 have few voids and do not exhibit the effects of the present invention.
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（ホソカワミクロン株式会社製）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 a powder is naturally dropped into a predetermined container, and is measured by a powder tester PT-X (manufactured by Hosokawa Micron Corporation) by the following method.
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。 A sample container (volume: 100 mL) is placed on the measuring table, and the sample hopper is vibrated at a setting of a vibration width of 1 mm, the sample is dropped through a mesh having an opening of 710 μm, and the sample container is filled into a heap, And then weigh with a spatula. 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、本発明の析出結晶粒子は、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。 Next, the precipitated crystal particles of the present invention can be obtained by a crystallization method from a saturated aqueous solution conventionally known by those skilled in the art.
つまり、マンニトールを水、アルコールなどの溶媒に溶解させ飽和溶液を準備したのち、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、種結晶を添加又は添加せず、結晶を析出させ、さらに結晶成長段階を経てもよく、溶媒中に結晶が得られるよう制御する。その後、濾過や遠心分離などで溶媒から結晶体のみを分離することで結晶を回収し、回収した結晶を乾燥し析出結晶粒子が得られる。得られた析出結晶粒子の結晶型はα、β、γのいずれの結晶型でも構わないが、β型結晶が最も安定で、一般的に入手しやすい。また、その結晶形状は針状であり、結晶化の際に溶媒中に析出した細長い形状の結晶、およびその長辺方向で配向した結晶の寄り集まりであることが多く、粉砕機などによる物理的微細化を受けていないものを本発明の析出結晶粒子という。 In other words, after mannitol is dissolved in a solvent such as water or alcohol to prepare a saturated solution, supersaturation is brought about by heating or cooling, and crystals are precipitated with or without the addition of seed crystals and further crystal growth. A step may be performed, and control is performed so that crystals are obtained in the solvent. Thereafter, the crystals are recovered by separating only the crystals from the solvent by filtration, centrifugation, or the like, and the recovered crystals are dried to obtain precipitated crystal particles. The crystal form of the obtained precipitated crystal particles may be any of α, β, and γ, but β-type crystals are the most stable and are easily available. In addition, the crystal shape is acicular, which is often a collection of elongated crystals precipitated in the solvent during crystallization and crystals oriented in the long side direction, and physical Those that have not been refined are referred to as precipitated crystal particles of the present invention.
析出結晶粒子の平均粒径は７０〜２００μｍであることが好ましい。平均粒径が７０μｍより小さいものは、流動性が悪く、混合などの作業効率が劣るし、平均粒径が２００μｍ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 precipitated crystal particles is preferably from 70 to 200 μm. When the average particle size is smaller than 70 μm, the fluidity is poor and the working efficiency of mixing and the like is inferior. When the average particle size is larger than 200 μm, the hardness of the obtained tablet decreases as in the case of the spherical crystal particles.
また、析出結晶粒子は安息角が３５〜５５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長細い形状の多面体であり、５５度より大きくなると流動性が非常に悪く、混合の際、粒子が偏析するため好ましくない為である。 Further, the precipitated crystal particles preferably have an angle of repose of 35 to 55 degrees. The mannitol crystals precipitated from the solution are polyhedrons having a needle-like elongated shape. When the angle is larger than 55 degrees, the fluidity is very poor, and the particles are segregated during mixing, which is not preferable.
本発明は、これまで説明したような球形結晶粒子と析出結晶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：析出結晶粒子が質量比で１：９９から５０：５０であり、好ましくは３０：７０から５０：５０である。球形結晶粒子のごく少量の添加でも、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るが、球形粒子が析出結晶粒子間に、適度に存在することで、球形結晶粒子の微細結晶が錠剤の割れやカケを低減する効果に寄与すると考えられる。 In the present invention, the spherical crystal particles and the precipitated crystal particles as described above are mixed at a specific ratio to obtain an excipient. The mixing ratio is from 1:99 to 50:50, preferably from 30:70 to 50:50, by mass ratio of spherical crystal particles: precipitated crystal particles. Even with the addition of a small amount of spherical crystal particles, cracking and chipping of the tablet, which is an effect of the present invention, can be reduced.However, the spherical particles are appropriately present between the precipitated crystal particles, so that the fineness of the spherical crystal particles can be reduced. It is thought that the crystals contribute to the effect of reducing cracking and chipping of the tablet.
また、球形結晶粒子：析出結晶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、賦形剤中に析出結晶粒子が多い場合に、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。 When the ratio of spherical crystal particles: precipitated crystal particles is larger than the ratio of 50:50, the cracking and chipping of the tablet can be reduced due to the characteristics of the spherical crystal particles. It was surprising that when a large amount of precipitated crystal particles were present in the excipient, cracking and chipping of the tablet could be significantly reduced only 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、球形結晶粒子と析出結晶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してもよいが、球形結晶粒子と析出結晶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ことが好ましい。これは、形状・大きさの異なる球形結晶粒子と析出結晶粒子の混合物中で、球形結晶粒子が偏在することを防ぎ、均一に球形結晶粒子が存在することで、本発明の効果をより得られる状態となるためである。 In addition, as an embodiment of the use of the excipient of the present invention, a mixture of spherical crystal particles and precipitated crystal particles, as an excipient, as a raw material for other tablets, pharmacologically active ingredients and other excipients May be mixed directly with a disintegrant, a lubricant or the like, and then tableted directly. However, it is preferable to mix the spherical crystal particles and the precipitated crystal particles and then granulate them before using them as a tablet excipient. . This prevents the spherical crystal particles from being unevenly distributed in the mixture of the spherical crystal particles and the precipitated crystal particles having different shapes and sizes, and the effects of the present invention can be further obtained by the uniform existence of the spherical crystal particles. It is because it becomes a state.
なお、球形結晶粒子と析出結晶粒子の混合は、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、球形結晶粒子と析出結晶粒子の造粒は、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、球形結晶粒子が析出結晶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 precipitated crystal particles can be mixed by any method as long as the powder can be uniformly mixed, and a tumbler-type mixer or a V-type mixer can be used. Further, the granulation of the spherical crystal particles and the precipitated crystal particles may be performed by a conventionally known method such as a stirring granulator, a fluidized bed granulator / dryer or an extrusion granulator. It is preferable to perform granulation while spraying the adhesive as a binder, since the spherical crystal particles are fixed in a state of being uniformly dispersed between the precipitated crystal particles, and appropriate aggregation is brought about.
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、本発明の技術範囲は以下の例に限定されるものではない。 Hereinafter, the content 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.
析出結晶粒子のみを賦形剤として用いた錠剤と、析出結晶粒子に球形結晶粒子を混合した賦形剤を用いた錠剤を作成し、本発明の効果である錠剤の割れやカケの程度を比較した。 A tablet using only precipitated crystal particles as an excipient and a tablet using an excipient obtained by mixing spherical crystal particles with precipitated crystal particles were prepared, and the degree of tablet cracking and chipping, which is the effect of the present invention, was compared. did.
比較の方法は次のようにした。錠剤４５錠を１５錠ずつに分けて各１回、１．５ｍの高さから大理石平面へ落下させ、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を落下破損率とした。対照となる析出結晶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、球形結晶粒子と析出結晶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。 The comparison method was as follows. Forty-five tablets are divided into fifteen tablets, each of which is dropped once from a height of 1.5 m onto a marble plane, and the value obtained by dividing the number of tablets having cracks or chips by the total number of tablets subjected to the test is given by: The drop breakage rate was used. Calculate the drop breakage rate of the tablet when only the control precipitated crystal particles are used as an excipient, compare them in the test section with the same target hardness, and determine the degree of drop damage when the spherical crystal particles and the precipitated crystal particles are mixed. The following equation was used to determine whether the 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 damage improvement rate (%) = [1- (Example drop damage rate / Control example drop damage rate)] × 100
ただし、高硬度の錠剤となるよう成形圧を設定して、対照となる析出結晶粒子のみを賦形剤として用いた場合の錠剤を製造した場合に、打錠時に既に割れなどが起きるキャッピングなどが起きた条件では、全数破損とみなして落下破損率を１００％とし、同目標硬度の試験区で、球形結晶粒子と析出結晶粒子を混合した場合の錠剤の落下破損率の改善率について上記の式で求めた。 However, by setting the molding pressure so as to be a tablet of high hardness, when manufacturing a tablet using only the precipitated crystal particles as a control as an excipient, capping etc., which already cracks at the time of tableting, etc. Under the conditions that occurred, the drop failure rate was regarded as 100% considering that all the pieces were broken, and the above-mentioned formula was used for the improvement rate of the drop damage rate of the tablet when the spherical crystal particles and the precipitated crystal particles were mixed in the test section having the same target hardness. I asked for it.
［対照例１］
析出結晶粒子として、三菱商事フードテック社製のマンニットＳを用いた。粉体の平均粒径などの物性を表１に示す。この析出結晶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９９質量部、崩壊剤（ＢＡＳＦジャパン社製「コリドンＣＬ−Ｆ」）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、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５ｋｇｆ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、打錠して得られた錠剤から５錠について硬度計（富山産業社製「ＴＨ−３０３ＭＰ」）を用いて測定し、平均値を採用した。
[Control Example 1]
Mannit S manufactured by Mitsubishi Corporation Foodtech Co., Ltd. was used as the precipitated crystal particles. Table 1 shows the physical properties such as the average particle size of the powder. Tablets were prepared using only the precipitated crystal particles as an excipient. Tablets were prepared by using a fluidized bed granulator with an excipient as an excipient, using an 8% solution of hydroxypropylcellulose (“HPC-SSL” manufactured by Nippon Soda Co., Ltd.) as a binder. After uniformly mixing 99 parts by mass of an excipient granulated by spraying and granulating so as to have a solid content of 1%, and 1 part by mass of a disintegrant ("Kolidone CL-F" manufactured by BASF Japan). This mixture was mixed with 1 part by weight of magnesium stearate as a lubricant, and pressed using a single-shot tableting machine ("NS-T100" manufactured by Nano Seeds Co., Ltd.) so as to have a weight of 180 mg in the form of a round corner having a diameter of 8 mm. Locked. The tableting pressure was a tableting condition for manufacturing tablets by appropriately changing the load and thickness at the time of tableting so that the hardness was 5 kgf. In addition, the tablet hardness was measured using a hardness meter (“TH-303MP” manufactured by Toyama Sangyo Co., Ltd.) from five tablets obtained by tableting, and the average value was adopted.
得られた錠剤について、硬度と落下破損率を表２に示す。 Table 2 shows the hardness and the drop breakage rate of the obtained tablets.
噴霧乾燥で得られた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、析出結晶粒子として対照例１と同じマンニットＳを用い、１：９９の比率で混合して賦形剤として用いて錠剤を製造した。使用したマンニットＱの平均粒径などの物性を表１に示す。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、硬度と落下破損率、落下破損改善率を表２に示す。 As spherical crystal particles obtained by spray drying, Mannit Q manufactured by Mitsubishi Corporation Foodtech Co., Ltd., and as the precipitated crystal particles, the same Mannit S as in Control Example 1 were mixed at a ratio of 1:99 and used as an excipient. Were used to make tablets. Table 1 shows the physical properties such as the average particle size of the used Mannit Q. Tablets were obtained by granulating excipients in the same manner as in Control Example 1 and mixing with other tablet raw materials to form tablets. Table 2 shows the hardness, drop breakage ratio, and drop breakage improvement ratio of the obtained tablets.
球形結晶粒子と析出結晶粒子の比率を、５：９５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、硬度と落下破損率、落下破損改善率を表２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 precipitated crystal particles was 5:95. Table 2 shows the hardness, drop breakage ratio, and drop breakage improvement ratio of the obtained tablets.
球形結晶粒子と析出結晶粒子の比率を、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、硬度と落下破損率、落下破損改善率を表２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 precipitated crystal particles was 10:90. Table 2 shows the hardness, drop breakage ratio, and drop breakage improvement ratio of the obtained tablets.
球形結晶粒子と析出結晶粒子の比率を、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、硬度と落下破損率、落下破損改善率を表２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 precipitated crystal particles was 30:70. Table 2 shows the hardness, drop breakage ratio, and drop breakage improvement ratio of the obtained tablets.
球形結晶粒子と析出結晶粒子の比率を、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、硬度と落下破損率、落下破損改善率を表２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 precipitated crystal particles was set to 50:50. Table 2 shows the hardness, drop breakage ratio, and drop breakage improvement ratio of the obtained tablets.
［対照例２］
析出結晶粒子として、対照例１とは別のロットのマンニットＳを用い、対照例１と同様に造粒し、賦形剤造粒物を得た。この賦形剤造粒物９８．５質量部、崩壊剤（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、対照例１と同様に単発式打錠機を用いて打錠した。打錠圧は、硬度が５ｋｇｆ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、使用したマンニットＳの物性を表３に示し、得られた錠剤について、硬度と、落下破損率を表４に示す。
[Control Example 2]
Using Mannit S of a different lot from Control Example 1 as the precipitated crystal particles, granulation was performed in the same manner as in Control Example 1 to obtain a granulated excipient. 98.5 parts by mass of this excipient granule, 1 part by mass of a disintegrant (Kolidone CL-F), and 0.5 part by mass of silicon dioxide ("Aerosil 200" manufactured by Nippon Aerosil Co., Ltd.) as a water-conducting agent are uniformly mixed. Thereafter, this mixture was mixed with 1 part by mass of magnesium stearate as a lubricant, and the mixture was tableted using a single-shot tableting machine as in Comparative Example 1. The tableting pressure was a tableting condition for manufacturing tablets by appropriately changing the load and thickness at the time of tableting so that the hardness was 5 kgf. Table 3 shows the physical properties of the used mannit S, and Table 4 shows the hardness and the drop breakage rate of the obtained tablets.
噴霧乾燥で得られた球形結晶粒子として実施例１とは別のロットのマンニットＱを、析出結晶粒子として対照例２と同じロットのマンニットＳを用い、１０：９０の比率で混合して賦形剤として用いた。使用した球形結晶粒子と析出結晶粒子の物性を表３に示す。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、落下破損率、落下破損改善率を表４に示す。 Mannit Q of a different lot from Example 1 was mixed as spherical crystal particles obtained by spray drying, and Mannit S of the same lot as Control Example 2 was mixed as precipitated crystal particles at a ratio of 10:90. Used as excipient. Table 3 shows the physical properties of the spherical crystal particles and the precipitated crystal particles used. Tablets were obtained by granulating excipients in the same manner as in Control Example 2, mixing with other tablet raw materials, and tableting. Table 4 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.
球形結晶粒子と析出結晶粒子の比率を、３０：７０とした以外は、実施例６と同様にして、錠剤を得た。得られた錠剤について、硬度と、落下破損率、落下破損改善率を表４に示す。 A tablet was obtained in the same manner as in Example 6, except that the ratio of the spherical crystal particles to the precipitated crystal particles was 30:70. Table 4 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.
球形結晶粒子と析出結晶粒子の比率を、５０：５０とした以外は、実施例６と同様にして、錠剤を得た。得られた錠剤について、硬度と、落下破損率、落下破損改善率を表４に示す。 A tablet was obtained in the same manner as in Example 6, except that the ratio of the spherical crystal particles to the precipitated crystal particles was set to 50:50. Table 4 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.
［対照例３］
析出結晶粒子として、対照例１、２とは別のロットのマンニットＳを用い、錠剤条件としての目標硬度を８ｋｇｆとなるよう変更したほかは対照例２と同様にして錠剤を得た。得られた錠剤はすべてキャッピングしており、硬度は測定できなかった。そのため落下破損率は、前述のとおり、１００％とした。なお、使用したマンニットＳの物性を表５に示す。
[Control Example 3]
Tablets were obtained in the same manner as in Control Example 2 except that Mannit S of a different lot from Control Examples 1 and 2 was used as the precipitated crystal particles, and the target hardness as the tablet condition was changed to 8 kgf. All the tablets obtained were capped and the hardness could not be measured. Therefore, the drop breakage rate was set to 100% as described above. Table 5 shows the physical properties of the used mannit S.
球形結晶粒子として実施例６と同じロットのマンニットＱを、析出結晶粒子として対照例３と同じロットのマンニットＳを用い、５０：５０の比率で混合して賦形剤として用いた。使用した球形結晶粒子と析出結晶粒子の物性を表５に示す。錠剤は、対照例３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、落下破損率、落下破損改善率を表６に示す。 Mannite Q of the same lot as in Example 6 was used as spherical crystal particles, and Mannite S of the same lot as Control Example 3 was used as precipitated crystal particles and mixed at a ratio of 50:50 and used as an excipient. Table 5 shows the physical properties of the spherical crystal particles and the precipitated crystal particles used. Tablets were obtained by granulating excipients in the same manner as in Control Example 3, mixing with other tablet raw materials, and tableting. Table 6 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.
［対照例４］
析出結晶粒子として、ロケットフレール社製のＰＥＡＲＬＩＴＯＬ１６０Ｃを使用した以外は対照例２と同様にして、錠剤を得た。使用したＰＥＡＲＬＩＴＯＬ１６０Ｃの物性を表７に示し、得られた錠剤について、硬度と、落下破損率を表８に示す。
[Control Example 4]
Tablets were obtained in the same manner as in Control Example 2 except that PEARLITOL160C manufactured by Rocket Frere was used as precipitated crystal particles. Table 7 shows the physical properties of PEARLITOL 160C used, and Table 8 shows the hardness and the drop breakage ratio of the obtained tablets.
噴霧乾燥で得られた球形結晶粒子として実施例１と同じロットのマンニットＱを、析出結晶粒子として対照例４と同じＰＥＡＲＬＩＴＯＬ１６０Ｃを用い、３０：７０の比率で混合して賦形剤として用いた。使用した球形結晶粒子と析出結晶粒子の物性を表７に示す。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、硬度と落下破損率、落下破損改善率を表８に示す。 Mannitol Q of the same lot as in Example 1 was used as spherical crystal particles obtained by spray drying, and PEARLITOL160C, the same as that of Control Example 4, was used as precipitated crystal particles and mixed at a ratio of 30:70 to be used as an excipient. . Table 7 shows the physical properties of the spherical crystal particles and the precipitated crystal particles used. Tablets were obtained by granulating excipients, mixing with other tablet raw materials and tableting in the same manner as in Control Example 2. Table 8 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.
球形結晶粒子と析出結晶粒子の比率を、５０：５０とした以外は、実施例１０と同様にして、錠剤を得た。得られた錠剤について、硬度と落下破損率、落下破損改善率を表８に示す。 A tablet was obtained in the same manner as in Example 10, except that the ratio of the spherical crystal particles to the precipitated crystal particles was set to 50:50. Table 8 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.
［対照例５］
錠剤条件としての目標硬度を８ｋｇｆとなるよう変更したほかは対照例４と同様にして錠剤を得た。使用した析出結晶粒子も対照例４と同様である。得られた錠剤について、硬度と落下破損率、落下破損改善率を表９に示す。
[Comparative Example 5]
A tablet was obtained in the same manner as in Control Example 4, except that the target hardness as the tablet condition was changed to 8 kgf. The precipitated crystal particles used were the same as in Comparative Example 4. Table 9 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.
球形結晶粒子として実施例１と同じロットのマンニットＱを、析出結晶粒子として対照例４と同じロットのマンニットＳを用い、３０：７０の比率で混合して賦形剤として用いた。錠剤は、対照例５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、落下破損率、落下破損改善率を表９に示す。 Mannite Q of the same lot as in Example 1 was used as the spherical crystal particles, and Mannit S of the same lot as the control example 4 was used as the precipitated crystal particles, and they were mixed at a ratio of 30:70 and used as an excipient. Tablets were obtained by granulating excipients in the same manner as in Control Example 5, mixing with other tablet raw materials, and tableting. Table 9 shows the hardness, the drop breakage rate, and the drop breakage improvement rate of the obtained tablets.
球形結晶粒子と析出結晶粒子の比率を、５０：５０とした以外は、実施例１２と同様にして、錠剤を得た。得られた錠剤について、硬度と落下破損率、落下破損改善率を表９に示す。 A tablet was obtained in the same manner as in Example 12, except that the ratio of the spherical crystal particles to the precipitated crystal particles was set to 50:50. Table 9 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.
以上の結果から、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、対照である析出結晶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 above results, the tablet using the tableting excipient of mannitol in a specific mixing ratio according to the present invention, compared with the tablet using the excipient consisting only of the precipitated crystal particles as a control, significantly. It can be seen that the drop breakage improvement rate is improved.
Claims (3)
An orally disintegrating tablet having a reduced drop breakage ratio using the tableting excipient according to claim 1 .
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