JP2009256344A - Coated particulate containing proton pump inhibitor - Google Patents
Coated particulate containing proton pump inhibitor Download PDFInfo
- Publication number
- JP2009256344A JP2009256344A JP2009074466A JP2009074466A JP2009256344A JP 2009256344 A JP2009256344 A JP 2009256344A JP 2009074466 A JP2009074466 A JP 2009074466A JP 2009074466 A JP2009074466 A JP 2009074466A JP 2009256344 A JP2009256344 A JP 2009256344A
- Authority
- JP
- Japan
- Prior art keywords
- fine particles
- proton pump
- coated
- pump inhibitor
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 239000000612 proton pump inhibitor Substances 0.000 title claims abstract description 31
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Landscapes
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Abstract
Description
本発明は、収率良く製造され、良好な薬剤放出特性を有する、口腔内崩壊錠の製造に好適なベンズイミダゾール系プロトンポンプ阻害剤の被覆微粒子およびその製造方法に関する。さらに本発明は、保存安定性に優れたベンズイミダゾール系プロトンポンプ阻害剤の口腔内崩壊錠に関する。 The present invention relates to coated fine particles of a benzimidazole proton pump inhibitor suitable for the production of orally disintegrating tablets, which are produced with good yield and have good drug release characteristics, and a method for producing the same. Furthermore, this invention relates to the orally disintegrating tablet of the benzimidazole type | system | group proton pump inhibitor excellent in storage stability.
ベンズイミダゾール系プロトンポンプ阻害剤は、その強力な胃酸分泌抑制作用により、胃潰瘍、十二指腸潰瘍などの治療剤として有用であり、広く使用されている。現在臨床応用されている経口用製剤は、腸溶錠もしくはカプセル剤が主であるが、近年、高齢化社会の到来や患者のコンプライアンス向上のため、水なしでも服用可能な口腔内崩壊錠を要望する声が高まっている。しかしながら、ベンズイミダゾール系プロトンポンプ阻害剤は、酸性条件下では極めて不安定な化合物であり、特に胃酸と接触すると速やかに分解されるため、製剤中の薬物の安定性を確保するとともに、腸内では薬物が良好に放出されて薬効が十分発現するよう、種々の製剤学的工夫が提案されており、例えば以下のような技術が知られている。 Benzimidazole proton pump inhibitors are useful as therapeutic agents for gastric ulcers, duodenal ulcers and the like because of their strong gastric acid secretion inhibitory action, and are widely used. Oral preparations currently in clinical application are mainly enteric-coated tablets or capsules, but in recent years, there has been a demand for orally disintegrating tablets that can be taken without water for the arrival of an aging society and improved patient compliance. The voice to do is increasing. However, benzimidazole proton pump inhibitors are extremely unstable compounds under acidic conditions, and are rapidly degraded especially when contacted with gastric acid, thus ensuring the stability of the drug in the formulation and in the intestines. Various pharmaceutical contrivances have been proposed so that the drug is released satisfactorily and the drug effect is sufficiently expressed. For example, the following techniques are known.
特許文献１には、マグネシウムおよび／またはカルシウムの塩基性無機塩を薬物に均一に接触させることにより安定化を図った組成物が開示されている。 Patent Document 1 discloses a composition which is stabilized by bringing a basic inorganic salt of magnesium and / or calcium into contact with a drug uniformly.
特許文献２には、特定のアルカリ化合物と薬物を含有する核部分に１層以上の不活性な中間層を被覆し、さらにその上に腸溶皮膜を被覆した経口用製剤が開示されている。 Patent Document 2 discloses an oral preparation in which a core portion containing a specific alkali compound and a drug is coated with one or more inert intermediate layers, and further an enteric coating is further coated thereon.
上記の技術は、腸溶錠やカプセル剤に応用する場合は薬物を十分に安定化することができるが、口腔内崩壊錠の場合、服用時の口当たりなどを考慮すると、平均粒子径が約３００〜４００μｍ程度の腸溶被覆微粒子中に薬物を封入しなければならず、そうすると薬物が酸性環境に接触する可能性が必然的に増加する上、打錠時の衝撃により腸溶被覆微粒子の腸溶皮膜が多少なりとも損なわれるため、上記技術のみでは十分な薬物安定化効果を得ることができない。さらなる技術改良が必要である。 The above technique can sufficiently stabilize the drug when applied to enteric tablets and capsules. However, in the case of orally disintegrating tablets, the average particle size is about 300 in consideration of the mouthfeel at the time of taking. The drug must be encapsulated in enteric-coated microparticles of about ~ 400 μm, which inevitably increases the possibility of the drug coming into contact with the acidic environment, and the enteric-coated microparticles enteric coating due to impact during tableting. Since the film is damaged to some extent, it is not possible to obtain a sufficient drug stabilizing effect only by the above technique. Further technical improvements are needed.
特許文献３には、ナトリウムまたはカリウムの水酸化物もしくは炭酸塩、アミノアルキルメタアクリレートコポリマーＥ、アルギニンアスパラギン酸塩、ヒドロキシプロピルセルロースおよびクロスポビドンから選ばれる1種以上を配合することにより安定化される組成物が開示されている。 Patent Document 3 is stabilized by blending one or more selected from sodium or potassium hydroxide or carbonate, aminoalkyl methacrylate copolymer E, arginine aspartate, hydroxypropyl cellulose, and crospovidone. A composition is disclosed.
特許文献４には、クロスポビドンと水酸化ナトリウムおよび／または水酸化カリウムを配合する安定化法が開示されている。 Patent Document 4 discloses a stabilization method in which crospovidone is mixed with sodium hydroxide and / or potassium hydroxide.
しかしながら、特許文献３および４に記載された腸溶錠は、４０℃、７５％ＲＨの環境下で１ヶ月保存した場合、薬物含量の大幅な低下や錠剤の変色が観察されていることから、腸溶錠よりもさらに十分な保存安定性を確保する必要のある口腔内崩壊錠用被覆微粒子へ応用可能であるとは考えにくい。 However, when the enteric tablets described in Patent Documents 3 and 4 are stored for 1 month in an environment of 40 ° C. and 75% RH, a significant decrease in drug content and discoloration of the tablets are observed. It is unlikely that the present invention can be applied to coated fine particles for orally disintegrating tablets that need to ensure even more sufficient storage stability than enteric tablets.
ベンズイミダゾール系プロトンポンプ阻害剤の口腔内崩壊錠として、唯一、臨床応用されているタケプロンOD錠（有効成分、ランソプラゾール）の製剤設計は、以下の文献により紹介されている。 The formulation of Takepron OD tablet (active ingredient, lansoprazole), the only benzimidazole proton pump inhibitor orally disintegrating tablet that is clinically applied, is introduced in the following literature.
特許文献５には、酸に不安定な生理活性物質を１０重量％以上含有する組成物が腸溶性被覆層で被覆された、平均粒径４００μｍ以下である細粒および添加剤を含有する口腔内崩壊錠が開示されているが、その腸溶性細粒は、糖を主成分とする核粒子に薬物を含む水性分散液を噴霧して製造されるため、製造工程中に核粒子の割れや造粒粒子の凝集が発生しやすく、一定の品質の造粒粒子を高収率で製造することは困難である。 Patent Document 5 discloses an oral cavity containing fine granules having an average particle diameter of 400 μm or less and an additive coated with an enteric coating layer containing a composition containing 10% by weight or more of an acid labile physiologically active substance. Disintegrating tablets are disclosed, but the enteric granules are produced by spraying an aqueous dispersion containing a drug on core particles mainly composed of sugar. Aggregation of the particle particles is likely to occur, and it is difficult to produce granulated particles of a certain quality in a high yield.
非特許文献１には、乳糖水和物を主成分とする球形の微粒子を核とし、ランソプラゾール等を含む水性分散液を噴霧して薬物層をコーティングした後、耐胃液性を確保すべく中間層１層および腸溶皮膜層を３重に被覆して製造されたランソプラゾール含有口腔内崩壊錠が開示されているが、上記特許文献５と同様、一定の品質の腸溶性微粒子を高収率で製造することは困難と考えられる。 Non-Patent Document 1 discloses that a spherical fine particle mainly composed of lactose hydrate is used as a nucleus, an aqueous dispersion containing lansoprazole is sprayed to coat a drug layer, and then an intermediate layer is provided to ensure gastric juice resistance. Lansoprazole-containing orally disintegrating tablets produced by coating one layer and three layers of enteric coating layers are disclosed, but as in Patent Document 5 above, enteric microparticles of a certain quality are produced in high yield. It seems difficult to do.
上記の通り、ベンズイミダゾール系プロトンポンプ阻害剤を含有する口腔内崩壊錠用被覆微粒子の安定化技術は未だ十分に確立されたとは言えず、また、口腔内崩壊錠用被覆微粒子を高品質かつ高収率で製造することは困難であった。 As mentioned above, the stabilization technology of coated fine particles for orally disintegrating tablets containing a benzimidazole proton pump inhibitor is not yet well established, and the coated fine particles for orally disintegrating tablets are of high quality and high quality. It was difficult to produce in a yield.
そこで、良好な薬物放出特性および保存安定性を有するのみならず、収率良く製造されうるベンズイミダゾール系プロトンポンプ阻害剤の口腔内崩壊錠用被覆微粒子、およびその製造方法の確立が求められている。 Accordingly, there is a demand for establishment of a coating fine particle for orally disintegrating tablets of a benzimidazole proton pump inhibitor that not only has good drug release characteristics and storage stability but also can be produced in good yield, and a method for producing the same. .
本発明は、極めて収率よく製造され、良好な薬物放出特性を有する、口腔内崩壊錠の製造に好適なベンズイミダゾール系プロトンポンプ阻害剤の被覆微粒子およびその製造方法を提供すること、さらに、優れた保存安定性を有するベンズイミダゾール系プロトンポンプ阻害剤の口腔内崩壊錠を提供することを目的とする。 The present invention provides coated microparticles of a benzimidazole proton pump inhibitor suitable for the production of orally disintegrating tablets, which are manufactured with extremely high yield and have good drug release characteristics, and a method for manufacturing the same. Another object of the present invention is to provide an orally disintegrating tablet of a benzimidazole proton pump inhibitor having excellent storage stability.
本発明者らは、上記課題を解決するために鋭意検討を行った結果、驚くべきことに、球形結晶セルロース粒子上に、ベンズイミダゾール系プロトンポンプ阻害剤と平均粒子径３〜１０μｍの微粉状クロスポビドンを含む薬物層を被覆した後、不活性中間層および腸溶皮膜層を被覆して得られる被覆微粒子が、製造工程中に何ら問題が発生することなく収率良く製造されること、所定の条件下で効率よく薬物を放出すること、さらに前記被覆微粒子を含む口腔内崩壊錠が保存安定性に優れることを発見し、本願発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have surprisingly found that a fine powdery cloth having a benzimidazole proton pump inhibitor and an average particle size of 3 to 10 μm is formed on spherical crystalline cellulose particles. The coated fine particles obtained by coating the drug layer containing povidone and then coating the inactive intermediate layer and the enteric coating layer are produced in good yield without any problems during the production process, It was discovered that the drug is efficiently released under the conditions, and that the orally disintegrating tablet containing the coated fine particles is excellent in storage stability, and the present invention has been completed.
すなわち、本発明の特徴は以下のとおりである。
〔１〕以下の（ａ）〜（ｄ）からなるベンズイミダゾール系プロトンポンプ阻害剤を含有する被覆微粒子。
（ａ）球形結晶セルロース粒子、
（ｂ）ベンズイミダゾール系プロトンポンプ阻害剤および微粉状クロスポビドンを含んでなる、前記（ａ）上の薬物層、
（ｃ）不活性中間層、および
（ｄ）腸溶皮膜層
〔２〕微粉状クロスポビドンの平均粒子径が３〜１０μｍである、請求項１記載の被覆微粒子。
〔３〕前記（ｂ）薬物層がさらにアルカリ化合物を含む、請求項１ないし２記載の被覆微粒子。
〔４〕アルカリ化合物が、メグルミン、Ｌ−アルギニン、酸化マグネシウム、無水リン酸水素カルシウム、炭酸マグネシウム、グリセロリン酸カルシウムおよび水酸化アルミニウム・炭酸ナトリウム共沈物からなる群から選択される、請求項３記載の被覆微粒子。
〔５〕ベンズイミダゾール系プロトンポンプ阻害剤がオメプラゾール、ラベプラゾール、ランソプラゾールまたはそれらの生理学的に許容される塩からなる群から選択される、請求項１ないし４記載の被覆微粒子。
〔６〕（ａ）球形結晶セルロース粒子、（ｂ）ベンズイミダゾール系プロトンポンプ阻害剤および微粉状クロスポビドンを含む前記（ａ）上の薬物層、（ｃ）不活性中間層および（ｄ）腸溶皮膜層からなるベンズイミダゾール系プロトンポンプ阻害剤を含有する被覆微粒子の製造方法であって、ベンズイミダゾール系プロトンポンプ阻害剤および微粉状クロスポビドンを含む水性分散液を球形結晶セルロース粒子に噴霧して薬物層を形成した後、不活性中間層および腸溶皮膜層を被覆してなる、前記被覆微粒子の製造方法。
〔７〕請求項１ないし５記載の被覆微粒子を含むことを特徴とする、口腔内崩壊錠。
That is, the features of the present invention are as follows.
[1] Coated fine particles containing a benzimidazole proton pump inhibitor comprising the following (a) to (d).
(A) spherical crystalline cellulose particles,
(B) a drug layer on (a) comprising a benzimidazole proton pump inhibitor and finely divided crospovidone;
The coated fine particles according to claim 1, wherein the average particle size of (c) an inert intermediate layer and (d) an enteric coating layer [2] fine powdered crospovidone is 3 to 10 µm.
[3] The coated fine particles according to claim 1 or 2, wherein the drug layer (b) further contains an alkali compound.
[4] The alkali compound according to claim 3, wherein the alkali compound is selected from the group consisting of meglumine, L-arginine, magnesium oxide, anhydrous calcium hydrogen phosphate, magnesium carbonate, calcium glycerophosphate and aluminum hydroxide / sodium carbonate coprecipitate. Coated fine particles.
[5] The coated microparticle according to any one of claims 1 to 4, wherein the benzimidazole proton pump inhibitor is selected from the group consisting of omeprazole, rabeprazole, lansoprazole, or a physiologically acceptable salt thereof.
[6] (a) Spherical crystalline cellulose particles, (b) a drug layer on (a) containing a benzimidazole proton pump inhibitor and finely divided crospovidone, (c) an inactive intermediate layer, and (d) an enteric solution A method for producing coated fine particles comprising a benzimidazole proton pump inhibitor comprising a coating layer, wherein an aqueous dispersion containing a benzimidazole proton pump inhibitor and fine powdered crospovidone is sprayed onto spherical crystalline cellulose particles. The method for producing the coated fine particles, wherein the layer is formed and then the inert intermediate layer and the enteric coating layer are coated.
[7] An orally disintegrating tablet comprising the coated fine particles according to any one of claims 1 to 5.
本発明によれば、高収率で製造され、良好な薬物放出特性を有する、口腔内崩壊錠に好適なベンズイミダゾール系プロトンポンプ阻害剤含有被覆微粒子およびその製造方法が提供される。さらに、該被覆微粒子を含み、優れた保存安定性を有する口腔内崩壊錠が提供される。 ADVANTAGE OF THE INVENTION According to this invention, the coating microparticles | fine-particles containing a benzimidazole type | system | group proton pump inhibitor suitable for an orally disintegrating tablet which are manufactured with a high yield and have favorable drug release characteristics are provided. Furthermore, an orally disintegrating tablet containing the coated fine particles and having excellent storage stability is provided.
以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
（本発明の被覆微粒子の構成成分）
本発明では、ベンズイミダゾール系プロトンポンプ阻害剤であるオメプラゾール、ラベプラゾール、ランソプラゾールまたはそれらの生理学的に許容される塩が好適に使用される。薬物の含有量は、被覆微粒子の全重量に対して、好ましくは５〜１５重量％、さらに好ましくは６〜１２重量％である。
(Constituent component of coated fine particles of the present invention)
In the present invention, omeprazole, rabeprazole, lansoprazole or physiologically acceptable salts thereof, which are benzimidazole proton pump inhibitors, are preferably used. The content of the drug is preferably 5 to 15% by weight, more preferably 6 to 12% by weight, based on the total weight of the coated fine particles.
本発明で使用される「球形結晶セルロース粒子」は、球形の形状を有するものであれば特に限定されないが、口腔内崩壊錠用の被覆微粒子を製造するためには、平均粒子径が５０〜３００μｍのものが好ましく、旭化成ケミカルズの製品（商品名セルフィア ＣＰ−１０２）が特に好ましい。その含有量は、被覆微粒子の全重量に対して、好ましくは５〜１５重量％、さらに好ましくは９〜１２重量％である。 The “spherical crystalline cellulose particles” used in the present invention are not particularly limited as long as they have a spherical shape, but in order to produce coated fine particles for orally disintegrating tablets, the average particle size is 50 to 300 μm. Asahi Kasei Chemicals products (trade name SELFIA CP-102) are particularly preferable. The content is preferably 5 to 15% by weight, more preferably 9 to 12% by weight, based on the total weight of the coated fine particles.
本発明で使用される「微粉状クロスポビドン」としては、平均粒子径が３〜１０μｍの範囲を有するものであれば特に限定されない。ＢＡＳＦ社の製品（商品名Ｋｏｌｌｉｄｏｎ ＣＬ−Ｍ）が好適であるが、より大きな平均粒子径を有するクロスポビドンを常法により１０μｍ以下に粉砕して使用してもよい。被覆微粒子中の微粉状クロスポビドンの含有量は、１〜１０重量％が好ましく、１．５〜６重量％がさらに好ましい。 The “fine powdered crospovidone” used in the present invention is not particularly limited as long as it has an average particle diameter of 3 to 10 μm. BASF products (trade name Kollidon CL-M) are suitable, but crospovidone having a larger average particle size may be pulverized to 10 μm or less by a conventional method. The content of finely divided crospovidone in the coated fine particles is preferably 1 to 10% by weight, and more preferably 1.5 to 6% by weight.
ここで、本発明において、平均粒子径とは、気流式分散器を用いる乾式法に基づいて測定した粒度分布における５０％累積粒径を表す。 Here, in this invention, an average particle diameter represents the 50% cumulative particle diameter in the particle size distribution measured based on the dry method using an airflow type | formula disperser.
本発明において、薬物層に含まれてもよいアルカリ化合物としては、製薬学的に許容しうる化合物の中から１種もしくは２種以上を適宜選択して使用することができるが、好ましくはメグルミン、Ｌ−アルギニン、グリセロリン酸カルシウム、クエン酸ナトリウム、カラギーナン、酢酸ナトリウム、酸化マグネシウム、炭酸マグネシウム、無水リン酸水素カルシウム、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、ケイ酸マグネシウム、水酸化マグネシウム、水酸化アルミナ・マグネシウム、合成ヒドロタルサイト、含水二酸化ケイ素または水酸化アルミニウム・炭酸ナトリウム共沈物（商品名クムライト、協和化学工業）である。被覆微粒子中のアルカリ化合物の含有量は、１〜２０重量％が好ましく、２〜１５重量％がより好ましい。 In the present invention, as the alkaline compound that may be contained in the drug layer, one or more kinds of pharmaceutically acceptable compounds can be appropriately selected and used, preferably meglumine, L-arginine, calcium glycerophosphate, sodium citrate, carrageenan, sodium acetate, magnesium oxide, magnesium carbonate, anhydrous calcium hydrogen phosphate, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate, magnesium hydroxide, alumina hydroxide Magnesium, synthetic hydrotalcite, hydrous silicon dioxide or aluminum hydroxide / sodium carbonate coprecipitate (trade name Kumlite, Kyowa Chemical Industry). The content of the alkali compound in the coated fine particles is preferably 1 to 20% by weight, and more preferably 2 to 15% by weight.
薬物層は、さらに結合剤を含んでもよい。好ましい結合剤としては、ヒドロキシプロピルセルロース、ポリビニルアルコール、ヒプロメロースなどが挙げられるが、ヒドロキシプロピルセルロースが特に好ましく、被覆微粒子中５重量％未満の含有量で使用すればよい。 The drug layer may further include a binder. Preferred binders include hydroxypropyl cellulose, polyvinyl alcohol, hypromellose and the like, but hydroxypropyl cellulose is particularly preferred and may be used at a content of less than 5% by weight in the coated fine particles.
不活性中間層は、主として製薬学的に不活性な重合体成分から構成され、さらに、適宜、Ｄ−マンニトールなどの賦形剤やタルク他の流動化剤などを添加して、常法により、薬物層上に被覆することができる。重合体成分としては、水溶性、水不溶性のいずれでも良く、例えば、ポリビニルアルコール、ポリビニルピロリドン、ヒドロキシプロピルセルロース、ヒプロメロース、エチルセルロースなどが挙げられ、これらを１種もしくは２種以上組み合わせて使用してもよい。被覆微粒子中の不活性中間層の含有量は、通常、１０〜２０重量％程度である。 The inactive intermediate layer is mainly composed of a pharmaceutically inactive polymer component. Further, an excipient such as D-mannitol, a fluidizing agent such as talc, and the like are appropriately added, It can be coated on the drug layer. The polymer component may be either water-soluble or water-insoluble, and examples thereof include polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl cellulose, hypromellose, and ethyl cellulose, and these may be used alone or in combination of two or more. Good. The content of the inert intermediate layer in the coated fine particles is usually about 10 to 20% by weight.
腸溶皮膜層の構成成分は特に限定されず、腸溶性ポリマー（例、セルロースアセテートフタレート、ヒプロメロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート（商品名ＡＱＯＡＴ、信越化学）、メタクリル酸コポリマーＬ（商品名オイドラギットＬ、レーム社）、メタクリル酸コポリマーＬＤ（商品名オイドラギットＬ３０Ｄ−５５、レーム社）、メタクリル酸コポリマーＳ（商品名オイドラギットＳ、レーム社）など）、胃溶性ポリマー（ポリビニルアセタールジエチルアミノアセテート（商品名ＡＥＡ「三共」）、アミノアルキルメタクリレートコポリマーＥ（商品名オイドラギットＥ、レーム社）など）、水不溶性ポリマー（エチルセルロース、アミノアルキルメタクリラートコポリマーＲＳ（商品名オイドラギットＲＳ、レーム社）、アクリル酸エチル・メタクリル酸メチルコポリマー（商品名オイドラギットＮＥ３０Ｄ、レーム社）など）、可塑剤（例、マクロゴール類、クエン酸トリエチル）、界面活性剤（例、ポリソルベート８０）などを、必要であれば適宜組み合わせて、常法により中間層上に被覆すればよい。通常、腸溶皮膜層は、被覆微粒子中４０〜７０重量％程度含有される。 The components of the enteric coating layer are not particularly limited, and enteric polymers (eg, cellulose acetate phthalate, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate (trade name AQOAT, Shin-Etsu Chemical), methacrylic acid copolymer L (trade name) Eudragit L, Laem Co.), methacrylic acid copolymer LD (trade name Eudragit L30D-55, Laem Co., Ltd.), methacrylic acid copolymer S (trade name Eudragit S, Laem Co., Ltd.)), gastric soluble polymer (polyvinyl acetal diethylaminoacetate (trade name) AEA “Sankyo”), aminoalkyl methacrylate copolymer E (trade name Eudragit E, Laem Co., etc.), water-insoluble polymer (ethyl cellulose, aminoalkyl methacrylate copolymer RS (trade name) Hydragit RS, Laem Co.), ethyl acrylate / methyl methacrylate copolymer (trade name Eudragit NE30D, Laem Co., etc.), plasticizer (eg, macrogol, triethyl citrate), surfactant (eg, polysorbate 80) And the like may be appropriately combined and coated on the intermediate layer by a conventional method. Usually, the enteric coating layer is contained in the coated fine particles in an amount of about 40 to 70% by weight.
（被覆微粒子の製造方法）
本発明の被覆微粒子は、いわゆる流動層造粒法を用いて製造することができる。造粒機としては、流動層造粒法に使用しうるものであれば特に限定されず、例えば、流動層造粒機(フロイント工業製、フローコーターなど)、転動流動層造粒機(パウレック製、マルチプレックスなど)、微粒子コーティング・造粒装置(パウレック製、ＳＦＰ)、遠心転動造粒コーティング装置(フロイント産業製、グラニュレックス)、複合型造粒コーティング装置(フロイント産業製、スパイラフロー)などが挙げられる。特に、転動流動層造粒機が好ましい。
具体的には、例えば、球形結晶セルロース粒子を転動流動層造粒機などに入れ、ベンズイミダゾール系プロトンポンプ阻害剤、微粉状クロスポビドン他の薬物層構成成分を含む水性分散液を噴霧して球形結晶セルロース粒子上に薬物層をコーティングし、得られた薬物層被覆粒子を乾燥後、慣用の方法を用いて不活性中間層および腸溶被膜層をコーティングすることにより、本発明の被覆微粒子を得ることができる。被覆微粒子の平均粒子径は、口中のザラツキや違和感など服用感の観点から、２５０〜４００μｍ程度であることが好ましい。
(Method for producing coated fine particles)
The coated fine particles of the present invention can be produced using a so-called fluidized bed granulation method. The granulator is not particularly limited as long as it can be used for the fluidized bed granulation method. Manufactured, multiplex, etc.), fine particle coating and granulating equipment (Paurek, SFP), centrifugal rolling granulating coating equipment (Freund Sangyo, Granurex), composite granulating coating equipment (Freund Sangyo, Spiraflow) Etc. In particular, a rolling fluidized bed granulator is preferable.
Specifically, for example, spherical crystalline cellulose particles are put into a rolling fluidized bed granulator or the like, and an aqueous dispersion containing a benzimidazole proton pump inhibitor, fine powdered crospovidone and other drug layer constituents is sprayed. The coated fine particles of the present invention are coated by coating a drug layer on spherical crystalline cellulose particles, drying the obtained drug layer-coated particles, and then coating an inert intermediate layer and an enteric coating layer using a conventional method. Obtainable. The average particle diameter of the coated fine particles is preferably about 250 to 400 μm from the viewpoint of taking feeling such as roughness in the mouth and uncomfortable feeling.
このようにして製造される本発明の被覆微粒子は、良好な薬物放出特性を有するのみならず、製造時に粒子凝集などのトラブルが発生することもなく高収率で所望の粒子が得られる。 The coated fine particles of the present invention produced in this way not only have good drug release characteristics, but also give desired particles in high yield without causing troubles such as particle aggregation during production.
本発明の被覆微粒子は、そのまま他の添加剤と混合した後、圧縮成形して口腔内崩壊錠を製造することができる。
あるいは、本発明の被覆微粒子に、乳糖、Ｄ−マンニトールなどの糖類や水溶性高分子類を常法によりオーバーコートした後、他の添加剤を混合して打錠してもよい。
The coated fine particles of the present invention can be directly mixed with other additives and then compression molded to produce an orally disintegrating tablet.
Alternatively, the coated fine particles of the present invention may be overcoated with saccharides such as lactose and D-mannitol and water-soluble polymers by a conventional method, and then mixed with other additives to be tableted.
本発明の被覆微粒子もしくはそのオーバーコートされた粒子の配合量は、口腔内崩壊錠の全重量に対し、好ましくは７０重量％未満、さらに好ましくは５５重量％未満である。 The amount of the coated fine particles of the present invention or the overcoated particles is preferably less than 70% by weight, more preferably less than 55% by weight, based on the total weight of the orally disintegrating tablet.
（口腔内崩壊錠）
本発明の被覆微粒子あるいはそのオーバーコートされた粒子以外に口腔内崩壊錠に使用される添加剤は特に限定されず、賦形剤、矯味剤、甘味剤、流動化剤、滑沢剤、香料、着色料などを適宜組み合わせて使用することができる。これら添加剤の含有量は特に限定されず、製剤学的に慣用の量を適宜選択すればよいが、本発明の微粒子もしくはそのオーバーコートされた粒子以外の添加剤の総量は、製剤重量に対して、３０重量％以上が好ましく、４５重量％以上がさらに好ましい。
賦形剤としては、乳糖、マンニトール、ソルビトール、キシリトール、トレハロース、シクロデキストリン、トウモロコシデンプン、蔗糖、結晶セルロース、無水リン酸水素カルシウム、炭酸カルシウム、メタケイ酸アルミン酸マグネシウム（商品名ノイシリン、富士化学工業）、合成ケイ酸アルミニウム、合成ケイ酸アルミニウム・ヒドロキシプロピルスターチ・結晶セルロース（商品名パーフィラー１０１、フロイント産業）、合成ヒドロタルサイトなどを適宜組み合わせて使用することができる。乳糖もしくはＤ−マンニトールが特に好ましい。
甘味剤の例としては、マンニトール、デンプン糖、還元麦芽糖水あめ、ソルビット、砂糖、果糖、乳糖、蜂蜜、キシリトール、エリスリトール、ソルビトール、サッカリン、甘草およびその抽出物、グリチルリチン酸、甘茶、アスパルテーム、ステビア、ソーマチン、アセスルファムＫ、スクラロースなどが挙げられる。
矯味剤としては、クエン酸、クエン酸ナトリウム、酒石酸、ＤＬ−リンゴ酸、グリシン、ＤＬ−アラニンなどが挙げられる。
流動化剤および／または滑沢剤としては、例えば、含水二酸化ケイ素、軽質無水ケイ酸、ケイ酸カルシウム、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸、タルク、ラウリル硫酸ナトリウム、水素添加植物油、マイクロクリスタリンワックス、ショ糖脂肪酸エステル、ポリエチレングリコールなどが挙げられる。
着香剤としては、ストロベリー、レモン、レモンライム、オレンジ、ｌ−メントール、ハッカ油などが用いられる。
着色料としては、黄色三二酸化鉄、三二酸化鉄、食用タール色素、天然色素などが挙げられる。
(Orally disintegrating tablets)
Additives used for orally disintegrating tablets other than the coated fine particles of the present invention or the overcoated particles thereof are not particularly limited, and include excipients, flavoring agents, sweeteners, fluidizing agents, lubricants, flavors, Coloring agents and the like can be used in appropriate combinations. The content of these additives is not particularly limited and may be appropriately selected from pharmacologically conventional amounts, but the total amount of additives other than the fine particles of the present invention or the overcoated particles is based on the formulation weight. 30% by weight or more is preferable, and 45% by weight or more is more preferable.
Excipients include lactose, mannitol, sorbitol, xylitol, trehalose, cyclodextrin, corn starch, sucrose, crystalline cellulose, anhydrous calcium hydrogen phosphate, calcium carbonate, magnesium metasilicate aluminate (trade name Neusilin, Fuji Chemical) Synthetic aluminum silicate, synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose (trade name Perfiller 101, Freund Sangyo), synthetic hydrotalcite, and the like can be used in appropriate combination. Lactose or D-mannitol is particularly preferred.
Examples of sweeteners include mannitol, starch sugar, reduced maltose starch syrup, sorbit, sugar, fructose, lactose, honey, xylitol, erythritol, sorbitol, saccharin, licorice and extracts thereof, glycyrrhizic acid, sweet tea, aspartame, stevia, thaumatin , Acesulfame K, sucralose and the like.
Examples of the corrigent include citric acid, sodium citrate, tartaric acid, DL-malic acid, glycine, and DL-alanine.
Examples of fluidizing agents and / or lubricants include hydrous silicon dioxide, light anhydrous silicic acid, calcium silicate, magnesium stearate, calcium stearate, stearic acid, talc, sodium lauryl sulfate, hydrogenated vegetable oil, microcrystalline wax. Sucrose fatty acid ester, polyethylene glycol and the like.
As a flavoring agent, strawberry, lemon, lemon lime, orange, l-menthol, peppermint oil, etc. are used.
Examples of the colorant include yellow iron sesquioxide, iron sesquioxide, edible tar dye, and natural dye.
上記の添加剤は、粉末の状態で、あるいは、数種の添加剤の混合物を慣用の方法により造粒した後に、本発明の被覆微粒子や着香剤、滑沢剤などと混合し、圧縮成形すればよい。 The above additives are mixed with the coated fine particles, flavoring agents, lubricants, etc. of the present invention in the powder state or after granulating a mixture of several kinds of additives by a conventional method, and compression molding. do it.
圧縮成形の方法は特に限定されず、慣用の方法、例えば打錠機を用いて行うことができる。打錠機は、医薬品の製造に使用しうるものであればよく、ロータリー式打錠機や単発打錠機などが使用される。 The compression molding method is not particularly limited, and can be performed using a conventional method such as a tableting machine. Any tableting machine may be used as long as it can be used in the manufacture of pharmaceuticals, and a rotary tableting machine, a single-punch tableting machine, or the like is used.
以下、試験例、実施例、比較例および実験例に基づいて本発明をより詳細に説明するが、本発明はこれらによって限定されるものではない。 Hereinafter, although this invention is demonstrated in detail based on a test example, an Example, a comparative example, and an experiment example, this invention is not limited by these.
〔試験例〕
球形結晶セルロース粒子（商品名セルフィアＣＰ−１０２、旭化成ケミカルズ製）３０重量部を転動流動層造粒機（パウレック社製、マルチプレックス ＭＰ−０１）に入れ、ランソプラゾール３０重量部、クムライト１０重量部およびヒドロキシプロピルセルロース（商品名ＨＰＣ（ＳＳＬ）、日本曹達製）１０重量部を水１８０重量部に分散させた液を噴霧しながらコーティングした。得られた薬物層被覆粒子を乾燥および分級後、ヒプロメロース（商品名ＴＣ−５ＥＷ、信越化学製）１７重量部、酸化チタン４重量部、タルク４重量部およびＤ−マンニトール１７重量部を含む中間層用コーティング液を用いて転動流動層造粒機により不活性中間層を被覆した。得られた不活性中間層被覆粒子を乾燥、分級後、オイドラギットＬ３０Ｄ−５５水分散液１９０重量部（固形分として５７重量部）、オイドラギットＮＥ３０Ｄ水分散液３０重量部（固形分として９重量部）、マクロゴール６０００を７．２重量部、モノステアリン酸グリセリン５．６重量部、ポリソルベート８０を１．２重量部、微量の三二酸化鉄、黄色三二酸化鉄およびクエン酸を含む腸溶コーティング液を用いて転動流動層造粒機により腸溶皮膜層を被覆し、さらにもう１回、同様の腸溶コーティング液を用いて腸溶被覆工程を行った後、得られた粒子を乾燥、分級し、平均粒子径約３００μｍの被覆微粒子を得た。
[Test example]
30 parts by weight of spherical crystalline cellulose particles (trade name SELPHYA CP-102, manufactured by Asahi Kasei Chemicals) are put into a rolling fluidized bed granulator (manufactured by POWREC, multiplex MP-01), 30 parts by weight of lansoprazole, 10 parts by weight of cumrite Then, 10 parts by weight of hydroxypropylcellulose (trade name HPC (SSL), manufactured by Nippon Soda Co., Ltd.) was coated while sprayed with a liquid dispersed in 180 parts by weight of water. After the obtained drug layer-coated particles are dried and classified, an intermediate layer containing 17 parts by weight of hypromellose (trade name TC-5EW, manufactured by Shin-Etsu Chemical), 4 parts by weight of titanium oxide, 4 parts by weight of talc and 17 parts by weight of D-mannitol The inactive intermediate layer was coated with a rolling fluidized bed granulator using the coating liquid. The obtained inert intermediate layer-coated particles are dried and classified, and then 190 parts by weight of Eudragit L30D-55 aqueous dispersion (57 parts by weight as solids) and 30 parts by weight of Eudragit NE30D aqueous dispersion (9 parts by weight as solids). An enteric coating solution containing 7.2 parts by weight of Macrogol 6000, 5.6 parts by weight of glyceryl monostearate, 1.2 parts by weight of polysorbate 80, a small amount of iron sesquioxide, yellow iron sesquioxide and citric acid. Using an oscillating fluidized bed granulator, the enteric coating layer is coated, and after another enteric coating step using the same enteric coating solution, the resulting particles are dried and classified. Thus, coated fine particles having an average particle diameter of about 300 μm were obtained.
また、以下の崩壊剤、クロスポビドン(商品名Ｐｏｌｙｐｌａｓｄｏｎｅ ＸＬ−１０、アイエスピー製)、カルボキシメチルスターチナトリウム（商品名Ｐｒｉｍｏｊｅｌ、ＤＭＶ製）または低置換度ヒドロキシプロピルセルロース（商品名Ｌ−ＨＰＣ ＬＨ−３２、信越化学製）各１０重量部を薬物層被覆用分散液に添加し、同様の操作によりランソプラゾールを含有する被覆微粒子を製造した。なお、クロスカルメロースナトリウム（商品名Ａｃ−Ｄｉ−Ｓｏｌ、旭化成ケミカルズ製）は、アルカリ化剤と反応して薬物層被覆用分散液をゲル化するため、被覆微粒子の製造が不可能であった。 In addition, the following disintegrants, crospovidone (trade name: Polyplastdone XL-10, manufactured by ISPE), sodium carboxymethyl starch (trade name: Primojel, manufactured by DMV) or low-substituted hydroxypropylcellulose (trade name: L-HPC LH-32) (Manufactured by Shin-Etsu Chemical Co., Ltd.) 10 parts by weight of each was added to the dispersion for coating the drug layer, and coated microparticles containing lansoprazole were produced by the same operation. In addition, since croscarmellose sodium (trade name Ac-Di-Sol, manufactured by Asahi Kasei Chemicals) reacts with an alkalizing agent to gel the dispersion for coating the drug layer, it was impossible to produce coated fine particles. .
得られた各被覆微粒子１５０重量部に結晶セルロース５０重量部、トウモロコシデンプン５０重量部、乳糖２５重量部および甘味剤５重量部などを添加混合後、卓上型打錠機を用いて打錠し、錠剤を製造した。これらの錠剤について、日本薬局方溶出試験法第２法（パドル法）に従いＪＰ２液を用いて溶出試験を行った。結果を表１に示す。 After adding and mixing 50 parts by weight of crystalline cellulose, 50 parts by weight of corn starch, 25 parts by weight of lactose and 5 parts by weight of a sweetener to 150 parts by weight of each coated fine particle thus obtained, tableting is performed using a tabletop tableting machine, Tablets were manufactured. These tablets were subjected to a dissolution test using JP2 solution in accordance with the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). The results are shown in Table 1.
表１から、薬物層中に崩壊剤を含まない被覆微粒子や、カルボキシメチルスターチナトリウムまたは低置換度ヒドロキシプロピルセルロースを含む被覆微粒子を用いて製造された錠剤は、ＪＰ２液３０分の薬物溶出率が５０％前後と低く、１２０分経過後ですら８０〜９０％程度にとどまっているため、生体内で薬効が十分に発現しない虞がある。
それに対し、薬物層中にクロスポビドンを含む被覆微粒子を用いて製造された錠剤は、３０分で７０％、６０分でほぼ全量の薬物を放出するという優れた薬物放出特性を示した。
Table 1 shows that tablets manufactured using coated fine particles containing no disintegrant in the drug layer or coated fine particles containing sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose have a drug dissolution rate of 30 minutes in JP2. Since it is as low as around 50% and remains at about 80 to 90% even after 120 minutes, there is a possibility that the medicinal effects are not sufficiently exhibited in vivo.
In contrast, tablets produced using coated microparticles containing crospovidone in the drug layer showed excellent drug release properties that released 70% in 30 minutes and almost the entire drug in 60 minutes.
上記試験例の結果に基づき、被覆微粒子の薬物層にクロスポビドンを添加することとし、一定品質の被覆微粒子が収率よく製造されるよう、さらに検討を行った。 Based on the results of the above test examples, crospovidone was added to the drug layer of the coated fine particles, and further studies were performed so that coated fine particles of a certain quality were produced with a high yield.
〔実施例１〕
(被覆微粒子の製造)
球形結晶セルロース粒子（セルフィアＣＰ−１０２）３０重量部を転動流動層造粒機（マルチプレックス ＭＰ−０１）に入れ、ランソプラゾール３０重量部、クムライト１０重量部、微粉状クロスポビドン（Ｋｏｌｌｉｄｏｎ ＣＬ−Ｍ、平均粒子径３．７μｍ）１０重量部、およびヒドロキシプロピルセルロース（ＨＰＣ（ＳＳＬ））１０重量部を水１８０重量部に分散させた液を噴霧しながらコーティングした。得られた薬物層被覆粒子を乾燥および分級後、ヒプロメロース（ＴＣ−５ＥＷ）１７重量部、酸化チタン４重量部、タルク４重量部およびＤ−マンニトール１７重量部を含む中間層用コーティング液を用いて転動流動層造粒機により不活性中間層を被覆した。得られた不活性中間層被覆粒子を乾燥、分級後、オイドラギットＬ３０Ｄ−５５水分散液１９０重量部（固形分として５７重量部）、オイドラギットＮＥ３０Ｄ水分散液３０重量部（固形分として９重量部）、マクロゴール６０００を７．２重量部、モノステアリン酸グリセリン５．６重量部、ポリソルベート８０を１．２重量部、微量の三二酸化鉄、黄色三二酸化鉄およびクエン酸を含む腸溶コーティング液を用いて転動流動層造粒機により腸溶皮膜層を被覆し、さらにもう１回、同様の腸溶コーティング液を用いて腸溶被覆工程を行った後、得られた粒子を乾燥、分級し、平均粒子径が約３００μｍの本発明の被覆微粒子を得た。
[Example 1]
(Manufacture of coated fine particles)
30 parts by weight of spherical crystalline cellulose particles (Selfia CP-102) are put into a rolling fluidized bed granulator (multiplex MP-01), 30 parts by weight of lansoprazole, 10 parts by weight of cumulite, fine powdered crospovidone (Kollidon CL-M). , 10 parts by weight of an average particle size of 3.7 μm) and 10 parts by weight of hydroxypropyl cellulose (HPC (SSL)) were coated while sprayed with 180 parts by weight of water. After drying and classifying the obtained drug layer-coated particles, an intermediate layer coating solution containing 17 parts by weight of hypromellose (TC-5EW), 4 parts by weight of titanium oxide, 4 parts by weight of talc and 17 parts by weight of D-mannitol was used. The inert intermediate layer was coated with a rolling fluidized bed granulator. The obtained inert intermediate layer-coated particles are dried and classified, and then 190 parts by weight of Eudragit L30D-55 aqueous dispersion (57 parts by weight as solids) and 30 parts by weight of Eudragit NE30D aqueous dispersion (9 parts by weight as solids). An enteric coating solution containing 7.2 parts by weight of Macrogol 6000, 5.6 parts by weight of glyceryl monostearate, 1.2 parts by weight of polysorbate 80, a small amount of iron sesquioxide, yellow iron sesquioxide and citric acid. Using an oscillating fluidized bed granulator, the enteric coating layer is coated, and after another enteric coating step using the same enteric coating solution, the resulting particles are dried and classified. The coated fine particles of the present invention having an average particle size of about 300 μm were obtained.
(口腔内崩壊錠)
結晶セルロース（セオラスＫＧ−８０２、旭化成ケミカルズ）１００重量部、トウモロコシデンプン１００重量部、乳糖５０重量部およびアスパルテーム８重量部を混合し、乳糖水溶液を結合液として流動層造粒機により添加剤造粒物を製造した。得られた造粒物に、上記のランソプラゾール含有被覆微粒子３００重量部、１２重量部のノイシリンＵＦＬ２、ステアリン酸マグネシウム１．２重量部および微量の着香剤を混合後、ロータリー式打錠機を用いて打圧６００ｋｇで打錠し、直径８．５ｍｍ、重量２８５ｍｇの錠剤を得た。
(Orally disintegrating tablets)
100 parts by weight of crystalline cellulose (Theorus KG-802, Asahi Kasei Chemicals), 100 parts by weight of corn starch, 50 parts by weight of lactose and 8 parts by weight of aspartame are mixed, and additive granulation is performed with a fluidized bed granulator using lactose aqueous solution as a binding liquid The thing was manufactured. After mixing 300 parts by weight of the above-mentioned lansoprazole-containing coated fine particles, 12 parts by weight of Neusilin UFL2, 1.2 parts by weight of magnesium stearate and a small amount of a flavoring agent, a rotary tableting machine was used. Tableting was performed at a pressure of 600 kg to obtain a tablet having a diameter of 8.5 mm and a weight of 285 mg.
〔比較例１〜２〕
Ｋｏｌｌｉｄｏｎ ＣＬ−Ｍの代わりに、平均粒子径１４．１０μｍのクロスポビドン（アイエスピー製、商品名Ｐｏｌｙｐｌａｓｄｏｎｅ ＩＮＦ−１０）または２４．０１μｍのクロスポビドン（アイエスピー製、商品名Ｐｏｌｙｐｌａｓｄｏｎｅ ＸＬ−１０）を添加した以外は実施例１と同様の操作でランソプラゾールを含有する被覆微粒子、および該被覆微粒子を含む口腔内崩壊錠を製造した。
[Comparative Examples 1-2]
In place of Kollidon CL-M, crospovidone with an average particle size of 14.10 μm (product name: Polyplacedone INF-10, manufactured by IPS) or 24.01 μm crospovidone (product name: Polyplasmone XL-10, made by IPS) is added. Except that, coated microparticles containing lansoprazole and an orally disintegrating tablet containing the coated microparticles were produced in the same manner as in Example 1.
〔実験例１〕
実施例１、比較例１および比較例２の各被覆微粒子の製造工程収率や製造時のトラブルの有無を確認した。また、日本薬局方溶出試験法第２法（パドル法）に従ってＪＰ２液を用いて実施例１、比較例１および比較例２で製造した口腔内崩壊錠の溶出試験を行い、ＨＰＬＣ法により各測定ポイントにおけるランソプラゾールの溶出量を測定した。それらの結果を表２に示す。
[Experimental Example 1]
The production process yield of each coated fine particle of Example 1, Comparative Example 1 and Comparative Example 2 and the presence or absence of trouble during production were confirmed. In addition, dissolution tests of the orally disintegrating tablets produced in Example 1, Comparative Example 1 and Comparative Example 2 were conducted using JP2 solution according to the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method), and each measurement was performed by HPLC method. The amount of lansoprazole eluted at the point was measured. The results are shown in Table 2.
上記のとおり、口腔内崩壊錠からの薬物溶出率に関しては、被覆微粒子に使用したクロスポビドンの平均粒子径に係わらず、いずれも良好な結果が得られたが、被覆微粒子製造時の造粒機への粉末付着・残留などのトラブルは、クロスポビドンの平均粒子径が大きくなるにつれて増加し、製造工程収率が顕著に低下した。それに対し、実施例１の被覆微粒子は、全くトラブルもなく、９４．１％と非常に高い製造工程収率で製造することができた。 As described above, regarding the drug dissolution rate from the orally disintegrating tablet, good results were obtained regardless of the average particle diameter of crospovidone used for the coated fine particles. Troubles such as powder adhesion / residue on the surface increased as the average particle size of crospovidone increased, and the yield of the production process decreased significantly. On the other hand, the coated fine particles of Example 1 could be produced with a very high production process yield of 94.1% without any trouble.
〔実施例２〕
クムライトの代わりにＬ−アルギニンを使用した他は実施例１と同様の操作により、ランソプラゾールを含有する被覆微粒子、および該被覆微粒子を含む口腔内崩壊錠（直径８．５ｍｍ、重量２８５ｍｇ）を製造した。被覆微粒子の製造時にトラブルは何ら発生せず、得られた口腔内崩壊錠の薬物溶出量は、ＪＰ１液６０分で０．６％、ＪＰ２液４５分で９３％であり、ベンズイミダゾール系プロトンポンプ阻害剤の生体内での薬効発現に必要な「耐胃液性」および「腸内での良好な薬物放出性」の両条件を満たしていた。
[Example 2]
A coated microparticle containing lansoprazole and an orally disintegrating tablet (8.5 mm in diameter and 285 mg in weight) containing the coated microparticle were produced in the same manner as in Example 1 except that L-arginine was used instead of cumulite. . No trouble occurred during the production of coated fine particles, and the drug dissolution amount of the obtained orally disintegrating tablet was 0.6% for JP1 solution 60 minutes and 93% for JP2 solution 45 minutes, and was a benzimidazole proton pump. Both the conditions of “gastric juice resistance” and “good drug release in the intestine” necessary for the development of the drug efficacy in vivo of the inhibitor were satisfied.
〔実施例３〜４〕
クムライトの代わりに炭酸マグネシウムまたはグリセロリン酸カルシウムを使用した他は実施例１と同様の操作により、ランソプラゾールの被覆微粒子、および該被覆微粒子を含む口腔内崩壊錠を製造した。いずれも何らトラブルもなく収率よく被覆微粒子が製造され、口腔内崩壊錠からの薬物放出特性も、実施例１および２と同様、良好であった。
[Examples 3 to 4]
Lansoprazole-coated microparticles and orally disintegrating tablets containing the coated microparticles were produced in the same manner as in Example 1 except that magnesium carbonate or calcium glycerophosphate was used instead of cumulite. In both cases, coated fine particles were produced with a good yield without any trouble, and the drug release characteristics from the orally disintegrating tablets were good as in Examples 1 and 2.
〔実験例２〕
実施例１で製造した口腔内崩壊錠をＰＴＰシートに封入し、乾燥剤とともにアルミピロー包装後、４０℃７５％ＲＨで６ヶ月間の保存安定性試験を行い、各ポイントにおける錠剤中の主剤含量、溶出量(ＪＰ１液６０分、ＪＰ２液４５分)、および錠剤の崩壊時間を測定した。さらに、０、３、６ヶ月目の錠剤の色調を分光式色差計（ＳＥ−２０００）を用いて測定し、錠剤の色調変化を調べた。それらの結果を表３に示す。
The orally disintegrating tablet produced in Example 1 was encapsulated in a PTP sheet, packaged with an aluminum pillow together with a desiccant, and then subjected to a storage stability test for 6 months at 40 ° C. and 75% RH. The dissolution amount (JP1 solution 60 minutes, JP2 solution 45 minutes) and the disintegration time of the tablet were measured. Furthermore, the color tone of the tablets at 0, 3, and 6 months was measured using a spectroscopic color difference meter (SE-2000), and the change in the color tone of the tablets was examined. The results are shown in Table 3.
上記のとおり、本発明の口腔内崩壊錠は、４０℃７５％ＲＨの条件下で６ヶ月間保存した後であっても、主剤含量、ＪＰ１液での溶出性(耐胃液性)、ＪＰ２液の溶出性(腸内での薬物放出性)、および錠剤崩壊時間の全ての項目について製造当初とほとんど変化が無く、極めて良好な保存安定性を有することが判明した。また、ベンズイミダゾール系プロトンポンプ阻害剤を含有する製剤は、一般に、保管期間中に変色などの外観変化が発生しがちであるのに対し、本発明の口腔内崩壊錠は、表３のとおり、４０℃７５％ＲＨの条件下で６ヶ月間保管した後であっても、肉眼では判別不可能な程度の僅かな色調変化を示したのみであった。 As described above, the orally disintegrating tablet of the present invention has the main agent content, the dissolution property with JP1 solution (gastric fluid resistance), JP2 solution, even after storage for 6 months under the condition of 40 ° C. and 75% RH. It was found that there was almost no change from the beginning of production in all items of dissolution property (drug release property in the intestine) and tablet disintegration time, and it had extremely good storage stability. In addition, formulations containing benzimidazole proton pump inhibitors generally tend to change appearance such as discoloration during the storage period, whereas the orally disintegrating tablets of the present invention are as shown in Table 3, Even after being stored for 6 months under the condition of 40 ° C. and 75% RH, it showed only a slight color change that was indistinguishable with the naked eye.
良好な薬物放出特性を有し、口腔内崩壊錠の製造に好適なベンズイミダゾール系プロトンポンプ阻害剤の被覆微粒子、およびその製造方法が提供される。本発明の被覆微粒子は、何らトラブルも発生せず高収率で製造されるため、製造コストの低減が可能である。さらに、該被覆微粒子を含む本発明の口腔内崩壊錠は、極めて優れた保存安定性を有する。 Provided are coated benzimidazole proton pump inhibitor coated microparticles having good drug release characteristics and suitable for the production of orally disintegrating tablets, and a method for producing the same. Since the coated fine particles of the present invention are produced in high yield without causing any trouble, the production cost can be reduced. Furthermore, the orally disintegrating tablet of the present invention containing the coated fine particles has extremely excellent storage stability.
Claims (7)
（ａ）球形結晶セルロース粒子、
（ｂ）ベンズイミダゾール系プロトンポンプ阻害剤および微粉状クロスポビドンを含んでなる、前記（ａ）上の薬物層、
（ｃ）不活性中間層、および
（ｄ）腸溶皮膜層 Coated fine particles containing a benzimidazole proton pump inhibitor comprising the following (a) to (d).
(A) spherical crystalline cellulose particles,
(B) a drug layer on (a) comprising a benzimidazole proton pump inhibitor and finely divided crospovidone;
(C) an inert intermediate layer, and (d) an enteric coating layer.
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