TWI606847B - Tablet disintegrating in oral cavity - Google Patents

Description

口腔內崩解錠 Oral disintegration ingot

本發明係有關含有氫離子幫浦抑制劑(proton pump inhibitor，以下稱為PPI)及乙醯水楊酸之口腔內崩解錠。更詳言之，本發明係有關活性成分之安定性優越，投予後藥理效果會安定且迅速表現之口腔內崩解錠。 The present invention relates to an orally disintegrating ingot containing a proton pump inhibitor (hereinafter referred to as PPI) and acetaminosalicylic acid. More specifically, the present invention relates to an orally disintegrating ingot in which the stability of the active ingredient is superior, and the pharmacological effect after administration is stabilized and rapidly manifested.

以抑制在腦血管、循環器領域之疾病中之血栓/栓塞之形成(抗血小板療法)為目的而投予低劑量之乙醯水楊酸時，會引起胃潰瘍或十二指腸潰瘍。由於若停止投予乙醯水楊酸則可能會形成血栓/栓塞，所以認為在抑制潰瘍發病之同時，繼續投予低劑量之乙醯水楊酸係屬重要。又，已知乙醯水楊酸為非類固醇性抗炎症藥(NSAIDs)，主要用於治療疼痛、發燒、炎症，惟NSAIDs會引起胃潰瘍或十二指腸潰瘍。尤其在治療風濕性關節炎或變形性關節炎等時，由於生活品質(QOL)顯著降低，而有難以停止投予NSAIDs之情況。因此，認為在抑制潰瘍發病之同時，繼續投予NSAIDs係屬重要。 When a low dose of acetyl salicylic acid is administered for the purpose of inhibiting the formation of thrombus/embolism in diseases of the cerebral blood vessels and circulators (antiplatelet therapy), it may cause gastric ulcer or duodenal ulcer. Since the thrombus/embolization may form if the administration of acetyl salicylic acid is stopped, it is considered that it is important to continue to administer a low dose of acetaminophen while suppressing the onset of ulceration. Further, it is known that acetaminophen salicylic acid is a non-steroidal anti-inflammatory drug (NSAIDs) mainly used for treating pain, fever, and inflammation, but NSAIDs may cause gastric ulcer or duodenal ulcer. In particular, when treating rheumatoid arthritis or osteoarthritis, the quality of life (QOL) is remarkably lowered, and it is difficult to stop the administration of NSAIDs. Therefore, it is considered that it is important to continue to invest in NSAIDs while suppressing the onset of ulcers.

另一方面，由於蘭素拉唑(Lansoprazole)、奥美拉唑(Omeprazole)等苯并咪唑系化合物之PPI具有強力之胃酸分泌抑制作用及胃黏膜防禦作用等，故廣泛作為消化性潰瘍治療劑等使用。尤其是蘭素拉唑製劑，近年來在日本亦被承認其「抑制在投予低劑量乙醯水楊酸時之胃潰瘍或十二指腸潰瘍之發病」及「抑制在投予非類固醇性抗炎症藥 時之胃潰瘍或十二指腸潰瘍之發病」之效能，證實在抑制因投予乙醯水楊酸而引起的胃潰瘍或十二指腸潰瘍發病之臨床效果。 On the other hand, since the PPI of a benzimidazole-based compound such as Lansoprazole or Omeprazole has a strong gastric acid secretion inhibitory action and a gastric mucosal defense effect, it is widely used as a therapeutic agent for peptic ulcer. Wait for use. In particular, lansalazole preparations have been recognized in Japan in recent years as "inhibiting the onset of gastric or duodenal ulcers when low-dose acetaminophen is administered" and "inhibiting the administration of non-steroidal anti-inflammatory drugs". The efficacy of the onset of gastric or duodenal ulcers has been shown to inhibit the clinical effects of gastric ulcer or duodenal ulcer caused by administration of acetaminosalicylic acid.

於專利文獻1揭示一種藥學性組成物，係含有：(a)對酸不安定之至少一種氫離子幫浦抑制劑的在治療上之有效量；(b)充分量之至少一種緩衝劑，其係用於使胃液之pH值上昇，以可防止至少數種氫離子幫浦抑制劑在胃液內之酸分解；以及(c)至少一種非類固醇性抗炎症藥的在治療上之有效量。 Patent Document 1 discloses a pharmaceutical composition comprising: (a) a therapeutically effective amount of at least one hydrogen ion pump inhibitor which is unstable to acid; (b) a sufficient amount of at least one buffer agent, Used to raise the pH of gastric juice to prevent acid decomposition of at least several hydrogen ion pump inhibitors in gastric juice; and (c) to treat a therapeutically effective amount of at least one non-steroidal anti-inflammatory drug.

於專利文獻2揭示一種經口投予用醫藥劑型，其同時含有酸感受性氫離子幫浦抑制劑、至少一種非類固醇性抗炎症藥(NSAID)、以及所期望之醫藥上容許之賦形劑。 Patent Document 2 discloses a pharmaceutical dosage form for oral administration which contains an acid-sensitive hydrogen ion pump inhibitor, at least one non-steroidal anti-inflammatory drug (NSAID), and a desired pharmaceutically acceptable excipient.

於專利文獻3揭示一種適合病患經口投予之單位劑型之藥劑組成物，係含有：(a)在投予1種或複數種上述單位劑型後，使上述病患胃內之pH值至少上昇至3.5的以有效量存在之酸抑制劑；以及(b)在投予1種或複數種上述單位劑型後，減輕或除去上述病患之疼痛或炎症之有效量之非類固醇性抗炎症藥；其特徵係上述單位劑型是在上述酸抑制劑之後將上述NSAID協調性地釋出。 Patent Document 3 discloses a pharmaceutical composition suitable for a unit dosage form for oral administration of a patient, which comprises: (a) after administering one or more of the above unit dosage forms, the pH of the stomach of the patient is at least at least An acid inhibitor present in an effective amount to rise to 3.5; and (b) an effective amount of a non-steroidal anti-inflammatory agent that reduces or eliminates pain or inflammation of the above-mentioned patient after administration of one or more of the above unit dosage forms The above unit dosage form is characterized in that the above NSAID is coordinatedly released after the above acid inhibitor.

另，蘭素拉唑等之PPI或乙醯水楊酸已有作為單劑而市售，惟目前仍未知同時含有PPI及乙醯水楊酸之口腔內崩解錠(積層錠之合劑)。 Further, PPI or acetaminosalicylic acid such as lansylazole has been commercially available as a single agent, but an orally disintegrating tablet (a mixture of laminated ingots) containing both PPI and acetyl salicylic acid is still unknown.

[先行技術文獻] [Advanced technical literature]

[專利文獻] [Patent Literature]

[專利文獻1]國際公開第2005/076987號說明書 [Patent Document 1] International Publication No. 2005/076987

[專利文獻2]國際公開第97/25064號說明書 [Patent Document 2] International Publication No. 97/25064

[專利文獻3]國際公開第2002/098352號說明書 [Patent Document 3] International Publication No. 2002/098352

提供含有PPI及乙醯水楊酸兩者作為活性成分之製劑(合劑)在臨床上之有用性極高。惟，要將含有複數種活性成分之製劑實用化，係比由單一活性成分所構成之製劑還不容易。例如由於活性成分從製劑中溶出之速度會影響投予後之經時性藥效特性(profile)，故在製劑實用化上，必須調整製劑組成而使活性成分之溶出速度成為最適當。惟若為合劑時，對於各活性成分需使溶出速度最適化，在製劑學上之困難性高。又，亦必須抑制因合劑中含有之複數種活性成分相互作用而引起之不良影響(經時性活性成分之分解或活性降低等保存或化學安定性降低，經時性活性成分溶出模式之變化等溶出安定性之降低等)。 It is clinically highly useful to provide a preparation (mixture) containing both PPI and acetyl salicylic acid as an active ingredient. However, it is not easy to put a preparation containing a plurality of active ingredients into a preparation which is composed of a single active ingredient. For example, since the rate of dissolution of the active ingredient from the preparation affects the time-dependent pharmacodynamic profile after administration, it is necessary to adjust the composition of the preparation to make the dissolution rate of the active ingredient optimum. However, in the case of a mixture, it is necessary to optimize the dissolution rate for each active ingredient, and the difficulty in preparation is high. Further, it is also necessary to suppress adverse effects caused by interaction of a plurality of active ingredients contained in the mixture (preservation such as decomposition or activity reduction of the active ingredient over time, reduction in chemical stability, change in dissolution profile of the active ingredient over time, etc.) Reduced dissolution stability, etc.).

另外，隨著人口高齡化/生活環境變化，期待開發出能保持屬於錠劑特徵之處理便利性，同時可容易服用，且在無水之情況下可輕鬆地在任何時間、任何地方隨時服用的口腔內崩解錠。 In addition, as the population ages and the living environment changes, it is expected to develop an oral cavity that can maintain the handling convenience of the tablet, and that can be easily taken, and can be easily taken at any time and anywhere without water. Intrinsic disintegration.

本發明人等經過深入研究，結果發現一種積層之口腔內崩解錠，係具有(1)含有包含氫離子幫浦抑制劑之腸溶性細粒的層及(2)含有乙醯水楊酸的層，該口腔內崩解錠之活性成分之安定性高，投予後活性成分之藥理效果會安定且 迅速表現，因而完成本發明。 As a result of intensive studies, the present inventors have found that a laminated orally disintegrating ingot has (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) an acetaminophen containing salicylic acid. a layer, the active ingredient of the orally disintegrating tablet has high stability, and the pharmacological effect of the active ingredient after administration is stable and The performance is quickly performed, thus completing the present invention.

亦即，本發明提供下述者：[1]一種積層之口腔內崩解錠，係具有：(1)含有包含氫離子幫浦抑制劑之腸溶性細粒的層、以及(2)含有乙醯水楊酸的層；[2]如上述[1]記載之口腔內崩解錠，其中，在含有腸溶性細粒的層中，於腸溶性細粒以外之部分含有制酸劑；[3]如上述[2]記載之口腔內崩解錠，其中，制酸劑為選自由金屬氧化物、金屬氫氧化物、鹼土金屬之碳酸鹽及甘胺酸鋁所成群組之至少一種成分；[4]如上述[3]記載之口腔內崩解錠，其中，金屬氧化物為選自由氧化鎂、矽酸鎂、乾燥氫氧化鋁凝膠及偏矽酸鋁鎂(magnesium aluminometasilicate)所成群組之至少一種；[5]如上述[3]記載之口腔內崩解錠，其中，金屬氫氧化物為選自由氫氧化鎂、氫氧化鋁、合成水滑石(hydritalcite)、氫氧化鋁與氫氧化鎂之共沉澱物、氫氧化鋁與碳酸鎂與碳酸鈣之共沉澱物、以及氫氧化鋁與碳酸氫鈉之共沉澱物所成群組之至少一種；[6]如上述[3]記載之口腔內崩解錠，其中，鹼土金屬之碳酸鹽為碳酸鈣或碳酸鎂；[7]如上述[2]記載之口腔內崩解錠，其中，制酸劑為碳酸鎂及甘胺酸鋁之混合物；[8]如上述[2]記載之口腔內崩解錠，其中，制酸劑之含量 為約10mg至約100mg；[9]如上述[1]記載之口腔內崩解錠，其中，氫離子幫浦抑制劑為蘭素拉唑、奥美拉唑、拉培拉唑(rabeprazole)、畔托拉唑(pantoprazole)、或其光學活性體是或其鹽；[10]如上述[1]記載之口腔內崩解錠，其中，乙醯水楊酸之含量在每錠為約70mg至約120mg；[11]如上述[1]記載之口腔內崩解錠，其中，在含有乙醯水楊酸的層中含有羧甲基纖維素；[12]如上述[1]記載之口腔內崩解錠，其中，在含有包含氫離子幫浦抑制劑之腸溶性細粒的層中，於腸溶性細粒以外之部分含有選自交聯聚維酮(crospovidone)及偏矽酸鋁鎂中之至少1種崩解劑；[13]如上述[1]記載之口腔內崩解錠，其中，在含有乙醯水楊酸的層中含有潤滑劑；[14]如上述[13]記載之口腔內崩解錠，其中，潤滑劑為硬化油；[15]如上述[1]記載之口腔內崩解錠，其為雙層錠；[16]如上述[1]記載之口腔內崩解錠，其中，在(1)含有包含氫離子幫浦抑制劑之腸溶性細粒的層與(2)含有乙醯水楊酸的層之間，具有中間層；[17]如上述[1]記載之口腔內崩解錠，其中，乙醯水楊酸不經腸溶包覆；[18]如上述[1]記載之口腔內崩解錠，其錠劑重量為約300mg至約800mg，(1)含有包含氫離子幫浦抑制劑之腸溶 性細粒的層與(2)含有乙醯水楊酸的層的重量比為約10：1至約1：10；[19]如上述[1]記載之口腔內崩解錠，其在打錠面有曲面；[20]如上述[1]記載之口腔內崩解錠，其在口腔內崩解之時間係在約60秒以內；[21]如上述[1]記載之口腔內崩解錠，其錠劑之硬度為約20至約100N。 That is, the present invention provides the following: [1] A laminated intraoral disintegrating tablet comprising: (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor; and (2) a layer B [2] The orally disintegrating tablet of the above-mentioned [1], wherein the layer containing the enteric fine particles contains an antacid in a portion other than the enteric fine particles; [3] The orally disintegrating tablet according to the above [2], wherein the antacid is at least one component selected from the group consisting of metal oxides, metal hydroxides, alkaline earth metal carbonates, and aluminum glycinate; [4] The orally disintegrating ingot according to [3] above, wherein the metal oxide is selected from the group consisting of magnesium oxide, magnesium citrate, dried aluminum hydroxide gel, and magnesium aluminometasilicate. [5] The orally disintegrating ingot according to the above [3], wherein the metal hydroxide is selected from the group consisting of magnesium hydroxide, aluminum hydroxide, hydritalcite, aluminum hydroxide and hydrogen. Coprecipitate of magnesium oxide, coprecipitate of aluminum hydroxide with magnesium carbonate and calcium carbonate, and aluminum hydroxide and carbon [6] The orally disintegrating ingot according to the above [3], wherein the alkaline earth metal carbonate is calcium carbonate or magnesium carbonate; [7] as described above [ (2) The orally disintegrating tablet of the present invention, wherein the antacid is a mixture of magnesium carbonate and aluminum sulphate; [8] the orally disintegrating tablet according to [2] above, wherein the antacid content The oral disintegrating tablet according to the above [1], wherein the hydrogen ion pump inhibitor is lansylazole, omeprazole, rabeprazole, The orally disintegrating tablet of the above-mentioned [1], wherein the content of acetyl salicylic acid is about 70 mg per ingot to the oral disintegrating tablet of the above [1]. [11] The orally disintegrating tablet according to the above [1], wherein the layer containing acetaminosalicylic acid contains carboxymethylcellulose; [12] in the oral cavity as described in [1] above. a disintegrating tablet, wherein, in a layer containing enteric fine particles containing a hydrogen ion pump inhibitor, a portion other than the enteric fine particles is selected from the group consisting of crospovidone and aluminum magnesium metasilicate. [13] The orally disintegrating tablet according to the above [1], wherein the layer containing the acetaminosalicylic acid contains a lubricant; [14] as described in the above [13] The orally disintegrating ingot, wherein the lubricant is a hardened oil; [15] the orally disintegrating ingot according to the above [1], which is a two-layer ingot; [16] the orally disintegrating as described in the above [1] Ingot And (1) having an intermediate layer between (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) a layer containing acetamidine salicylic acid; [17] an oral cavity as described in [1] above In the case of the orally disintegrating ingot, the orally disintegrating tablet of the above-mentioned [1] has a tablet weight of about 300 mg to about 800 mg, and (1) contains Enteric solution containing hydrogen ion pump inhibitor The weight ratio of the layer of the fine granules to (2) the layer containing acetamidine salicylic acid is from about 10:1 to about 1:10; [19] The orally disintegrating ingot according to the above [1], which is hitting [20] The orally disintegrating ingot according to the above [1], wherein the disintegration time in the oral cavity is within about 60 seconds; [21] orally disintegrating as described in [1] above. The ingot has a tablet hardness of from about 20 to about 100N.

本發明之口腔內崩解錠，係由於含有具有強力抑制酸分泌作用之PPI，以及可作為在腦血管、循環器領域之疾病之預防/治療劑，例如狹心症(慢性安定狹心症、不安定狹心症)、心肌梗塞中之血栓/栓塞形成之抑制劑、缺血性腦血管障礙(暫時性腦缺血發作(TIA)、腦梗塞)之預防/治療劑、在冠動脈繞道手術(CABG)或經皮經血管冠動脈形成術(PTCA)施行後之血栓/栓塞形成之抑制劑、或川崎病(包含因川崎病所引起之心血管後遺症)之預防/治療劑使用的乙醯水楊酸，故以一邊繼續投予乙醯水楊酸、一邊治療或抑制胃潰瘍或十二指腸潰瘍發病為目的時，可投予本專利申請案之口腔內崩解錠。 The orally disintegrating tablet of the present invention contains a PPI having a strong inhibitory effect on acid secretion, and can be used as a prophylactic/therapeutic agent for diseases in the field of cerebrovascular and circulator, such as angina (chronic stability stenosis, Inhibition of thrombosis/embolic formation in myocardial infarction, prevention/therapeutic agent for ischemic cerebrovascular disease (temporary ischemic attack (TIA), cerebral infarction), coronary artery bypass surgery (in coronary artery bypass surgery) CABG) or an inhibitor of thrombus/embolization after percutaneous transluminal coronary angioplasty (PTCA) or a preventive/therapeutic agent for Kawasaki disease (including cardiovascular sequelae caused by Kawasaki disease) The acid can be administered to the orally disintegrating ingot of the present patent application for the purpose of continuing to administer acetyl salicylic acid while treating or inhibiting the onset of gastric ulcer or duodenal ulcer.

此外，乙醯水楊酸為非類固醇性抗炎症藥(NSAIDs)之一種，主要亦可用於治療疼痛、發燒、炎症，故以一邊繼續投予NSAIDs、一邊治療或抑制胃潰瘍或十二指腸潰瘍發病為目的時，亦可投予本專利申請案之口腔內崩解錠。 In addition, acetaminophen salicylic acid is one of non-steroidal anti-inflammatory drugs (NSAIDs), which can also be used to treat pain, fever, and inflammation. Therefore, it is intended to continue to administer NSAIDs while treating or inhibiting the onset of gastric ulcer or duodenal ulcer. Intraoral disintegration tablets of the present patent application can also be administered.

本發明之口腔內崩解錠係活性成分之安定性高，投予 後活性成分之藥理效果會安定且迅速地表現。 The orally disintegrating tablet active ingredient of the present invention has high stability and is administered The pharmacological effects of the post-active ingredients will be stable and rapid.

本發明之口腔內崩解錠在確保處理便利性之同時，亦可容易服用，且在無水之情況下可輕鬆地在任何時間、任何地方隨時服用。 The orally disintegrating tablet of the present invention can be easily taken while ensuring handling convenience, and can be easily taken at any time and anywhere without water.

(發明之詳細說明) (Detailed description of the invention)

以下，對本發明加以詳細說明。 Hereinafter, the present invention will be described in detail.

本發明之固形製劑係藉由將(1)含有包含氫離子幫浦抑制劑之腸溶性細粒的層及(2)含有乙醯水楊酸的層予以組合而形成，尤其是以積層之口腔內崩解錠為特徵。 The solid preparation of the present invention is formed by combining (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) a layer containing acetaminosalicylic acid, especially a laminated oral cavity. The intrinsic disintegration is characterized.

(1)「含有包含PPI之腸溶性細粒的層」 (1) "Layer containing enteric fine particles containing PPI" (1)-1：關於PPI (1)-1: About PPI

PPI較好為例如下述式(I)表示之化合物[以下，亦稱為化合物(I)]。 The PPI is preferably a compound represented by the following formula (I) [hereinafter, also referred to as a compound (I)].

化合物(I)可列舉式(I)表示之化合物、或其光學活性體或是其鹽： [式中，環A表示可具有取代基之苯環，R¹表示氫原子、可具有取代基之芳烷基、醯基或醯基氧基；R²、R³及R⁴各自可相同或不同，表示氫原子、可具有取代基之烷基、可具有取代基之烷氧基、或可具有取代基之胺基，Y表示氮原子或CH]。 The compound (I) may, for example, be a compound represented by the formula (I), or an optically active substance thereof or a salt thereof: Wherein ring A represents a benzene ring which may have a substituent, R ¹ represents a hydrogen atom, an aralkyl group which may have a substituent, a fluorenyl group or a decyloxy group; and each of R ² , R ³ and R ⁴ may be the same or Different, it represents a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, or an amine group which may have a substituent, and Y represents a nitrogen atom or CH].

上述化合物(I)中，環A表示之「可具有取代基之苯環」之「取代基」可列舉例如鹵素原子、氰基、硝基、可具有取代基之烷基、羥基、可具有取代基之烷氧基、芳基、芳基氧基、羧基、醯基、醯基氧基、5至10員雜環基等，該等取代基在苯環可取代1至3個左右。取代基之數在2個以上時，各個取代基可相同或不同。該等取代基中，較好為鹵素原子、可具有取代基之烷基、可具有取代基之烷氧基等。 In the above-mentioned compound (I), the "substituent" of the "benzene ring which may have a substituent" represented by the ring A may, for example, be a halogen atom, a cyano group, a nitro group, an alkyl group which may have a substituent, a hydroxyl group, or may have a substitution. The alkoxy group, the aryl group, the aryloxy group, the carboxyl group, the decyl group, the decyloxy group, the 5- to 10-membered heterocyclic group, etc., may be substituted in the benzene ring by about 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different. Among these substituents, a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, etc. are preferable.

鹵素原子可列舉氟原子、氯原子、溴原子等。其中，較好為氟原子。 Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Among them, a fluorine atom is preferred.

「可具有取代基之烷基」之「烷基」可列舉例如C_1-7烷基(例如甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、己基、庚基等)。「可具有取代基之烷基」之「取代基」可列舉例如鹵素原子、羥基、C_1-6烷氧基(例如甲氧基、乙氧基、丙氧基、丁氧基等)、C_1-6烷氧基羰基(例如甲氧基羰基、乙氧基羰基、丙氧基羰基等)、胺基甲醯基等，該等取代基之數可為1至3個左右。取代基之數在2個以上時，各個取代基可相同或不同。 The "alkyl group" of the "alkyl group which may have a substituent" may, for example, be a C _1-7 alkyl group (e.g., methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, second butyl group, Third butyl, pentyl, hexyl, heptyl, etc.). Examples of the "substituent" of the "alkyl group which may have a substituent" include a halogen atom, a hydroxyl group, a C _1-6 alkoxy group (e.g., a methoxy group, an ethoxy group, a propoxy group, a butoxy group, etc.), C. _An alkoxycarbonyl group (e.g., a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, etc.), an aminomethylcarbenyl group, etc., and the number of these substituents may be about 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

「可具有取代基之烷氧基」之「烷氧基」可列舉例如C_1-6烷氧基(例如甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、戊氧基等)等。「可具有取代基之烷氧基」之「取代基」可例示與上述「可具有取代基之烷基」之「取代基」相同之基，取代基之取代數亦相同。 The "alkoxy group" of the "alkoxy group which may have a substituent" may, for example, be a C _1-6 alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, or different). Butoxy, pentyloxy, etc.). The "substituent" of the "alkoxy group which may have a substituent" is the same as the "substituent" of the above-mentioned "alkyl group which may have a substituent", and the substitution number of the substituent is also the same.

「芳基」可列舉例如C_6-14芳基(例如苯基、1-萘基、 2-萘基、聯苯基、2-蒽基等)等。 Examples of the "aryl group" include a C _6-14 aryl group (e.g., a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a biphenyl group, a 2-indenyl group, etc.).

「芳基氧基」可列舉例如C_6-14芳基氧基(例如苯基氧基、1-萘基氧基、2-萘基氧基等)等。 The "aryloxy group" may, for example, be a C _6-14 aryloxy group (for example, a phenyloxy group, a 1-naphthyloxy group or a 2-naphthyloxy group).

「醯基」可列舉例如甲醯基、烷基羰基、烷氧基羰基、胺基甲醯基、烷基胺基甲醯基、烷基亞磺醯基、烷基磺醯基等。 Examples of the "fluorenyl group" include a methyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an aminomethyl fluorenyl group, an alkylaminocarbamyl group, an alkylsulfinyl group, an alkylsulfonyl group, and the like.

「烷基羰基」可列舉C_1-6烷基羰基(例如乙醯基、丙醯基等)等。 Examples of the "alkylcarbonyl group" include a C _1-6 alkylcarbonyl group (e.g., an ethyl fluorenyl group, a propyl fluorenyl group, etc.).

「烷氧基羰基」可列舉例如C_1-6烷氧基羰基(例如甲氧基羰基、乙氧基羰基、丙氧基羰基、丁氧基羰基等)等。 The "alkoxycarbonyl group" may, for example, be a C _1-6 alkoxycarbonyl group (for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group or a butoxycarbonyl group).

「烷基胺基甲醯基」可列舉N-C_1-6烷基胺基甲醯基(例如甲基胺基甲醯基、乙基胺基甲醯基等)、N,N-二-C_1-6烷基胺基甲醯基(例如N,N-二甲基胺基甲醯基、N,N-二乙基胺基甲醯基等)等。 The "alkylaminocarbamyl group" may, for example, be an NC _1-6 alkylaminocarboxamyl group (e.g., methylaminocarbinyl group, ethylaminomethylmercapto group, etc.), N,N-di-C _{1 -6} alkylaminocarbamyl (e.g., N,N-dimethylaminocarbamimidyl, N,N-diethylaminocarbamyl, etc.), and the like.

「烷基亞磺醯基」可列舉例如C_1-7烷基亞磺醯基(例如甲基亞磺醯基、乙基亞磺醯基、丙基亞磺醯基、異丙基亞磺醯基等)。 The "alkylsulfinyl" group may, for example, be a C _1-7 alkylsulfinyl group (for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinonium). Base, etc.).

「烷基磺醯基」可列舉例如C_1-7烷基磺醯基(例如甲基磺醯基、乙基磺醯基、丙基磺醯基、異丙基亞磺醯基等)。 The "alkylsulfonyl group" may, for example, be a C _1-7 alkylsulfonyl group (for example, a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfinyl group or the like).

「醯基氧基」可列舉例如烷基羰基氧基、烷氧基羰基氧基、胺基甲醯基氧基、烷基胺基甲醯基氧基、烷基亞磺醯基氧基、烷基磺醯基氧基等。 Examples of the "decyloxy group" include an alkylcarbonyloxy group, an alkoxycarbonyloxy group, an aminomethylcarbonyloxy group, an alkylaminocarbyloxy group, an alkylsulfinyloxy group, and an alkyl group. Alkylsulfonyloxy and the like.

「烷基羰基氧基」可列舉C_1-6烷基羰基氧基(例如乙醯基氧基、丙醯基氧基等)等。 The "alkylcarbonyloxy group" may, for example, be a C _1-6 alkylcarbonyloxy group (e.g., an ethyl fluorenyloxy group or a propyl fluorenyloxy group).

「烷氧基羰基氧基」可列舉例如C_1-6烷氧基羰基氧基(例如甲氧基羰基氧基、乙氧基羰基氧基、丙氧基羰基氧基、丁氧基羰基氧基等)等。 The "alkoxycarbonyloxy group" may, for example, be a C _1-6 alkoxycarbonyloxy group (e.g., a methoxycarbonyloxy group, an ethoxycarbonyloxy group, a propoxycarbonyloxy group, a butoxycarbonyloxy group). and many more.

「烷基胺基甲醯基氧基」可列舉C_1-6烷基胺基甲醯基氧基(例如甲基胺基甲醯基氧基、乙基胺基甲醯基氧基等)等。 Examples of the "alkylaminomethylmercaptooxy group" include a C _1-6 alkylaminocarbyloxy group (e.g., a methylaminomethyl decyloxy group, an ethylaminomethyl decyloxy group, etc.). .

「烷基亞磺醯基氧基」可列舉例如C_1-7烷基亞磺醯基氧基(例如甲基亞磺醯基氧基、乙基亞磺醯基氧基、丙基亞磺醯基氧基、異丙基亞磺醯基氧基等)等。 The "alkylsulfinyloxy group" may, for example, be a C _1-7 alkylsulfinyloxy group (e.g., methylsulfinyloxy, ethylsulfinyloxy, propylsulfinyl). Alkoxy group, isopropylsulfinyloxy group, etc.).

「烷基磺醯基氧基」可列舉例如C_1-7烷基磺醯基氧基(例如甲基磺醯基氧基、乙基磺醯基氧基、丙基磺醯基氧基、異丙基磺醯基氧基等)。 The "alkylsulfonyloxy group" may, for example, be a C _1-7 alkylsulfonyloxy group (e.g., methylsulfonyloxy group, ethylsulfonyloxy group, propylsulfonyloxy group, or different). Propylsulfonyloxy, etc.).

「5至10員雜環基」可列舉例如除了碳原子以外另含有選自氮原子、硫原子及氧原子中之1個以上(例如1至3個)雜原子的5至10員(較好為5或6員)雜環基，具體例可列舉2-或3-噻吩基；2-、3-或4-吡啶基；2-或3-呋喃基；1-、2-或3-吡咯基；2-、3-、4-、5-或8-喹啉基；1-、3-、4-或5-異喹啉基；1-、2-或3-吲哚基等。其中，較好為1-、2-或3-吡咯基等5或6員雜環基。 The "5 to 10 membered heterocyclic group" may, for example, be 5 to 10 members (more preferably, one or more (for example, 1 to 3) hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. a 5- or 6-membered heterocyclic group, and specific examples thereof include 2- or 3-thienyl; 2-, 3- or 4-pyridyl; 2- or 3-furyl; 1-, 2- or 3-pyrrole; 2-; 3-, 3-, 4-, 5- or 8-quinolinyl; 1-, 3-, 4- or 5-isoquinolinyl; 1-, 2- or 3-indenyl and the like. Among them, a 5- or 6-membered heterocyclic group such as a 1-, 2- or 3-pyrrolyl group is preferred.

較好之環A為可具有選自鹵素原子、可經鹵化之C_1-4烷基、可經鹵化之C_1-4烷氧基及5或6員雜環基中之1或2個取代基的苯環。 The ring A is preferably selected from a halogen atom may be, it may be substituted with a halogenated C _1-4 alkyl halogenated C _1-4 alkoxy group and the 5- or 6-membered heterocyclic group of 1 or 2 Base benzene ring.

R¹表示之「可具有取代基之芳烷基」之「芳烷基」可列舉例如C_7-16芳烷基(例如苯甲基、苯乙基等C_6-10芳基C_1-6 烷基等)等。「可具有取代基之芳烷基」之「取代基」可例示與上述「可具有取代基之烷基」之「取代基」相同之取代基，取代基之數為約1至4個。取代基之數在2個以上時，各個取代基可相同或不同。 The "aralkyl group" of the "aralkyl group which may have a substituent" represented by R ¹ may, for example, be a C _7-16 aralkyl group (e.g., a C _6-10 aryl C _1-6 such as a benzyl group or a phenethyl group). Alkyl, etc.). The "substituent" of the "aroyl group which may have a substituent" is exemplified by the same substituent as the "substituent" of the above-mentioned "alkyl group which may have a substituent", and the number of the substituents is about 1 to 4. When the number of the substituents is two or more, the respective substituents may be the same or different.

R¹表示之「醯基」可列舉例如以作為上述環A之取代基而記載之「醯基」。 The "mercapto group" represented by R ¹ may, for example, be a "mercapto group" described as a substituent of the ring A.

R¹表示之「醯基氧基」可列舉例如以作為上述環A之取代基而記載之「醯基氧基」。 The "mercaptooxy group" represented by R ¹ may, for example, be a "mercaptooxy group" described as a substituent of the above ring A.

較好之R¹為氫原子。 Preferably, R ¹ is a hydrogen atom.

R²、R³或R⁴表示之「可具有取代基之烷基」可列舉以作為上述環A之取代基而記載之「可具有取代基之烷基」。 The "alkyl group which may have a substituent" represented by R ² , R ³ or R ⁴ is exemplified by the "alkyl group which may have a substituent" described as the substituent of the above ring A.

R²、R³或R⁴表示之「可具有取代基之烷氧基」可列舉以作為上述環A之取代基而記載之「可具有取代基之烷氧基」。 The "alkoxy group which may have a substituent" represented by R ² , R ³ or R ⁴ is exemplified by the "alkoxy group which may have a substituent" described as the substituent of the above ring A.

R²、R³或R⁴表示之「可具有取代基之胺基」可列舉例如胺基、單-C_1-6烷基胺基(例如甲胺基、乙胺基等)、單-C_6-14芳基胺基(例如苯基胺基、1-萘基胺基、2-萘基胺基等)、二-C_1-6烷基胺基(例如二甲基胺基、二乙基胺基等)、二-C_6-14芳基胺基(例如二苯基胺基等)等。 Examples of the "amino group which may have a substituent" represented by R ² , R ³ or R ⁴ may, for example, be an amine group, a mono-C _1-6 alkylamino group (e.g., a methylamino group, an ethylamino group, etc.), a mono-C. _6-14 arylamino (eg phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C _1-6 alkylamino (eg dimethylamino, diethyl) Amino group, etc.), a di-C _6-14 arylamine group (for example, a diphenylamino group, etc.), and the like.

較佳之R²為C_1-6烷基、C_1-6烷氧基、C_1-6烷氧基-C_1-6烷氧基、二-C_1-6烷基胺基。更好之R²為C_1-3烷基或C_1-3烷氧基。 Desirable R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-C _1-6 alkoxy group or a di-C _1-6 alkylamino group. More preferably, R ² is a C _1-3 alkyl group or a C _1-3 alkoxy group.

較佳之R³為氫原子、C_1-6烷氧基-C_1-6烷氧基、或可經鹵化之C_1-6烷氧基。更好之R³為可經鹵化或經C_1-3烷氧基 取代之C_1-3烷氧基。 The preferred R ³ is a hydrogen atom, C _1-6 alkoxy -C _1-6 alkoxy, or the halogenated C _1-6 alkoxy group. More preferably, R ³ is a C _1-3 alkoxy group which may be halogenated or substituted with a C _1-3 alkoxy group.

較佳之R⁴為氫原子或C_1-6烷基。更好之R⁴為氫原子或C_1-3烷基(尤其是氫原子)。 Preferably, R ⁴ is a hydrogen atom or a C _1-6 alkyl group. More preferably, R ⁴ is a hydrogen atom or a C _1-3 alkyl group (especially a hydrogen atom).

較佳之Y為氮原子。 Preferably Y is a nitrogen atom.

較佳之式(I)化合物係環A為可具有選自鹵素原子、可經鹵化之C_1-4烷基、可經鹵化之C_1-4烷氧基及5或6員雜環基中之取代基的苯環，R¹為氫原子，R²為C_1-6烷基、C_1-6烷氧基、C_1-6烷氧基-C_1-6烷氧基或二-C_1-6烷基胺基，R³為氫原子、C_1-6烷氧基-C_1-6烷氧基或可經鹵化之C_1-6烷氧基，R⁴為氫原子或C_1-6烷基，Y為氮原子之化合物。 Preferably, the compound of the formula (I) is a ring A which may have a halogen atom, a halogenated C _1-4 alkoxy group, a halogenated C _1-4 alkoxy group and a 5 or 6 membered heterocyclic group. a benzene ring of a substituent, R ¹ is a hydrogen atom, and R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-C _1-6 alkoxy group or a di-C _{1 a -6} alkylamino group, R ³ is a hydrogen atom, a C _1-6 alkoxy-C _1-6 alkoxy group or a halogenated C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or C _{1- 6} alkyl, Y is a compound of a nitrogen atom.

化合物(I)中，如式(Ia)表示之化合物： [式中，R¹為氫原子，R²為C_1-3烷基或C_1-3烷氧基，R³為可經鹵化或經C_1-3烷氧基取代之C_1-3烷氧基，R⁴為氫原子或C_1-3烷基，R⁵為氫原子、可經鹵化之C_1-3烷氧基或吡咯基(例如1-、2-或3-吡咯基)]。 In the compound (I), the compound represented by the formula (Ia): [Wherein, R ¹ is a hydrogen atom, R ² is C _1-3 alkyl or a C _1-3 alkoxy group, R ³ is substituted it may be halogenated by a C _1-3 alkoxy group or a C _1-3 alkoxy An oxy group, R ⁴ is a hydrogen atom or a C _1-3 alkyl group, and R ⁵ is a hydrogen atom, a halogenated C _1-3 alkoxy group or a pyrrolyl group (for example, 1-, 2- or 3-pyrrolyl)] .

於式(Ia)中，更好係R¹為氫原子，R²為C_1-3烷基，R³為可經鹵化之C_1-3烷氧基，R⁴為氫原子，R⁵為氫原子或可經鹵化之C_1-3烷氧基的化合物。 In the formula (Ia), more preferably R ¹ is a hydrogen atom, R ² is a C _1-3 alkyl group, R ³ is a halogen-substituted C _1-3 alkoxy group, R ⁴ is a hydrogen atom, and R ⁵ is A hydrogen atom or a compound of a C _1-3 alkoxy group which may be halogenated.

化合物(I)之具體例可列舉下述之化合物。 Specific examples of the compound (I) include the following compounds.

2-[[[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲 基]亞磺醯基]-1H-苯并咪唑、2-[[(3,5-二甲基-4-甲氧基-2-吡啶基)甲基]亞磺醯基]-5-甲氧基-1H-苯并咪唑(奥美拉唑)、2-[[[4-(3-甲氧基丙氧基)-3-甲基-2-吡啶基]甲基]亞磺醯基]-1H-苯并咪唑(拉培拉唑)‧鈉鹽、5-二氟甲氧基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]亞磺醯基]-1H-苯并咪唑(畔托拉唑)等。 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]- Sulfhydryl]-1H-benzimidazole, 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-5-A oxy-1H-benzimidazole (omeprazole), 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl -1H-benzimidazole (lapelaprazole) ‧ sodium salt, 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfin Base]-1H-benzimidazole (pantoprazole) and the like.

該等化合物中，較好為2-[[[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲基]亞磺醯基]-1H-苯并咪唑(蘭素拉唑)。 Among these compounds, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H- is preferred. Benzimidazole (lansalazole).

化合物(I)可為消旋體，亦可為R-體、S-體等光學活性體。例如，化合物(I)亦可為(R)-2-[[[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲基]亞磺醯基]-1H-苯并咪唑等之光學活性體，較好為該光學活性體。 The compound (I) may be a racemate or an optically active substance such as an R-body or an S-body. For example, the compound (I) may also be (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinium sulfonium The optically active substance such as -1H-benzimidazole is preferably the optically active substance.

化合物(I)或其光學活性體之鹽較好為藥學上容許之鹽，可列舉例如化合物(I)或其光學活性體之與無機鹼之鹽、與有機鹼之鹽、與鹼性胺基酸之鹽等。 The salt of the compound (I) or an optically active substance thereof is preferably a pharmaceutically acceptable salt, and examples thereof include a compound (I) or an optically active substance thereof, a salt with an inorganic base, a salt with an organic base, and a basic amino group. Salt of acid, etc.

與無機鹼之鹽之較佳例可列舉例如鈉鹽、鉀鹽等鹼金屬鹽；鈣鹽、鎂鹽等鹼土金屬鹽；銨鹽等。 Preferable examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; and an ammonium salt.

與有機鹼之鹽之較佳例可列舉例如與烷基胺(三甲基胺、三乙基胺等)、雜環式胺(吡啶、甲基吡啶等)、烷醇胺(乙醇胺、二乙醇胺、三乙醇胺等)、二環己胺、N,N’-二苯甲基乙二胺等之鹽。 Preferable examples of the salt with an organic base include, for example, an alkylamine (trimethylamine, triethylamine, etc.), a heterocyclic amine (pyridine, methylpyridine, etc.), an alkanolamine (ethanolamine, diethanolamine). , triethanolamine, etc.), dicyclohexylamine, N, N'-diphenylmethylethylenediamine and the like.

與鹼性胺基酸之鹽之較佳例可列舉例如與精胺酸、離胺酸、鳥胺酸等之鹽。 Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, and ornithine.

該等鹽中較好為鹼金屬鹽或鹼土金屬鹽。尤其是以鈉鹽較佳。 Among these salts, an alkali metal salt or an alkaline earth metal salt is preferred. Especially sodium salts are preferred.

化合物(I)可根據本身即公知之方法製造，例如根據日本特開昭61-50978號公報、美國專利4,628,098號說明書、日本特開平10-195068號公報、國際公開第98/21201號說明書等記載之方法或以該等為基準之方法製造。 The compound (I) can be produced by a method known per se, for example, according to JP-A-61-50978, US Pat. No. 4,628,098, JP-A-10-195068, and International Publication No. 98/21201. The method is manufactured by the method based on the above.

化合物(I)之光學活性體可根據光學離析法(分別再結晶法、掌性管柱(chiral column)法、非鏡像異構物法、使用微生物或酵素之方法等)、不對稱氧化等之方法獲得。例如蘭素拉唑為R體時，可根據國際公開第00/78745號說明書、國際公開第01/83473號說明書、國際公開第01/87874號說明書及國際公開第02/44167號說明書記載之方法製造。 The optically active substance of the compound (I) may be subjected to an optical separation method (recrystallization method, chiral column method, non-image isomer method, method using microorganisms or enzymes, etc.), asymmetric oxidation, or the like. The method is obtained. For example, when the lansinazole is the R body, the method described in the specification of International Publication No. 00/78745, International Publication No. 01/83473, International Publication No. 01/87874, and International Publication No. 02/44167 can be used. Manufacturing.

本發明使用之PPI，較好為選自如蘭素拉唑、奥美拉唑、拉培拉唑、畔托拉唑等具有抗潰瘍作用之苯并咪唑系化合物、該等之光學活性體及該等之藥學上容許之鹽者。 The PPI used in the present invention is preferably a benzimidazole compound having an antiulcer effect such as lansilerazole, omeprazole, lapelaprazole, and pantoprazole, and the optically active substance and the like. The pharmaceutically acceptable salt.

(1)-2：關於「包含PPI之腸溶性細粒」 (1)-2: About "Enteric-coated fine particles containing PPI"

「包含PPI之腸溶性細粒」係指將含有PPI之組成物以腸溶性包覆層包覆，且平均粒徑在約400μm以下之細粒。 The "enteric-soluble fine particles containing PPI" means fine particles in which a composition containing PPI is coated with an enteric coating layer and an average particle diameter is about 400 μm or less.

「包覆」不只限於將被包覆對象(例如核)表面整體包覆之情況，亦包含部分被包覆之情況、或被吸附或吸收之情況。「平均粒徑」若無特別說明，即表示體積基準中值粒徑(中值粒徑：相當於累積分布50%之粒徑)。其測定方 法可列舉例如雷射繞射式粒度分布測定法，具體例可列舉使用雷射繞射式粒度分布測定裝置HEROS RODOS(Sympatec公司(德國)製造)之方法。 The "coating" is not limited to the case where the surface of the object to be coated (for example, the core) is entirely covered, and the case where the surface is covered or adsorbed or absorbed. The "average particle diameter" means a volume-based median diameter (median particle diameter: a particle diameter corresponding to a cumulative distribution of 50%) unless otherwise specified. Its measuring side For example, a laser diffraction type particle size distribution measuring method can be cited, and a specific example thereof is a method using a laser diffraction type particle size distribution measuring apparatus HEROS RODOS (manufactured by Sympatec Co., Germany).

關於「將含有PPI之組成物以腸溶性包覆層包覆，且平均粒徑在約400μm以下之細粒」，為了使人在口中不會感覺到粗糙感或不諧調感，該平均粒徑係在約400μm以下。較好之平均粒徑為300至400μm。 The "average particle size of a composition containing a PPI coated with an enteric coating layer and having an average particle diameter of about 400 μm or less" is used to prevent a person from feeling rough or uncomfortable in the mouth. It is below about 400 μm. A preferred average particle diameter is from 300 to 400 μm.

當並非該「細粒」之平均粒徑而是規定最大粒子之大小時，粒徑實質上係在425μm以下，較好係實質上在400μm以下。較好之範圍係粒徑實質上為300至425μm，更好係實質上為300至400μm。 When the size of the largest particles is not the average particle diameter of the "fine particles", the particle diameter is substantially 425 μm or less, preferably 400 μm or less. A preferred range is a particle size of substantially 300 to 425 μm, more preferably substantially 300 to 400 μm.

「粒徑實質上在425μm以下」及「粒徑實質上在400μm以下」之「實質上」的意義，係指只要是不可避免而混入之粒子，即可含有少量(約5重量%以下)超出上述範圍之粒徑之粒子。 The meaning of "substantially" such as "the particle size is substantially 425 μm or less" and "the particle diameter is substantially 400 μm or less" means that a small amount (about 5% by weight or less) is contained as long as it is inevitably mixed. Particles having a particle size in the above range.

於本發明中，「含有PPI之組成物」(在經腸溶性包覆層包覆前之組成物)中之PPI之含量係例如約5重量%以上，較好為約10至50重量%，更好為約15至50重量%，特好為約20至約50重量%。 In the present invention, the content of the PPI in the "composition containing PPI" (the composition before coating with the enteric coating layer) is, for example, about 5% by weight or more, preferably about 10 to 50% by weight. More preferably, it is from about 15 to 50% by weight, particularly preferably from about 20 to about 50% by weight.

製劑整體中之PPI之含量係例如為約1重量%以上，較好為約1.5重量%以上、10.0重量%以下，更好為約2.0重量%以上、8.0重量%以下。 The content of the PPI in the entire preparation is, for example, about 1% by weight or more, preferably about 1.5% by weight or more and 10.0% by weight or less, more preferably about 2.0% by weight or more and 8.0% by weight or less.

上述「組成物」中，為了使該生理活性物質(PPI)在製劑中安定化，較好為調配鹼性無機鹽。 In the above "composition", in order to stabilize the physiologically active substance (PPI) in the preparation, it is preferred to formulate a basic inorganic salt.

該「鹼性無機鹽」可列舉例如鈉、鉀、鎂及/或鈣之鹼性無機鹽。較好為鎂及/或鈣之鹼性無機鹽。更好為鎂之鹼性無機鹽。 The "basic inorganic salt" may, for example, be an alkali inorganic salt of sodium, potassium, magnesium and/or calcium. It is preferably an alkaline inorganic salt of magnesium and/or calcium. More preferably, it is an alkaline inorganic salt of magnesium.

該鈉之鹼性無機鹽可列舉例如碳酸鈉、碳酸氫鈉等。 Examples of the basic inorganic salt of sodium include sodium carbonate, sodium hydrogencarbonate and the like.

該鉀之鹼性無機鹽可列舉例如碳酸鉀、碳酸氫鉀等。 The basic inorganic salt of potassium may, for example, be potassium carbonate or potassium hydrogencarbonate.

該鎂之鹼性無機鹽可列舉例如重質碳酸鎂、碳酸鎂、氧化鎂、氫氧化鎂、矽酸鋁鎂、矽酸鎂、鋁酸鎂、合成水滑石[Mg₆Al₂(OH)₁₆‧CO₃‧4H₂O]及氫氧化鋁‧鎂[2.5MgO‧Al₂O₃‧xH₂O]，較好為重質碳酸鎂、碳酸鎂、氧化鎂、氫氧化鎂等。 Examples of the basic inorganic salt of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, aluminum magnesium niobate, magnesium niobate, magnesium aluminate, and synthetic hydrotalcite [Mg ₆ Al ₂ (OH) ₁₆ ‧CO ₃ ‧4H ₂ O] and aluminum hydroxide ‧ magnesium [2.5MgO‧Al ₂ O ₃ ‧xH ₂ O], preferably heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, and the like.

該鈣之鹼性無機鹽可列舉例如沉澱碳酸鈣、氫氧化鈣等。 Examples of the alkaline inorganic salt of calcium include precipitated calcium carbonate, calcium hydroxide and the like.

該「鹼性無機鹽」更好可列舉重質碳酸鎂、碳酸鎂、氧化鎂、氫氧化鎂等。 The "basic inorganic salt" is more preferably a heavy magnesium carbonate, magnesium carbonate, magnesium oxide or magnesium hydroxide.

該等鎂及鈣等之鹼性無機鹽只要是其1%水溶液或懸濁液之pH值表示鹼性(pH7以上)者即可。 The basic inorganic salt such as magnesium or calcium may be any one of a 1% aqueous solution or a suspension having a pH value indicating that it is alkaline (pH 7 or higher).

該鹼性無機鹽(較好為鎂、鈣之鹼性無機鹽)可調配1種或組合2種以上調配，其調配量只要根據鹼性無機鹽之種類適當選擇即可。調配量例如相對於PPI而調配約0.3至200重量%，較好為約1至100重量%，更好為約10至50重量%，最好為約20至40重量%。 The basic inorganic salt (preferably an alkaline inorganic salt of magnesium or calcium) may be used singly or in combination of two or more kinds, and the amount of the compound may be appropriately selected depending on the type of the basic inorganic salt. The compounding amount is, for example, about 0.3 to 200% by weight, preferably about 1 to 100% by weight, more preferably about 10 to 50% by weight, most preferably about 20 to 40% by weight, based on the PPI.

該「組成物」亦可含有水溶性高分子、後述之通常製造製劑所使用之黏合劑、潤滑劑、賦形劑等。添加量為通常製劑使用之量。 The "composition" may also contain a water-soluble polymer, a binder, a lubricant, an excipient, or the like used in a preparation for general production to be described later. The amount added is the amount used in the usual preparation.

「水溶性高分子」可列舉乙醇可溶性水溶性高分子[例如羥丙基纖維素(以下，亦記載為HPC)等纖維素衍生物、聚乙烯基吡咯啶酮等]、乙醇不溶性水溶性高分子[例如羥丙基甲基纖維素(以下，亦記載為HPMC)、甲基纖維素、羧甲基纖維素鈉等纖維素衍生物、聚丙烯酸鈉、聚乙烯醇、褐藻酸鈉、關華豆膠(Guar Gum)等]等。 Examples of the "water-soluble polymer" include ethanol-soluble water-soluble polymers (for example, cellulose derivatives such as hydroxypropylcellulose (hereinafter also referred to as HPC), polyvinylpyrrolidone, etc.], and ethanol-insoluble water-soluble polymers. [For example, hydroxypropylmethylcellulose (hereinafter also referred to as HPMC), cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, and Guanhua beans Gum (Guar Gum), etc.].

使用水溶性高分子時，可藉由將乙醇可溶性之水溶性高分子與乙醇不溶性之水溶性高分子併用，或是將黏度不同之水溶性高分子組合使用，而控制藥物(PPI)之溶出性。 When a water-soluble polymer is used, the dissolution property of the drug (PPI) can be controlled by using an ethanol-soluble water-soluble polymer in combination with an ethanol-insoluble water-soluble polymer or a water-soluble polymer having a different viscosity. .

於本發明中，較佳之水溶性高分子可列舉HPC、HPMC、甲基纖維素等纖維素衍生物、聚乙烯醇，更好為HPC、HPMC等纖維素衍生物。 In the present invention, preferred water-soluble polymers include cellulose derivatives such as HPC, HPMC, and methyl cellulose, and polyvinyl alcohol, and more preferably cellulose derivatives such as HPC and HPMC.

該HPC含有羥基丙氧基例如約53.4至77.5重量%，較好約60至70重量%。HPC在20℃時之2重量%水溶液之黏度通常為約1至150000cps(厘泊(centipoise))。如此之HPC係使用日本藥典之羥丙基纖維素等(以下，HPC之黏度皆為在20℃時之2重量%水溶液之值)。 The HPC contains a hydroxypropoxy group, for example, from about 53.4 to 77.5 wt%, preferably from about 60 to 70 wt%. The viscosity of HPC's 2% by weight aqueous solution at 20 ° C is typically from about 1 to 150,000 cps (centipoise). Such HPC is a hydroxypropylcellulose of the Japanese Pharmacopoeia (hereinafter, the viscosity of HPC is a value of a 2% by weight aqueous solution at 20 ° C).

該HPMC係由甲氧基及羥基丙氧基所結合成之混合醚。HPMC中之甲氧基之含量為例如約19至30重量%，羥基丙氧基之含量為例如約4至12重量%。HPMC在20℃時之2重量%水溶液之黏度通常為約1至40000厘沲(centistokes)。如此之HPMC係使用日本藥典之羥丙基甲基纖維素2208、日本藥典之羥丙基甲基纖維素2906及日本藥典羥丙基甲基纖維素2910等。羥丙基甲基纖維素可使 用一種，亦可將二種以上混合使用。 The HPMC is a mixed ether composed of a methoxy group and a hydroxypropoxy group. The content of the methoxy group in the HPMC is, for example, about 19 to 30% by weight, and the content of the hydroxypropoxy group is, for example, about 4 to 12% by weight. The viscosity of a 2% by weight aqueous solution of HPMC at 20 ° C is typically from about 1 to 40,000 centistokes. Such HPMC uses hydroxypropylmethylcellulose 2208 of the Japanese Pharmacopoeia, hydroxypropylmethylcellulose 2906 of the Japanese Pharmacopoeia, and hydroxypropylmethylcellulose 2910 of the Japanese Pharmacopoeia. Hydroxypropyl methylcellulose can make One type may be used in combination of two or more types.

關於HPC及/或HPMC等水溶性高分子之含量，為了可控制含有PPI之組成物中之PPI之溶出性且保持高含量之生理活性物質，通常為約0.1至50重量%，較好為約1至30重量%。 The content of the water-soluble polymer such as HPC and/or HPMC is usually from about 0.1 to 50% by weight, preferably about 0.1 to 50% by weight, in order to control the dissolution of the PPI in the PPI-containing composition and maintain a high content. 1 to 30% by weight.

將上述「含有PPI之組成物」包覆之「腸溶性包覆層」可使用例如乙酸鄰苯二甲酸纖維素(CAP)、羥丙基甲基纖維素鄰苯二甲酸酯(以下，記載為HP-55)、羥甲基纖維素乙酸酯琥珀酸酯、甲基丙烯酸共聚物[例如尤特奇(Eudragit)L30D-55(商品名；埃伯尼克(Evonik)公司製造)、可利克美(Kollicoat)MAE 30DP(商品名；BASF公司製造)、波利奎(Polyquid)PA30(商品名；三洋化成公司製造)等]、羧甲基乙基纖維素、蟲膠(shellac)等水系腸溶性高分子基劑；甲基丙烯酸酯共聚物[例如尤特奇NE30D(商品名)、尤特奇RL30D(商品名)、尤特奇RS30D(商品名)、尤特奇RS30D(商品名)等]等緩釋性基劑；水溶性高分子；檸檬酸三乙酯、聚乙二醇、乙醯化單甘油酯、甘油三乙酸酯、萞麻油等可塑劑等。該等可使用一種或將二種以上混合使用。 For example, the "enteric coating layer" coated with the "component containing PPI" may be, for example, cellulose acetate phthalate (CAP) or hydroxypropyl methylcellulose phthalate (hereinafter, described) It is HP-55), hydroxymethyl cellulose acetate succinate, methacrylic acid copolymer [for example, Eudragit L30D-55 (trade name; manufactured by Evonik), Klik Kollicoat MAE 30DP (trade name; manufactured by BASF), Polyquid PA30 (trade name; Sanyo Chemical Co., Ltd.), etc., carboxymethylethylcellulose, shellac, etc. Soluble polymer base; methacrylate copolymer [for example, Utech NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), Eudragit RS30D (trade name), etc. And other sustained release base; water-soluble polymer; triethyl citrate, polyethylene glycol, acetylated monoglyceride, triacetin, castor oil and other plasticizers. These may be used alone or in combination of two or more.

水系腸溶性高分子基劑較好為甲基丙烯酸共聚物(methacrylic acid copolymer)。 The aqueous enteric polymer base is preferably a methacrylic acid copolymer.

緩釋性基劑較好為甲基丙烯酸酯共聚物(methacrylate copolymer)，尤其是丙烯酸乙酯與甲基丙烯酸甲酯之共聚物。 The sustained release base is preferably a methacrylate copolymer, especially a copolymer of ethyl acrylate and methyl methacrylate.

緩釋性基劑之使用量係相對於水系腸溶性高分子基 劑100重量%而為約5至30重量%，較好為約5至15重量%。可塑劑之較佳使用量係相對於水系腸溶性高分子基劑100重量%而為5至30重量%。 The sustained-release base is used in relation to the aqueous enteric polymer base. The agent is from about 5 to 30% by weight, preferably from about 5 to 15% by weight, based on 100% by weight. The plasticizer is preferably used in an amount of 5 to 30% by weight based on 100% by weight of the aqueous enteric polymer base.

上述「含有PPI之組成物」可根據公知之造粒法製造。 The above "PPI-containing composition" can be produced by a known granulation method.

「造粒法」可列舉轉動造粒法(例如離心轉動造粒法)、流動造粒法(例如轉動流動層造粒、流動造粒等)、攪拌造粒法等。其中，較好為流動造粒法。更好為轉動流動層造粒法。 Examples of the "granulation method" include a rotary granulation method (for example, centrifugal granulation granulation method), a flow granulation method (for example, turbulent flow layer granulation, flow granulation, etc.), a stirring granulation method, and the like. Among them, the flow granulation method is preferred. Better granulation for rotating the flow layer.

該轉動造粒法之具體例可列舉例如使用佛洛因德(FREUND)公司製造之「CF裝置」等之方法。該轉動流動層造粒法之具體例可列舉使用例如「司必拉流動管(spireflow)」帕雷克(POWREX)公司製造之「多重回路(Multiplex)」、不二帕塔魯(Fuji Paudal)公司製造之「新瑪路美(New Marume)」等之方法。混合液之噴霧方法可根據造粒裝置之種類適當選擇，可為例如頂噴霧方式、底噴霧方式、切線噴霧(tangential spray)方式等中之任何一種方法。其中，較好為切線噴霧方式。 Specific examples of the tumbling granulation method include a method using a "CF device" manufactured by Freund et (FREUND). Specific examples of the tumbling flow layer granulation method include, for example, "Multiplex" manufactured by POWREX, and Fuji Paudal. The company's "New Marume" and other methods. The spraying method of the mixed solution can be appropriately selected depending on the type of the granulating device, and may be, for example, any of a top spray method, a bottom spray method, a tangential spray method, and the like. Among them, a tangential spray method is preferred.

「含有PPI之組成物」例如可藉由將PPI包覆在含有結晶纖維素及乳糖之核而製造。 The "component containing PPI" can be produced, for example, by coating PPI on a core containing crystalline cellulose and lactose.

可列舉例如日本特開平5-092918號公報記載之製造法(塗佈方法)等記載之對於含有結晶纖維素及乳糖之核，將對酸不安定之生理活性物質及視需要之鹼性無機鹽、黏合劑、潤滑劑、賦形劑、水溶性高分子等(以下，亦簡稱為包覆層)包覆之方法。例如將對酸不安定之生理活性物質及 鹼性無機鹽包覆於核，再包覆黏合劑、潤滑劑、賦形劑、水溶性高分子等之方法。 For example, the production method (coating method) described in JP-A-H05-092918, etc., for the nucleus containing crystalline cellulose and lactose, and the physiologically active substance which is unstable to acid and, if necessary, an alkaline inorganic salt A method of coating a binder, a lubricant, an excipient, a water-soluble polymer, or the like (hereinafter, simply referred to as a coating layer). For example, physiologically active substances that are unstable to acid and A method in which an alkaline inorganic salt is coated on a core and then coated with a binder, a lubricant, an excipient, a water-soluble polymer, or the like.

該「核」之平均粒徑只要是在約250μm以下即可，為約50至250μm，較好為約100至250μm，更好為約100至200μm。具有如此之平均粒徑之核，係包含：全部通過50號(300μm)篩子，且殘留在60號(250μm)篩子之粒子在整體約5w/w%以下，並且通過282號(53μm)篩子之粒子在全體約10w/w%以下之粒子。「核」之比容係在約5mL/g以下，較好為在約3mL/g以下。 The average particle diameter of the "core" may be about 50 to 250 μm, preferably about 100 to 250 μm, more preferably about 100 to 200 μm, as long as it is about 250 μm or less. The core having such an average particle diameter comprises: all passing through a No. 50 (300 μm) sieve, and the particles remaining in the No. 60 (250 μm) sieve are below about 5 w/w% as a whole, and passed through a No. 282 (53 μm) sieve. The particles are particles of about 10 w/w% or less in total. The specific capacity of the "nucleus" is about 5 mL/g or less, preferably about 3 mL/g or less.

該「核」可列舉例如：(1)結晶纖維素及乳糖之球形造粒品、(2)結晶纖維素之約150至250μm之球形造粒品(旭化成股份有限公司製造，艾維素(Avicel)SP)、(3)由乳糖(9份)及α澱粉(1份)所成之約50至250μm之攪拌造粒品、(4)日本特開昭61-213201號公報記載之將微結晶纖維素球形顆粒分級之約250μm以下之微粒、(5)經由噴霧冷卻或溶融造粒而形成為球狀之蠟類等之加工品、(6)油成分之明膠珠狀品等之加工品、(7)矽酸鈣、(8)澱粉、(9)幾丁質、纖維素及幾丁聚糖等多孔性粒子、(10)細粒糖、結晶乳糖、結晶纖維素或氯化鈉等之簡裝品及該等之製劑加工品等。另外，可根據本身即公知之粉碎方法或造粒方法製造該等核，並過篩而調製所期待之粒徑之粒子。 The "nucleus" may, for example, be: (1) spherical granulated product of crystalline cellulose and lactose, and (2) spherical granulated product of about 150 to 250 μm of crystalline cellulose (Avicel, manufactured by Asahi Kasei Co., Ltd., Avicel) (SP), (3) a stirred granulated product of about 50 to 250 μm made of lactose (9 parts) and α-starch (1 part), and (4) a microcrystal described in JP-A-61-213201 a processed product such as a fine particle of about 250 μm or less of cellulose spherical particles, (5) a processed product obtained by spray cooling or melt granulation to form a spherical wax, and (6) a gelatinous bead product of an oil component, (7) calcium citrate, (8) starch, (9) chitin, porous particles such as cellulose and chitosan, (10) fine granulated sugar, crystalline lactose, crystalline cellulose or sodium chloride Simple items and processed products of these preparations. Further, the cores can be produced by a known pulverization method or granulation method, and sieved to prepare particles having a desired particle diameter.

該「結晶纖維素及乳糖之球形造粒品」可列舉例如：(i)由結晶纖維素(3份)及乳糖(7份)所成之約100至200μm之球形造粒品(例如極品(nonpareil)105(70-140)(粒 徑100至200μm)，佛洛因德(FREUND)公司製造)、(ii)由結晶纖維素(3份)及乳糖(7份)所成之約150至250μm之球形造粒品(例如極品NP-7：3，佛洛因德公司製造)、(iii)由結晶纖維素(4.5份)及乳糖(5.5份)所成之約100至200μm之球形造粒品(例如極品105T(70-140)(粒徑100至200μm)、佛洛因德公司製造)等、(iv)由結晶纖維素(5份)及乳糖(5份)所成之約150至250μm之球形造粒品(例如極品NP-5：5，佛洛因德公司製造)等。 The "spherical granulated product of crystalline cellulose and lactose" may, for example, be (i) a spherical granulated product of about 100 to 200 μm made of crystalline cellulose (3 parts) and lactose (7 parts) (for example, the best product (for example) Nonpareil) 105 (70-140) 100 to 200 μm), manufactured by Freuned (FREUND), (ii) spherical granulated product of about 150 to 250 μm made of crystalline cellulose (3 parts) and lactose (7 parts) (for example, the best NP) -7:3, manufactured by Freund Corporation, (iii) spherical granulated product of about 100 to 200 μm made of crystalline cellulose (4.5 parts) and lactose (5.5 parts) (for example, the best product 105T (70-140) (particle size 100 to 200 μm), manufactured by Freund Corporation, etc., (iv) spherical granulated product of about 150 to 250 μm made of crystalline cellulose (5 parts) and lactose (5 parts) (for example, the best) NP-5: 5, manufactured by Freund Corporation).

為了製造保持適當強度且同時溶解性亦優越之製劑，該「核」較好為由結晶纖維素及乳糖所成之球形造粒品，更好為可列舉如由結晶纖維素及乳糖所成之球形造粒品且含有乳糖50重量%以上者。較好為含有結晶纖維素40至50重量%及乳糖50至60重量%者。 In order to produce a preparation which maintains an appropriate strength and is also excellent in solubility, the "nucleus" is preferably a spherical granulated product made of crystalline cellulose and lactose, and more preferably, it is composed of crystalline cellulose and lactose. The spherical granulated product contains 50% by weight or more of lactose. It is preferably 40 to 50% by weight of crystalline cellulose and 50 to 60% by weight of lactose.

本發明使用之核較好為結晶纖維素及乳糖之球形造粒品，更好為由結晶纖維素(4.5份)及乳糖(5.5份)所成之約100至200μm之球形造粒品。 The core used in the present invention is preferably a spherical granulated product of crystalline cellulose and lactose, more preferably a spherical granulated product of about 100 to 200 μm made of crystalline cellulose (4.5 parts) and lactose (5.5 parts).

該「核」可含有PPI，但由於可經由含有該PPI之包覆層而控制PPI之釋出性，故核亦可不含PPI。 The "nucleus" may contain a PPI, but since the release of the PPI can be controlled via a coating layer containing the PPI, the core may not contain the PPI.

該「核」可為細粒狀，為了使包覆之差異情形變小，較好係盡可能為均一之球狀。 The "nucleus" may be in the form of fine particles, and in order to make the difference in the coating smaller, it is preferable to be as uniform as possible.

「包覆層」相對於該「核」之比例，可在可控制生理活性物質之溶出性及組成物之粒度的範圍選擇，例如，相對於核100重量份，通常為約50至400重量份。 The ratio of the "coating layer" to the "core" may be selected within a range that can control the dissolution property of the physiologically active substance and the particle size of the composition, for example, usually about 50 to 400 parts by weight with respect to 100 parts by weight of the core. .

「包覆層」可由複數層形成，只要複數層之包覆層至 少有1層含有PPI即可。可適當選擇構成複數層包覆層的不具有活性成分之包覆層、或底襯用包覆層、腸溶性包覆層等種種包覆層之組合。 The "cladding layer" may be formed of a plurality of layers as long as the coating of the plurality of layers is There is one layer that contains PPI. A combination of a coating layer having no active component constituting the plurality of layer coating layers, a coating layer for a backing layer, and an enteric coating layer can be appropriately selected.

包覆核時，例如可將PPI及水溶性高分子作成混合液使用。該混合液可為溶液，亦可為分散液，可使用水或乙醇等有機溶劑或該等之混合液調製。 When the core is coated, for example, a PPI and a water-soluble polymer can be used as a mixed liquid. The mixed solution may be a solution or a dispersion, and may be prepared using an organic solvent such as water or ethanol or a mixture thereof.

關於混合液中之水溶性高分子之濃度，為了保持PPI對於核之結合力，且同時使混合液之黏度維持為不降低作業性之程度，故根據PPI及添加劑之比例而異，但通常為約0.1至50重量%，較好為約0.5至10重量%。 The concentration of the water-soluble polymer in the mixed solution is maintained in accordance with the ratio of the PPI and the additive, in order to maintain the binding force of the PPI to the core and maintain the viscosity of the mixed solution at the same time. It is about 0.1 to 50% by weight, preferably about 0.5 to 10% by weight.

包覆層係以複數層形成時，可選定水溶性高分子之調配比例或黏度之梯度，或是使用變更PPI或其他添加劑之比例之混合液依序包覆，使各層之PPI濃度連續性或階段性地變動。於該情況下，只要包覆層整體含有水溶性高分子約0.1至50重量%，即亦可用超出約0.1至50重量%範圍之調配比例的混合液包覆。另外，亦可根據公知之方法形成惰性包覆膜，以將含有PPI之各層之間遮断的方式，製成由複數層所成之包覆層。 When the coating layer is formed by a plurality of layers, the blending ratio or viscosity gradient of the water-soluble polymer may be selected, or the mixture of the PPI or other additives may be sequentially coated to make the PPI concentration continuity of each layer or Change in stages. In this case, as long as the entire coating layer contains the water-soluble polymer in an amount of about 0.1 to 50% by weight, it may be coated with a mixed solution in a proportion exceeding the range of about 0.1 to 50% by weight. Further, an inert coating film may be formed by a known method to form a coating layer composed of a plurality of layers so as to block each layer containing PPI.

將上述包覆物乾燥後，經由篩子獲得粒度一致之組成物。組成物之形狀，通常是對應於核，故亦可獲得略球形之組成物。篩子可使用例如50號(300μm)之圓篩，藉由挑選通過該50號圓篩之粒子，而獲得組成物。 After drying the above-mentioned coating, a composition having a uniform particle size was obtained through a sieve. The shape of the composition generally corresponds to the core, so that a slightly spherical composition can also be obtained. The sieve can be obtained by using a circular sieve of, for example, No. 50 (300 μm), by picking particles passing through the No. 50 round sieve.

「包含PPI之腸溶性細粒」係根據與上述相同之造粒法，以保護PPI或賦予腸溶性為目的，將含有PPI之組成 物以腸溶性包覆層包覆而製造。根據需要，亦可更進一步以水溶性糖醇(較好為甘露糖醇)包覆。經水溶性糖醇包覆時，可提昇含有細粒之口腔內崩解錠之強度。 "Enteric-coated fine particles containing PPI" is a composition containing PPI for the purpose of protecting PPI or imparting enteric solubility according to the same granulation method as described above. The article was produced by coating with an enteric coating. Further, it may be further coated with a water-soluble sugar alcohol (preferably mannitol) as needed. When coated with a water-soluble sugar alcohol, the strength of the orally disintegrating ingot containing fine particles can be enhanced.

腸溶性包覆層較好係將含有PPI組成物之表面整體以約20至70μm，較好為約30至50μm之厚度包覆之層。因此，該組成物之粒徑越小、腸溶性包覆層占細粒整體之重量%變越大。「包含PPI之腸溶性細粒」中之腸溶性包覆層為細粒整體之約30至70重量%，較好為約50至70重量%。 The enteric coating layer is preferably a layer which is coated with the entire surface of the PPI composition in a thickness of about 20 to 70 μm, preferably about 30 to 50 μm. Therefore, the smaller the particle diameter of the composition, the larger the weight % of the enteric coating layer as a whole of the fine particles. The enteric coating layer in the "enteric soluble fine particles containing PPI" is about 30 to 70% by weight, preferably about 50 to 70% by weight, based on the whole of the fine particles.

腸溶性包覆層可由複數層(例如2至3層)形成。例如，可列舉：對於組成物，將含有聚乙二醇之腸溶性包覆層包覆，並將含有檸檬酸三乙酯之腸溶性包覆層包覆，更進一步將含有聚乙二醇之腸溶性包覆層包覆之方法等。 The enteric coating layer may be formed of a plurality of layers (for example, 2 to 3 layers). For example, the composition may be coated with an enteric coating layer containing polyethylene glycol, and coated with an enteric coating layer containing triethyl citrate, and further containing polyethylene glycol. A method of coating an enteric coating layer or the like.

(1)-3：關於「含有包含PPI之腸溶性細粒的層」 (1)-3: About "layer containing enteric fine particles containing PPI"

本發明之積層之口腔內崩解錠中，「含有包含PPI之腸溶性細粒的層」係含有：1)將含有PPI之組成物以腸溶性包覆層包覆，且平均粒徑約400μm以下之細粒；以及2)添加劑。該添加劑為腸溶性細粒以外之部分中含有之成分。 In the layered orally disintegrating tablet of the present invention, the "layer containing enteric fine particles containing PPI" contains: 1) the PPI-containing composition is coated with an enteric coating layer, and the average particle diameter is about 400 μm. The following fine particles; and 2) additives. The additive is a component contained in a portion other than the enteric fine particles.

「含有包含PPI之腸溶性細粒的層」中「包含PPI之腸溶性細粒」之調配量，係相對於「含有包含PPI之腸溶性細粒的層」100重量份而為約20至約80重量份，較好為約30至約70重量份。 The blending amount of "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI" is about 20 to about 100 parts by weight with respect to 100 parts by weight of "layer containing enteric fine particles containing PPI". 80 parts by weight, preferably from about 30 to about 70 parts by weight.

「添加劑」可使用選自例如制酸劑、水溶性糖醇、結 晶纖維素、低取代度羥丙基纖維素等中之1種以上者，可更進一步使用黏合劑、酸味料、發泡劑、人口甜味料、香料、潤滑劑、著色劑、安定化劑、賦形劑、崩解劑等。 The "additive" can be selected from, for example, an antacid, a water-soluble sugar alcohol, and a knot. Further, one or more of crystalline cellulose and low-substituted hydroxypropyl cellulose may further use a binder, a sour material, a foaming agent, a sweetener, a fragrance, a lubricant, a colorant, and a stabilizer. , excipients, disintegrators, etc.

本發明之口腔內崩解錠係以在腸溶性細粒以外之部分中含有制酸劑為較佳。 The orally disintegrating tablet of the present invention preferably contains an antacid in a portion other than the enteric fine particles.

上述制酸劑較好為選自由金屬氧化物、金屬氫氧化物、鹼土金屬之碳酸鹽及甘胺酸鋁所成群組之至少1種(更好為1至15種，又更好為1至10種)。 The antacid is preferably at least one selected from the group consisting of metal oxides, metal hydroxides, alkaline earth metal carbonates, and aluminum glycinates (more preferably 1 to 15 types, more preferably 1). Up to 10 types).

上述金屬氧化物較好為使用選自由醫藥用之氧化鎂、矽酸鎂(2MgO‧3SiO₂‧xH₂O)、乾燥氫氧化鋁凝膠(Al₂O₃‧xH₂O)及偏矽酸鋁鎂(Al₂O₃‧MgO‧2SiO₂‧xH₂O)所成群組之至少1種(更好為1至3種)。 The metal oxide is preferably selected from the group consisting of magnesium oxide for medical use, magnesium citrate (2MgO‧3SiO ₂ ‧xH ₂ O), dried aluminum hydroxide gel (Al ₂ O ₃ ‧xH ₂ O), and metafluoric acid At least one group (more preferably 1 to 3 kinds) of aluminum magnesium (Al ₂ O ₃ ‧MgO‧2SiO ₂ ‧xH ₂ O) is grouped.

其中，更好為氧化鎂。氧化鎂係以可作為醫療用使用者，且酸反應性優越並具有中和力者為較佳。如此之氧化鎂可使用以通常之製造法獲得者或市售品，但較好為經低溫燒成之所謂輕煅燒氧化鎂(light-burned magnesia)。通常以在約500至約1000℃之溫度燒成者為佳，特別是從中和力之觀點而言，較好為在約600至900℃燒成者，最好為在約800℃燒成者。如此之氧化鎂中，BET比表面積通常為10至50m²/g，較好為20至50m²/g者。 Among them, it is more preferably magnesium oxide. Magnesium oxide is preferred as a medical user and has excellent acid reactivity and neutralizing power. Such a magnesium oxide can be obtained by a usual production method or a commercial product, but is preferably a so-called light-burned magnesia which is fired at a low temperature. It is usually preferred to fire at a temperature of from about 500 to about 1000 ° C, especially from the viewpoint of neutralization, preferably from about 600 to 900 ° C, preferably from about 800 ° C. . In such magnesium oxide, the BET specific surface area is usually from 10 to 50 m ² /g, preferably from 20 to 50 m ² /g.

此處，BET比表面積係指經由氮氣吸附法測定之比表面積，包括定量之氧化鎂表面及氮氣所進入之範圍內之細孔，經由氮氣之吸附量而測定比表面積。 Here, the BET specific surface area means a specific surface area measured by a nitrogen gas adsorption method, and includes pores in a range of a predetermined amount of magnesium oxide and a range in which nitrogen gas enters, and the specific surface area is measured by the amount of adsorption of nitrogen.

氧化鎂可列舉例如市售之重質氧化鎂(協和化學工業 股份有限公司製造)、重質氧化鎂(富田製藥股份有限公司製造)、重質30氧化鎂(協和化學工業股份有限公司製造)、輕質氧化鎂(協和化學工業股份有限公司製造)等。較好為重質30氧化鎂(協和化學工業股份有限公司製造)等。 Magnesium oxide may, for example, be a commercially available heavy magnesium oxide (Concord Chemical Industry) (manufactured by the company), heavy magnesium oxide (manufactured by Tomita Pharmaceutical Co., Ltd.), heavy 30 magnesia (manufactured by Kyowa Chemical Industry Co., Ltd.), light magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.), etc. It is preferably heavy magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.) or the like.

金屬氫氧化物例如較好為使用選自由醫藥用之氧化鎂、氫氧化鋁、合成水滑石(Mg₆Al₂(OH)₁₆CO₃‧4H₂O)、氫氧化鋁與氫氧化鎂之共沉澱物、氫氧化鋁與碳酸鎂與碳酸鈣之共沉澱物、以及氫氧化鋁與碳酸氫鈉之共沉澱物所成群組之至少1種(更好為1至3種)。該等中，從製劑崩解性、PPI溶出性之觀點等而言，較好為氫氧化鎂。 The metal hydroxide is preferably used, for example, from magnesium oxide, aluminum hydroxide, synthetic hydrotalcite (Mg ₆ Al ₂ (OH) ₁₆ CO ₃ ‧4H ₂ O), aluminum hydroxide and magnesium hydroxide. At least one (more preferably 1 to 3) of the precipitate, a coprecipitate of aluminum hydroxide and a mixture of magnesium carbonate and calcium carbonate, and a coprecipitate of aluminum hydroxide and sodium hydrogencarbonate. Among these, magnesium hydroxide is preferred from the viewpoints of disintegration properties and PPI elution properties.

上述鹼土金屬之碳酸鹽可列舉醫藥用之碳酸鈣、碳酸鎂等。較好為碳酸鎂。 The carbonate of the alkaline earth metal may, for example, be calcium carbonate or magnesium carbonate for medical use. It is preferably magnesium carbonate.

上述金屬氧化物、金屬氫氧化物、鹼土金屬之碳酸鹽及甘胺酸鋁可為單獨使用，亦可將2種以上(較好為2至3種)組合。 The metal oxide, the metal hydroxide, the alkaline earth metal carbonate, and the aluminum glycinate may be used singly or in combination of two or more (preferably two to three).

制酸劑較好為鹼土金屬之碳酸鹽與甘胺酸鋁的混合物，又以碳酸鎂與甘胺酸鋁之混合物更佳。 The antacid is preferably a mixture of an alkaline earth metal carbonate and an aluminum glycinate, and is preferably a mixture of magnesium carbonate and aluminum glycinate.

金屬氧化物、金屬氫氧化物中，有在製造時會將製劑機器之表面研磨而使錠劑表面整體或部分地變黑，或是造成黑點、黑線、黑面，而附著於製錠時之杵上者。該等之物性係使製造性顯著受損，故在選擇具有研磨性、杵附著性之金屬氧化物、金屬氫氧化物時，可藉由使用不具有該等特性之金屬氧化物與金屬氫氧化物之組合，或是與可作 為醫藥品使用之添加劑(例如後述之賦形劑、黏合劑、崩解劑等)一起進行濕式或乾式造粒，而抑制研磨作用或杵附著性。 In metal oxides and metal hydroxides, the surface of the preparation machine is ground at the time of manufacture to blacken the surface of the tablet in whole or in part, or to cause black spots, black lines, and black spots, and to adhere to the ingot. The time is right. These physical properties are markedly impaired in manufacturability. Therefore, when metal oxides or metal hydroxides having abrasive properties and ruthenium adhesion properties are selected, metal oxides and metal hydroxides having no such properties can be used. Combination of things, or with The additive used in the pharmaceutical product (for example, an excipient, a binder, a disintegrator or the like described later) is subjected to wet or dry granulation together to suppress the polishing action or the adhesion of the crucible.

制酸劑可藉由預先與添加劑(例如後述之賦形劑、黏合劑等)一起進行濕式或乾式造粒，而極力減少與乙醯水楊酸之接觸，以有助於乙醯水楊酸之安定化。 The antacid can be wet- or dry-granulated by pre-mixing with an additive (for example, an excipient, a binder, etc. described later), and the contact with acetaminosalicylic acid is minimized to contribute to the sulphur The acid is stabilized.

上述制酸劑之含量係根據各個制酸劑中和胃酸之能力而異，但在本發明之口腔內崩解錠中為0mg至約200mg，較好為約10mg至約100mg。 The content of the above antacids varies depending on the ability of each antacid to neutralize gastric acid, but is from 0 mg to about 200 mg, preferably from about 10 mg to about 100 mg, in the orally disintegrating tablet of the present invention.

相對於「含有包含PPI之腸溶性細粒的層」中的「包含PPI之腸溶性細粒」以外之成分100重量份，制酸劑通常以0至50重量份調配，較好為以10至40重量份調配。 The antacid is usually formulated in an amount of from 0 to 50 parts by weight, preferably from 10 to 100 parts by weight, based on 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". 40 parts by weight of the formulation.

上述「水溶性糖醇」係指將糖醇1g加入水中，於20℃每隔5分鐘強力振動30秒鐘使混合，在約30分鐘以內溶化時，其所需之水量未達30mL之糖醇。 The above-mentioned "water-soluble sugar alcohol" means that 1 g of sugar alcohol is added to water, and the mixture is vigorously shaken at 30 ° C for 30 seconds for mixing for 30 seconds, and when it is dissolved within about 30 minutes, the required amount of water is less than 30 mL of sugar alcohol. .

該「水溶性糖醇」可列舉例如山梨糖醇、甘露糖醇、麥芽糖醇、還原澱粉糖化物、木糖醇、還原帕拉金糖(reduced palatinose)、赤藻糖醇(erythritol)等，該等可將其2種以上(較好為2至3種)以適當比例混合使用。 Examples of the "water-soluble sugar alcohol" include sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced palatinose, erythritol, and the like. Two or more (preferably 2 to 3) may be used in an appropriate ratio.

該「水溶性糖醇」可列舉較好為甘露糖醇、木糖醇、赤藻糖醇，更好為甘露糖醇、赤藻糖醇，又以甘露糖醇最佳。赤藻糖醇通常係使用由將葡萄糖作為原料，並經由酵母菌等發酵而生產，且粒度在50篩孔(mesh)以下者。該赤藻糖醇可由市售品[日研化學股份有限公司製造等]購得。 The "water-soluble sugar alcohol" is preferably mannitol, xylitol or erythritol, more preferably mannitol or erythritol, and most preferably mannitol. The erythritol is usually produced by using glucose as a raw material, fermented by yeast or the like, and having a particle size of 50 or less. This erythritol is commercially available from a commercial product [manufactured by Nikko Chemical Co., Ltd., etc.].

為了獲得充分之製劑強度及充分之口腔內崩解性，相對於「含有包含PPI之腸溶性細粒的層」中的「包含PPI之腸溶性細粒」以外之成分100重量份，該「水溶性糖醇」通常係使用約5至97重量份，較好為使用約10至90重量份。 In order to obtain sufficient formulation strength and sufficient in-oral disintegration, the water-soluble solution is 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". The "sugar alcohol" is usually used in an amount of about 5 to 97 parts by weight, preferably about 10 to 90 parts by weight.

上述「結晶纖維素」只要是將α-纖維素進行部分性地解聚並精製者即可。又，亦包含被稱為微結晶纖維素者。關於該結晶纖維素，具體而言可列舉例如協歐拉斯(Ceolus)KG801、艾維素(Avicel)PH101、艾維素PH102、艾維素PH301、艾維素PH302、艾維素RC-591(結晶纖維素‧羧甲基纖維素鈉)等。較好者可列舉如被稱為高成形艾維素之協歐拉斯KG801。該等結晶纖維素可單獨使用，亦可併用2種以上(較好為2至3種)。該等結晶纖維素可由市售品[旭化成股份有限公司製造]購得。 The above "crystalline cellulose" may be obtained by partially depolymerizing and refining α-cellulose. Also, it is also known as microcrystalline cellulose. Specific examples of the crystalline cellulose include Ceolus KG801, Avicel PH101, Avicel PH102, Avicin PH301, Avicin PH302, and Avicin RC-591. (crystalline cellulose ‧ carboxymethyl cellulose sodium) and the like. Preferred examples are the Eurasian KG801, which is called high-formed Avicel. These crystalline celluloses may be used singly or in combination of two or more (preferably two to three). These crystalline celluloses are commercially available from the commercial product [made by Asahi Kasei Co., Ltd.].

相對於「含有包含PPI之腸溶性細粒的層」中的「包含PPI之腸溶性細粒」以外之成分100重量份，該結晶纖維素通常只要以約3至50重量份，較好為以約5至40重量份，最好為以約5至20重量份調配即可。 The crystalline cellulose is usually used in an amount of about 3 to 50 parts by weight, preferably 100 parts by weight, based on 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". It is preferably from 5 to 40 parts by weight, preferably from about 5 to 20 parts by weight.

上述「低取代度羥丙基纖維素」係指羥丙基纖維素中之羥基丙氧基之含量(以下，亦簡稱為HPC基含量)為約5.0至9.9重量%之低取代度羥丙基纖維素，其中，尤其意指約5.0至7.0重量%之低取代度羥丙基纖維素及約7.0至9.9重量%之低取代度羥丙基纖維素等。 The above "low-substituted hydroxypropyl cellulose" means a low-substituted hydroxypropyl group having a hydroxypropoxy group content (hereinafter, also referred to as HPC group content) in the hydroxypropyl cellulose of about 5.0 to 9.9% by weight. Cellulose, among them, particularly means about 5.0 to 7.0% by weight of low-substituted hydroxypropylcellulose and about 7.0 to 9.9% by weight of low-substituted hydroxypropylcellulose and the like.

HPC基含量為約7.0至9.9%之該低取代度羥丙基纖 維素可列舉例如LH-22、LH-32及該等之混合物等，該等可由市售品[信越化學股份有限公司製造]購得。又，可根據本身即公知之方法，例如以下敘述之日本特公昭57-53100號公報記載之方法或以該等為基準之方法製造。 The low-substituted hydroxypropyl fiber having an HPC group content of about 7.0 to 9.9% The vitamins may, for example, be LH-22, LH-32, and the like, and the like, which are commercially available from Shin-Etsu Chemical Co., Ltd. Further, it can be produced by a method known per se, for example, a method described in Japanese Patent Publication No. Sho 57-53100, or a method based on the above.

HPC含量為約5.0至7.0%之該低取代度羥丙基纖維素可列舉例如LH-23、LH-33及該等之混合物等，該等可根據本身即公知之方法，例如日本特公昭57-53100號公報記載之方法或以該等為基準之方法製造。 The low-substituted hydroxypropylcellulose having an HPC content of about 5.0 to 7.0% may, for example, be LH-23, LH-33, and the like, and the like may be a method known per se, for example, Japanese Patent Publication No. 57 A method described in the publication No. -53100 or a method based on the above.

「羥基丙氧基含量為5.0至7.0重量%之低取代度羥丙基纖維素」之粒徑係例如平均粒徑為約5至60μm，較好為約10至40μm。 The particle diameter of the "low-substituted hydroxypropylcellulose having a hydroxypropoxy group content of 5.0 to 7.0% by weight" is, for example, an average particle diameter of about 5 to 60 μm, preferably about 10 to 40 μm.

在該等範圍中，若使用粒徑較大的L-HPC(例如，平均粒徑為約26至40μm之L-HPC)，則可製造崩解性優越之製劑。另一方面，若使用粒徑較小之L-HPC(例如，平均粒徑為約10至25μm之L-HPC)，則可製造製劑強度優越之製劑。 In such a range, if a large particle size L-HPC (for example, L-HPC having an average particle diameter of about 26 to 40 μm) is used, a formulation having excellent disintegration properties can be produced. On the other hand, if L-HPC having a small particle diameter (for example, L-HPC having an average particle diameter of about 10 to 25 μm) is used, a preparation excellent in the strength of the preparation can be produced.

因此，L-HPC之粒徑可根據作為目的之製劑特性而適當選擇。 Therefore, the particle diameter of L-HPC can be appropriately selected depending on the characteristics of the preparation for the purpose.

關於HPC基含量為5.0至7.0重量%之低取代度羥丙基纖維素、HPC基含量為7.0至9.9%之該低取代度羥丙基纖維素，為了獲得充分之口腔內崩解性及充分之製劑強度，故相對於「含有包含PPI之腸溶性細粒的層」中的「包含PPI之腸溶性細粒」以外之成分100重量份，通常使用0至約50重量份，較好為使用0至約40重量份，更好為 使用0至約20重量份。 The low-substituted hydroxypropylcellulose having a HPC group content of 5.0 to 7.0% by weight and the HPC group content of 7.0 to 9.9%, in order to obtain sufficient oral disintegration and sufficient The strength of the preparation is usually from 0 to 50 parts by weight, preferably from 100 parts by weight, based on 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". 0 to about 40 parts by weight, more preferably From 0 to about 20 parts by weight is used.

上述「黏合劑」可列舉例如羥丙基纖維素、羥丙基甲基纖維素、結晶纖維素、α化澱粉、聚乙烯基吡咯啶酮、***膠粉末、明膠、普路蘭(pullulan)、低取代度羥丙基纖維素等。該黏合劑使用結晶纖維素時，可在保持優越之口腔內崩解性之情況下，獲得製劑強度更大之固形製劑。 Examples of the above-mentioned "adhesive" include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, gelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, and pullulan. Low substitution hydroxypropyl cellulose and the like. When the binder is a crystalline cellulose, a solid preparation having a stronger preparation can be obtained while maintaining excellent disintegration in the oral cavity.

上述「酸味劑」可列舉例如檸檬酸(無水檸檬酸)、酒石酸、蘋果酸等。 Examples of the above "acidulant" include citric acid (anhydrous citric acid), tartaric acid, malic acid and the like.

上述「發泡劑」可列舉例如鹼金屬碳酸鹽(例如碳酸鈉、碳酸鉀等)、鹼金屬碳酸氫鹽(例如碳酸氫鈉、碳酸氫鉀等)及碳酸銨等。 Examples of the "foaming agent" include an alkali metal carbonate (for example, sodium carbonate or potassium carbonate), an alkali metal hydrogencarbonate (for example, sodium hydrogencarbonate or potassium hydrogencarbonate), and ammonium carbonate.

上述「人口甜味料」可列舉例如糖精鈉、甘草酸二鉀、阿斯巴甜(aspartame)、甜菊(stevia)、索馬甜(thaumatin)等。 Examples of the above-mentioned "population sweetener" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

上述「香料」可為合成物及天然物之任何一種，可列舉例如檸檬、萊姆、橘子、薄荷、草莓等。 The above-mentioned "fragrance" may be any of a composition and a natural product, and examples thereof include lemon, lime, orange, mint, strawberry, and the like.

上述「潤滑劑」可列舉例如硬脂酸鎂、蔗糖脂肪酸酯、聚乙二醇、滑石粉、硬脂酸、硬化油等。 Examples of the "lubricant" include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, and hardened oil.

上述「著色劑」可列舉例如食用黃色5號、食用紅色2號、食用藍色2號等食用色素；食用色澱色素、氧化鐵紅等。 Examples of the "coloring agent" include food coloring agents such as edible yellow No. 5, edible red No. 2, and edible blue No. 2; edible lake coloring matter, iron oxide red, and the like.

上述「安定化劑」可列舉上述之鹼性無機鹽等。 Examples of the above-mentioned "stabilizing agent" include the above-mentioned basic inorganic salts and the like.

上述「賦形劑」可列舉例如乳糖、白糖、D-甘露糖醇、澱粉、玉米澱粉、結晶纖維素、輕質無水矽酸、氧化鈦等。 Examples of the "excipient" include lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous citric acid, titanium oxide, and the like.

上述「崩解劑」可使用在製劑領域慣用之崩解劑，可列舉例如(1)交聯聚維酮(例如交聯聚維酮CL-F)、(2)交聯羧甲基纖維素鈉(FMC-旭化成公司製造)、羧甲基纖維素鈣(五德藥品公司製造)等被稱為超級崩解劑之崩解劑、(3)羧甲基澱粉鈉(例如松谷化學股份有限公司製造)、(4)低取代度羥丙基纖維素(例如信越化學股份有限公司製造)、(5)玉米澱粉、(6)偏矽酸鋁鎂(例如鈕西林(neusilin)UFL2)等。更佳之崩解劑為例如交聯聚維酮及/或偏矽酸鋁鎂。 The above-mentioned "disintegrant" may be a disintegrator which is conventionally used in the field of preparation, and examples thereof include (1) crospovidone (for example, crospovidone CL-F) and (2) croscarmellose. Sodium (made by FMC-Asahi Kasei Co., Ltd.), carboxymethylcellulose calcium (manufactured by Wude Pharmaceutical Co., Ltd.), etc. is called a disintegrant of super disintegrant, and (3) sodium carboxymethyl starch (for example, Songgu Chemical Co., Ltd.) (manufacturing), (4) low-substituted hydroxypropyl cellulose (for example, manufactured by Shin-Etsu Chemical Co., Ltd.), (5) corn starch, (6) aluminum magnesium metasilicate (such as neusilin UFL2), and the like. More preferred disintegrants are, for example, crospovidone and/or aluminum magnesium metasilicate.

該「交聯聚維酮」亦包含被稱為聚乙烯基聚吡咯啶酮(PVPP)、1-乙烯基-2-吡咯啶酮均聚物者，可為具有稱為1-乙烯基-2-吡咯啶酮均聚物之化學名且經交聯之聚合物之任何一種，具體例為克利酮(Kollidon)CL(BASF公司製造)、聚維酮(polyplasdone)XL(ISP公司製造)、聚維酮XL-10(ISP公司製造)、聚維酮INF-10(ISP公司製造)等。通常分子量超過1,000,000。 The "cross-linked povidone" also includes a polyvinyl polypyrrolidone (PVPP), 1-vinyl-2-pyrrolidone homopolymer, which may have a 1-vinyl-2 Any one of the chemical names of the pyrrolidone homopolymer and the crosslinked polymer, and specific examples thereof are Kollidon CL (manufactured by BASF Corporation), polyplasdone XL (manufactured by ISP), and poly Waxone XL-10 (manufactured by ISP), povidone INF-10 (manufactured by ISP), and the like. Usually the molecular weight exceeds 1,000,000.

該等崩解劑除了可單獨使用之外，亦可併用二種以上。可列舉例如單獨使用交聯聚維酮，或併用交聯聚維酮與其他之崩解劑。 These disintegrators may be used alone or in combination of two or more. For example, crospovidone may be used alone or crospovidone may be used in combination with other disintegrants.

相對於「含有包含PPI之腸溶性細粒的層」中的「包含PPI之腸溶性細粒」以外之成分100重量份，該等崩解劑通常使用約3至約20重量份，較好為使用約5至約18重量份。 The disintegrating agent is usually used in an amount of from about 3 to about 20 parts by weight, based on 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". About 5 to about 18 parts by weight are used.

本發明中之「包含PPI之腸溶性細粒」亦可含有作為隱蔽劑之例如氧化鈦等。 The "enteric soluble fine particles containing PPI" in the present invention may contain, for example, titanium oxide or the like as a concealing agent.

本專利申請案之發明中，「含有包含PPI之腸溶性細粒的層」之較佳態樣為含有1)將含有PPI之組成物以腸溶性包覆層包覆之細粒(較好為平均粒徑約400μm以下之細粒)、2)在該腸溶性細粒以外之部分中含有制酸劑及3)上述添加劑之層。 In the invention of the present application, a preferred embodiment of the "layer containing enteric fine particles containing PPI" is a fine particle containing 1) a composition containing PPI coated with an enteric coating layer (preferably A fine particle having an average particle diameter of about 400 μm or less), 2) a layer containing an acid generator and 3) the above additive in a portion other than the enteric fine particles.

尤其是含有1)將含有PPI之組成物以腸溶性包覆層包覆之細粒(較好為平均粒徑約400μm以下之細粒)、2)在該腸溶性細粒以外之部分中含有制酸劑及添加劑(i)之造粒物、以及3)另在該腸溶性細粒及該造粒物以外之部分中含有添加劑(ii)之層。 In particular, it contains 1) fine particles (preferably fine particles having an average particle diameter of about 400 μm or less) coated with an enteric coating layer, and 2) contained in a portion other than the enteric fine particles. The antacid and the granulated product of the additive (i), and 3) a layer containing the additive (ii) in the portion other than the enteric fine particle and the granulated product.

添加物(i)及(ii)可從上述之水溶性糖醇、結晶纖維素、低取代度羥丙基纖維素、黏合劑、酸味料、發泡劑、人口甜味料、香料、潤滑劑、著色劑、安定化劑、賦形劑、崩解劑等中適當選擇。 Additives (i) and (ii) may be derived from the above-mentioned water-soluble sugar alcohols, crystalline cellulose, low-substituted hydroxypropyl cellulose, binders, sour materials, foaming agents, bulk sweeteners, perfumes, lubricants A colorant, a stabilizer, an excipient, a disintegrator or the like is appropriately selected.

其中，添加物(i)較好為：甘露糖醇等水溶性糖醇；結晶纖維素等賦形劑；羥丙基纖維素等黏合劑。 Among them, the additive (i) is preferably a water-soluble sugar alcohol such as mannitol, an excipient such as crystalline cellulose, or a binder such as hydroxypropylcellulose.

添加物(ii)較好為：交聯聚維酮、偏矽酸鋁鎂等崩解劑；結晶纖維素等賦形劑；硬脂酸鎂等潤滑劑等。 The additive (ii) is preferably a disintegrant such as crospovidone or aluminum magnesium metasilicate; an excipient such as crystalline cellulose; a lubricant such as magnesium stearate or the like.

(2)「含有乙醯水楊酸的層」 (2) "Layer containing acetyl salicylic acid"

本發明之積層之口腔內崩解錠中之「含有乙醯水楊酸的層」係含有：1)乙醯水楊酸及2)添加劑。 The "layer containing acetamidine salicylic acid" in the laminated orally disintegrating tablet of the present invention contains: 1) acetamidine salicylic acid and 2) an additive.

乙醯水楊酸之含量在每錠為約70至約400mg。關於每錠之乙醯水楊酸之含量，就非類固醇性抗炎症藥(NSAIDs)而言，主要以治療疼痛、發燒、炎症為目的時，調配約250 至約400mg。 The content of acetyl salicylic acid is from about 70 to about 400 mg per ingot. Regarding the content of acetyl salicylic acid per ingot, for non-steroidal anti-inflammatory drugs (NSAIDs), mainly for the purpose of treating pain, fever, inflammation, about 250 Up to about 400mg.

另一方面，以抑制在腦血管、循環器領域之疾病中之血栓/栓塞形成(抗血小板療法)等為目的時，調配約70mg至約120mg。 On the other hand, when it is intended to suppress thrombus/embolization (anti-platelet therapy) in diseases such as cerebral blood vessels and circulators, about 70 mg to about 120 mg is formulated.

前述「添加劑」係使用上述之水溶性糖醇、結晶纖維素、低取代度羥丙基纖維素、黏合劑、酸味料、發泡劑、人口甜味料、香料、潤滑劑、著色劑、安定化劑、賦形劑等，較好為使用水溶性糖醇、酸味料、人口甜味料、潤滑劑、賦形劑等。另外，亦可使用羧甲基纖維素(carmellose)、交聯羧甲基纖維素鈉、結晶纖維素、α化澱粉、明膠等崩解劑或輕質無水矽酸、含水二氧化矽、滑石粉、硬脂酸等液態化劑。 The aforementioned "additives" are the above-mentioned water-soluble sugar alcohols, crystalline cellulose, low-substituted hydroxypropyl cellulose, binders, sour materials, foaming agents, pops, flavors, lubricants, colorants, and stability. As the agent, excipient or the like, it is preferred to use a water-soluble sugar alcohol, a sour material, a sweetener, a lubricant, an excipient or the like. In addition, carboxymethylcellulose (carmellose), croscarmellose sodium, crystalline cellulose, gelatinized starch, gelatin and other disintegrants or light anhydrous citric acid, aqueous cerium oxide, talcum powder may also be used. , liquefied agent such as stearic acid.

上述之成分中，水溶性糖醇可列舉甘露糖醇、木糖醇、赤藻糖醇，更好為甘露糖醇。 Among the above components, the water-soluble sugar alcohol may, for example, be mannitol, xylitol or erythritol, and more preferably mannitol.

相對於「含有乙醯水楊酸的層」100重量份，該水溶性糖醇之調配量為約10至約100重量份，較好為約25至約85重量份。 The water-soluble sugar alcohol is formulated in an amount of from about 10 to about 100 parts by weight, preferably from about 25 to about 85 parts by weight, per 100 parts by weight of the "layer containing acetamidine salicylic acid".

從抑制打錠障礙之觀點而言，潤滑劑較好為使用硬化油。尤其是將硬脂酸鎂等作為潤滑劑使用時，乙醯水楊酸之安定性會降低，發生打錠障礙。 From the viewpoint of suppressing the barging barrier, the lubricant is preferably a hardened oil. In particular, when magnesium stearate or the like is used as a lubricant, the stability of acetyl salicylic acid is lowered, and tableting failure occurs.

相對於「含有乙醯水楊酸的層」100重量份，潤滑劑之調配量為約0.5至約10重量份，較好為約0.5至約7重量份。 The lubricant is formulated in an amount of from about 0.5 to about 10 parts by weight, preferably from about 0.5 to about 7 parts by weight, per 100 parts by weight of the "layer containing acetamidine salicylic acid".

從提昇乙醯水楊酸安定性之觀點而言，崩解劑較好為 使用羧甲基纖維素(carmellose)。 From the viewpoint of improving the stability of acetaminophen salicylic acid, the disintegrant is preferably Carmellose was used.

相對於「含有乙醯水楊酸的層」100重量份，崩解劑之調配量為約1至約20重量份，較好為約5至約15重量份。 The disintegrant is formulated in an amount of from about 1 to about 20 parts by weight, preferably from about 5 to about 15 parts by weight, per 100 parts by weight of the "layer containing acetamidine salicylic acid".

乙醯水楊酸及添加劑可以原狀進行均質混合，亦可使用乙醯水楊酸與賦形劑之預混合品(例如乙醯水楊酸：玉米澱粉=90：10，乾式造粒品)，與其他添加劑一起均質混合使用。 Acetyl salicylic acid and additives may be mixed as they are, or may be premixed with acetaminosalicylic acid and excipients (for example, acetyl salicylic acid: corn starch = 90:10, dry granulated product). Mix well with other additives.

本發明之口腔內崩解錠中使用之乙醯水楊酸係以不經腸溶包覆者較佳。 The acetaminosalicylic acid used in the orally disintegrating tablet of the present invention is preferably coated without enteric coating.

(3)積層之口腔內崩解錠 (3) laminated intraoral disintegration ingot

積層之口腔內崩解錠之錠劑重量為約300mg至約800mg。「含有包含PPI之腸溶性細粒的層」與「含有乙醯水楊酸的層」之重量比為約10：1至約1：10，較好為約5：1至約1：5，更好為約3：1至約1：3較理想。 The tablet of the laminar orally disintegrating tablet has a weight of from about 300 mg to about 800 mg. The weight ratio of "layer containing enteric fine particles containing PPI" to "layer containing acetamidine salicylic acid" is from about 10:1 to about 1:10, preferably from about 5:1 to about 1:5. More preferably from about 3:1 to about 1:3 is preferred.

本發明之「口腔內崩解錠」係經由在製劑領域中慣用之方法製造。 The "intraoral disintegration tablet" of the present invention is produced by a method conventionally used in the field of preparation.

[製造法1] [Manufacturing Method 1]

用以構築「含有包含PPI之腸溶性細粒的層」之組成物，係例如可藉由將「包含PPI之腸溶性細粒」與「添加劑」根據本身即公知之方法混合而製造(組成物1)。 The composition for "construction of a layer containing enteric fine particles containing PPI" can be produced, for example, by mixing "insoluble fine particles containing PPI" and "additive" according to a known method. 1).

用以構築「含有乙醯水楊酸的層」之組成物，係可藉由將乙醯水楊酸與「添加物」根據本身即公知之方法混合，並以原狀或根據期望而經由本身即公知之方法進行造粒， 而製造(組成物2)。 The composition for constructing the "layer containing acetamidine salicylic acid" can be mixed with the "additive" according to a method known per se, and can be passed as it is or as desired. a known method for granulation, And manufactured (composition 2).

藉由將組成物1與組成物2以本身即公知之打錠法打錠，即可製造積層之口腔內崩解錠。 A laminated intraoral disintegrating ingot can be produced by ingoting the composition 1 and the composition 2 by a known ingot method.

[製造法2] [Manufacturing Method 2]

在「含有包含PPI之腸溶性細粒的層」中，在「添加劑」中調配制酸劑時，可將1)制酸劑與2)賦形劑、黏合劑、崩解劑等添加劑先暫時混合後，經由流動層造粒法、高速攪拌造粒法等方法造粒，並根據期望而乾燥，以製造細粒(組成物3)。 In the "layer containing enteric fine particles containing PPI", when the acid agent is prepared in the "additive", the additives such as 1) antacid and 2) excipients, binders, disintegrators, etc. may be temporarily suspended. After mixing, granulation is carried out by a method such as a fluidized bed granulation method or a high-speed stirring granulation method, and dried as desired to produce fine particles (composition 3).

經由將該組成物3、「包含PPI之腸溶性細粒」及其他添加劑(崩解劑、人口甜味料、賦形劑、潤滑劑等)混合，而製造用以構築「含有包含PPI之腸溶性細粒的層」之組成物，藉由將其與上述組成物2一起進行打錠，即可製造積層之口腔內崩解錠。 By mixing the composition 3, "the enteric fine particles containing PPI", and other additives (disintegrant, bulk sweetener, excipient, lubricant, etc.), it is manufactured to construct "the intestine containing the PPI. By laminating the composition of the layer of the soluble fine particles together with the above composition 2, a laminated orally disintegrating ingot can be produced.

「混合」根據通常使用之混合方法，例如混合、練合、造粒等進行。該「混合」係使用例如立式造粒機(vertical granulator)VG10(帕雷克公司製造)、萬能練合機(畑鐵工所製造)、流動層造粒機LAB-1、FD-3A(帕雷克公司製造)、V型混合機、轉鼓(tumbler)混合機等裝置進行。 The "mixing" is carried out according to a commonly used mixing method such as mixing, blending, granulation, and the like. The "mixing" is, for example, a vertical granulator VG10 (manufactured by Parek Corporation), a universal machine (manufactured by 畑铁工工), a fluidized layer granulator LAB-1, FD-3A ( It is carried out by a device such as a Parec company, a V-type mixer, and a tumbler mixer.

上述製造法中之「造粒法」可列舉：轉動造粒法(例如離心轉動造粒法)、流動造粒法(例如轉動流動層造粒、流動造粒等)、攪拌造粒法等。其中，較好為流動造粒法。更好為轉動流動層造粒法。 Examples of the "granulation method" in the above production method include a tumbling granulation method (for example, centrifugal granulation granulation method), a flow granulation method (for example, turbulent flow layer granulation, flow granulation, etc.), a stirring granulation method, and the like. Among them, the flow granulation method is preferred. Better granulation for rotating the flow layer.

該轉動造粒法之具體例可列舉例如使用佛洛因德公 司製造之「CF裝置」等之方法。該轉動流動層造粒法之具體例可列舉使用例如「司必拉流動管(spiraflow)」、帕雷克公司製造之「多重回路(Multiplex)」、不二帕塔魯公司製造之「新瑪路美(New Marume)」等之方法。混合液之噴霧方法可根據造粒裝置之種類適當選擇，可為例如頂噴霧方式、底噴霧方式、切線噴霧方式等中之任何一種方法。其中，較好為切線噴霧方式。 Specific examples of the tumbling granulation method include, for example, the use of Freund The method of "CF device" manufactured by the company. Specific examples of the tumbling flow layer granulation method include, for example, "spiraflow", "multiplex" manufactured by Parek, and "Xinma" manufactured by Fujita. Ways such as New Marume. The spraying method of the mixed solution can be appropriately selected depending on the type of the granulating device, and may be any one of a top spray method, a bottom spray method, a tangential spray method, and the like. Among them, a tangential spray method is preferred.

「打錠」係使用單發錠劑機(菊水製作所製造)、旋轉式打錠機(菊水製作所製造)、旋轉式積層打錠機(畑鐵工所製造)等，以1至80kN/cm²、5至50kN/cm²之壓力，較好以15至40kN/cm²之壓力進行打錠。又，若為旋轉式打錠機時，只要以通常之旋轉數，例如3至40min^-1，較好為3至30min^-1，更好為5至25min^-1進行打錠即可。 "Ingot" is a single-shot tablet machine (manufactured by Kikusui Seisakusho Co., Ltd.), a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.), a rotary laminating ingot machine (manufactured by Nippon Iron Works Co., Ltd.), etc., at 1 to 80 kN/cm ^{2 .} , a pressure of 5 to 50kN / cm ^2, the pressure is preferably tableted 15 to 40kN / cm ² of. Further, in the case of a rotary type ingot machine, it is only necessary to perform ingot casting at a normal number of rotations, for example, 3 to 40 min ^-1 , preferably 3 to 30 min ^-1 , more preferably 5 to 25 min ^-1 .

本發明中之口腔內崩解錠之形態，從錠劑強度之觀點而言，以打錠面有曲面較佳，亦可一部分含有平面。 In the form of the orally disintegrating ingot of the present invention, from the viewpoint of the strength of the tablet, the ingot surface has a curved surface, and a part thereof may have a flat surface.

「乾燥」可根據例如真空乾燥、流動層乾燥等製劑通常乾燥使用之任何一種方法。較好為經由真空乾燥進行乾燥。 "Drying" can be carried out by any of the methods usually used for drying, such as vacuum drying, fluidized bed drying, and the like. Drying is preferably carried out by vacuum drying.

本發明之口腔內崩解錠之打錠方法可在室溫下進行，亦可在超過室溫之溫度中進行打錠。「室温」係指通常在製造錠劑時進行打錠之室內温度，該溫度通常為約20℃至約23℃。「超過室溫之溫度」為超過該溫度之溫度，較好只要下限為約25℃即可。該溫度係根據使用之原料粉末或細粒等而異，但通常較好為約25℃至約50℃。該溫可 根據所期望錠劑之品質加以變更。 The tableting method of the orally disintegrating tablet of the present invention can be carried out at room temperature, or can be carried out at a temperature exceeding room temperature. "Room temperature" means the room temperature at which the tableting is usually carried out at the time of manufacture of the tablet, and the temperature is usually from about 20 ° C to about 23 ° C. The "temperature exceeding room temperature" is a temperature exceeding the temperature, and preferably the lower limit is about 25 °C. The temperature varies depending on the raw material powder or fine particles used, but is usually preferably from about 25 ° C to about 50 ° C. The warm It is changed according to the quality of the desired tablet.

本發明之口腔內崩解錠較好係作成具有「含有包含PPI之腸溶性細粒的層」及「含有乙醯水楊酸的層」之雙層錠，在「含有包含PPI之腸溶性細粒的層」與「含有乙醯水楊酸的層」之間可具有中間層。 The orally disintegrating tablet of the present invention is preferably a double-layer ingot having "a layer containing enteric fine particles containing PPI" and "a layer containing acetyl salicylic acid", and "containing enteric fines containing PPI" There may be an intermediate layer between the "layer of particles" and the "layer containing acetamidine salicylic acid".

經由該中間層，可藉由遮斷「含有包含PPI之腸溶性細粒的層」與「含有乙醯水楊酸的層」之直接接觸，而更加提昇PPI及乙醯水楊酸之安定性。 Through the intermediate layer, the stability of PPI and acetyl salicylic acid can be further improved by blocking the direct contact between "a layer containing enteric fine particles containing PPI" and "a layer containing acetamidine salicylic acid". .

上述中間層用之材料可列舉例如在低取代度羥丙基纖維素、羥丙基纖維素、羥丙基甲基纖維素(例如TC-5等)、聚乙烯基吡咯啶酮、聚乙烯醇、甲基纖維素、羥乙基甲基纖維素等高分子基材中適當調配蔗糖[精製白糖(經粉碎者(粉糖)或未經粉碎者)等]、玉米澱粉等澱粉糖、乳糖、蜂蜜及糖醇(D-甘露糖醇、赤藻糖醇等)等糖類者等。另外，對於中間層，有必要時可適當加入賦形劑(例如隱蔽劑(氧化鈦等)、抗靜電劑(氧化鈦、滑石粉等))等。 The material for the above intermediate layer may, for example, be a low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (for example, TC-5, etc.), polyvinylpyrrolidone, or polyvinyl alcohol. , such as methyl cellulose, hydroxyethyl methyl cellulose and other polymer substrates, sucrose (refined white sugar (powdered sugar) or unsmashed), corn starch, starch sugar, lactose, etc. Honey and sugar alcohol (D-mannitol, erythritol, etc.) and other sugars. Further, as the intermediate layer, an excipient (for example, a concealing agent (titanium oxide or the like), an antistatic agent (titanium oxide, talc, etc.)) or the like may be appropriately added as necessary.

關於錠劑中之中間層之調配量，在錠劑每錠中通常為約5重量份至約50重量份，較好為約10至約45重量份。 The amount of the intermediate layer in the tablet is usually from about 5 parts by weight to about 50 parts by weight, preferably from about 10 to about 45 parts by weight, per tablet.

中間層之形成可根據常法進行。 The formation of the intermediate layer can be carried out according to the usual method.

又，中間層不只可為1層，亦可形成複數層(較好為2至3層)。 Further, the intermediate layer may be not only one layer but also a plurality of layers (preferably 2 to 3 layers).

關於本發明之「口腔內崩解錠」，錠劑之直徑若作成約5至20mm，較好為約7至15mm，更好為約8至13mm，則有利於服用之處理。 In the "oral disintegration tablet" of the present invention, the diameter of the tablet is preferably about 5 to 20 mm, preferably about 7 to 15 mm, more preferably about 8 to 13 mm, which is advantageous for the treatment.

本發明之「口腔內崩解錠」顯示在口腔內迅速之崩解性或溶解性、以及適當之製劑強度。 The "oral disintegration tablet" of the present invention exhibits rapid disintegration or solubility in the oral cavity, and an appropriate formulation strength.

本發明之口腔內崩解錠之口腔內崩解時間(使用健康成人男性及女性口腔內之唾液，直到口腔內崩解錠完全崩解為止之時間)係在約60秒以內，通常在約50秒以內，較好為在約40秒以內。 The intraoral disintegration time of the orally disintegrating tablet of the present invention (the time from the use of saliva in healthy adult males and female oral cavities until the disintegrating ingot in the oral cavity completely disintegrates) is within about 60 seconds, usually at about 50 Within seconds, preferably within about 40 seconds.

另外，本發明之口腔內崩解錠之崩解時間(使用藥典記載之崩解試驗裝置，且使用水作為試驗液，液溫為37±2℃，實施崩解試驗時之直到口腔崩解錠完全崩解為止之時間)係在約90秒以內，較好為在約60秒以內，更好為在約50秒以內。 Further, the disintegration time of the orally disintegrating tablet of the present invention (using the disintegration test device described in the Pharmacopoeia, using water as a test solution, the liquid temperature is 37 ± 2 ° C, and the disintegration test is carried out until the orally disintegrating ingot The time until complete disintegration is within about 90 seconds, preferably within about 60 seconds, more preferably within about 50 seconds.

又，本發明之口腔內崩解錠具有在製劑步驟、流通過程中不會損傷之程度之適當硬度，口腔內崩解錠之強度(由錠劑硬度計所測定之值)通常為約20至約100N，更好為約30至約90N。 Further, the orally disintegrating tablet of the present invention has an appropriate hardness to such an extent that it is not damaged during the formulation step and the circulation, and the strength of the orally disintegrating tablet (the value measured by the tablet hardness meter) is usually about 20 to About 100N, more preferably from about 30 to about 90N.

本發明之口腔內崩解錠可不用水或可與水一起服用。服用方法可列舉：(1)含在口中不吞下，以少量水或不用水而以口腔內之唾液，使其溶解或崩解而服用之方法；或是(2)與水一起吞下之服用方法。又，亦可將錠劑以水溶解或崩解後，再服用。 The orally disintegrating tablet of the present invention may be used without water or with water. The method of administration may be exemplified by: (1) a method of taking it in the mouth without swallowing it, using a small amount of water or not using water to dissolve or disintegrate it in the oral cavity; or (2) swallowing it with water. How to take it. Further, the tablet may be dissolved or disintegrated in water and then taken.

本發明之口腔內崩解錠由於含有PPI，故具有優越的抗潰瘍作用、抑制胃酸分泌作用、保護黏膜作用、抗幽門螺旋桿菌(Helicobacter pylori)作用等。 Since the orally disintegrating tablet of the present invention contains PPI, it has an excellent anti-ulcer effect, inhibits gastric acid secretion, protects mucosa, and acts against Helicobacter pylori.

另一方面，本發明之口腔內崩解錠由於含有乙醯水楊 酸，故可作為抑制在腦血管、循環器領域之疾病，例如狹心症(慢性安定狹心症、不安定狹心症)、心肌梗塞中之血栓/栓塞之形成；預防/治療缺血性腦血管障礙(暫時性腦缺血發作(TIA)、腦梗塞)；抑制在冠動脈繞道手術(CABG)或經皮經血管冠動脈形成術(PTCA)施行後之血栓/栓塞之形成；川崎病(包含因川崎病所引起之心血管後遺症)之預防/治療劑使用。因此，以一邊繼續投予乙醯水楊酸且一邊治療或抑制胃潰瘍或十二指腸潰瘍之發病為目的，可投予本專利申請案之口腔內崩解錠。以預防/治療相關疾病為目的時，PPI每日投藥約10mg至約40mg，乙醯水楊酸每日投藥約70mg至約120mg(低劑量)。 On the other hand, the orally disintegrating tablet of the present invention contains Ethylhydrazine Acid, it can be used as a disease inhibiting the formation of cerebrovascular and circulatory diseases, such as angina (chronic stability angina, restless angina), thrombosis / embolism in myocardial infarction; prevention / treatment of ischemic Cerebrovascular disorder (temporary ischemic attack (TIA), cerebral infarction); inhibition of thrombus/embolization after coronary artery bypass surgery (CABG) or percutaneous transluminal coronary angioplasty (PTCA); Kawasaki disease (including Use of preventive/therapeutic agents for cardiovascular sequelae caused by Kawasaki disease. Therefore, the orally disintegrating ingot of the present patent application can be administered for the purpose of continuing to administer acetaminosaliside while treating or inhibiting the onset of gastric ulcer or duodenal ulcer. For the purpose of preventing/treating a related disease, PPI is administered from about 10 mg to about 40 mg per day, and acetaminosalicylic acid is administered from about 70 mg to about 120 mg per day (low dose).

又，乙醯水楊酸亦可作為非類固醇性抗炎症藥(NSAIDs)之一種，而用於治療疼痛、發燒、炎症。由於NSAIDs會引起胃潰瘍或十二指腸潰瘍，尤其是在治療風濕性關節炎或變形性關節炎等時會使QOL降低，故有難以停止投予NSAIDs之情況。在該等情況下，以一邊繼續投予NSAIDs且一邊治療或抑制胃潰瘍或十二指腸潰瘍之發病為目的，可投予本專利發明案之口腔內崩解錠。 In addition, acetaminophen can also be used as a non-steroidal anti-inflammatory drug (NSAIDs) for the treatment of pain, fever, and inflammation. Since NSAIDs cause gastric ulcer or duodenal ulcer, especially when treating rheumatoid arthritis or deformed arthritis, QOL is lowered, so it is difficult to stop the administration of NSAIDs. In such cases, the orally disintegrating ingot of the present invention can be administered for the purpose of continuing to administer NSAIDs while treating or inhibiting the onset of gastric ulcer or duodenal ulcer.

以如此之治療為目的時，PPI每日投藥約10mg至約40mg，乙醯水楊酸每日投藥約240mg至約400mg。 For the purpose of such treatment, PPI is administered from about 10 mg to about 40 mg per day, and acetaminosalicylic acid is administered from about 240 mg to about 400 mg per day.

因此，如此之本發明之口腔內崩解錠係可作為毒性低且安全之PPI與乙醯水楊酸之併用醫藥使用。 Therefore, the orally disintegrating ingot of the present invention can be used as a combination of PPI and acetaminosalicylic acid which are low in toxicity and safe.

就本發明之口腔內崩解錠而言，對於哺乳動物(例如人類、猴子、羊、馬、狗、貓、兔子、大鼠(rat)、小鼠(mouse) 等)，以抑制腦血管、循環器領域之疾病中之血栓/栓塞之形成，治療及預防由非類固醇性抗炎症劑所造成之潰瘍等為目的，可進行經口投予。 For the orally disintegrating ingot of the present invention, for mammals (for example, humans, monkeys, sheep, horses, dogs, cats, rabbits, rats, mice) Etc., for the purpose of inhibiting the formation of thrombus/embolism in diseases in the field of cerebral blood vessels and circulators, and treating and preventing ulcers caused by non-steroidal anti-inflammatory agents, for oral administration.

又，除了上述目的以外，為了將幽門螺旋桿菌除菌或輔助除菌，可將本發明之口腔內崩解錠與盤尼西林系抗生素(例如安莫西林(amoxicillin)等)及紅黴素系抗生素(例如開羅理黴素(clarithromycin))合併使用。 Further, in addition to the above object, in order to sterilize or assist in sterilization of H. pylori, the orally disintegrating ingot of the present invention may be combined with penicillin-based antibiotics (for example, amoxicillin) and erythromycin-based antibiotics ( For example, clarithromycin is used in combination.

本發明之固形製劑的1日之投予量係根據症狀之程度、投予對象之年齡、性別、體重、投予時期、間隔、有效成分之種類等而異，並無特別限制。又，本發明之口腔內崩解錠可1日1次或分成2至3次投予。 The dose of the solid preparation of the present invention for one day is not particularly limited depending on the degree of symptoms, the age, sex, body weight, administration period, interval, and type of active ingredient of the subject to be administered. Further, the orally disintegrating tablet of the present invention can be administered once a day or divided into two to three times.

[實施例] [Examples]

以下，根據參考例、實施例及評估(試驗例)對本發明作更詳細之說明，惟本發明不只限於該等例。以下，在參考例、實施例中使用之製劑添加劑係使用藥典適合品/醫藥品添加物規格適合品。 Hereinafter, the present invention will be described in more detail based on Reference Examples, Examples, and Evaluations (Test Examples), but the present invention is not limited to the examples. Hereinafter, the formulation additives used in the reference examples and the examples are suitable for the Pharmacopoeia Applicables/Pharmaceutical Additives.

參考例1 Reference example 1 蘭素拉唑腸溶性細粒之製造 Manufacture of lansprazole enteric fine granules 主藥細粒 Main drug fine

將極品(nonpareil)105(商品名)39.6kg放入轉動流動層型塗佈造粒機(帕雷克公司製造，MP-400)中，將預先調製之下述組成之主藥塗佈液噴霧塗佈。另將預先調製之 下述組成之中間層塗佈液噴霧塗佈。塗佈完成後，進行乾燥，獲得主藥細粒145.2kg。 39.6 kg of nonpareil 105 (trade name) was placed in a rotary flow layer type coating granulator (manufactured by Parek, MP-400), and a pre-mixed main drug coating liquid of the following composition was sprayed. Coating. Pre-modulation The intermediate layer coating liquid of the following composition was spray-coated. After the coating was completed, it was dried to obtain 145.2 kg of main drug fine particles.

〔主藥塗佈液〕 [main drug coating solution]

[中間層塗佈液] [Intermediate layer coating solution]

蘭素拉唑腸溶性細粒 Lansalazole enteric fine granule

將主藥細粒44.0kg放入轉動流動層型塗佈造粒機(帕雷克公司製造，MP-400)中，將預先調製之下述組成之腸溶性塗佈液1噴霧塗佈。接著，將預先調製之下述組成之腸溶性塗佈液2噴霧塗佈。另將預先調製之防護塗佈(overcoating)液噴霧塗佈。塗佈完成後，進行乾燥，獲得 蘭素拉唑腸溶性細粒108kg。 44.0 kg of the main drug fine particles were placed in a tumbling flow layer type coating granulator (manufactured by Parek, MP-400), and the enteric coating liquid 1 having the following composition prepared in advance was spray-coated. Next, the enteric coating liquid 2 of the following composition prepared previously was spray-coated. A pre-modulated overcoating solution was also spray coated. After coating is completed, drying is performed to obtain Lansalazole enteric fine particles 108kg.

[單硬脂酸甘油液] [monostearic acid glycerin solution]

[腸溶性塗佈液1] [Enteric coating liquid 1]

[腸溶性塗佈液2] [Enteric coating liquid 2]

[防護塗佈液] [Protective coating liquid]

實施例1 Example 1

秤取乙醯水楊酸預混品(乙醯水楊酸：玉米澱粉=90：10，乾式造粒品，羅迪亞(Rhodia)公司製造之羅迪(Rhoine)2312)1080g、甘露糖醇(羅克德(Roquette)公司製造之Pearlitol 200SD)924g、羧甲基纖維素240g、無水檸檬酸21.6g、阿斯巴甜24.0g、硬化油110.4g，予以混合，作為顆粒A。將甘胺酸鋁88.0g、碳酸鎂176.0g、甘露糖醇(羅克德公司製造之Pearlitol 200SD)403.3g、結晶纖維素47.7g在流動層乾燥機(帕雷克公司製造之LAB-1)中秤取，將5%羥丙基纖維素(HPC-L)溶液540.8g噴霧，進行造粒。然後予以乾燥，獲得顆粒。另外，將以相同地反覆操作而獲得之顆粒與先前製造之顆粒混合，作為顆粒B。秤取顆粒B 1113.0g、蘭素拉唑腸溶性細粒1620g、交 聯聚維酮179.4g、阿斯巴甜32.4g、結晶纖維素259.2g(旭化成公司製造之協歐拉斯KG-1000)、鈕西林(Neusilin)(富士化學公司製造，商品名)66.0g、硬脂酸鎂30.0g，予以混合，作成顆粒C。將顆粒A及顆粒C使用打錠機(RIVA公司製造之Piccola)以打錠壓11kN進行打錠，獲得直徑11mm之積層錠(製劑1)。將該製劑1每錠之組成表示於表1。 Weighing the yttrium salicylic acid premix (Ethyl salicylic acid: corn starch = 90:10, dry granulation, Rhoine 2312 by Rhodia) 1080g, mannitol (Pearlitol 200SD manufactured by Roquette Co., Ltd.) 924 g, 240 g of carboxymethylcellulose, 21.6 g of anhydrous citric acid, 24.0 g of aspartame, and 110.4 g of hardened oil were mixed as pellet A. 88.0 g of aluminum glycinate, 176.0 g of magnesium carbonate, 403.3 g of mannitol (Pearlitol 200SD manufactured by Rockford), and 47.7 g of crystalline cellulose were weighed in a fluidized bed dryer (LAB-1 manufactured by Parek). A solution of 540.8 g of a 5% hydroxypropylcellulose (HPC-L) solution was sprayed and granulated. It is then dried to obtain granules. Further, the particles obtained by the same operation in the same manner were mixed with the previously produced particles as the particles B. Weighing granule B 1113.0g, lansinazole, enteric fine granules 1620g, 179.4 g of videtone, 32.4 g of aspartame, 259.2 g of crystalline cellulose (Coordination KG-1000 manufactured by Asahi Kasei Co., Ltd.), and 66.0 g of Neusilin (trade name, manufactured by Fuji Chemical Co., Ltd.) 30.0 g of magnesium stearate was mixed and made into pellet C. The pellet A and the pellet C were subjected to tableting using a tableting machine (Piccola manufactured by RIVA Co., Ltd.) at a spindle pressure of 11 kN to obtain a laminated ingot having a diameter of 11 mm (formulation 1). The composition of each of the preparations 1 was shown in Table 1.

實施例2 Example 2

秤取乙醯水楊酸預混品(乙醯水楊酸：玉米澱粉=90：10，乾式造粒品，羅迪亞公司製造之羅迪2312)1800g、甘露糖醇(羅克德公司製造之Pearlitol 200SD)1540g、羧甲基纖維素400g、無水檸檬酸36.0g、阿斯巴甜40.0g、硬化油184.0g，予以混合，作為顆粒D。將甘露糖醇(羅克德公司製造之Pearlitol 200SD)604.9g、結晶纖維素71.5g在流動層乾燥機(帕雷克公司製造之MP-01)中秤取，將5%羥丙基纖維素溶液811.2g噴霧，進行造粒。然後乾燥，獲得顆粒E。秤取顆粒E 298.9g、蘭素拉唑腸溶性細粒675g、交聯聚維酮74.75g、阿斯巴甜13.52g、結晶纖維素108g(旭化成公司製造之協歐拉斯KG-1000)、鈕西林(富士化學公司製造，商品名)27.48g、硬脂酸鎂12.5g，予以混合，作為顆粒F。將顆粒D及顆粒F使用打錠機(RIVA公司製造Piccola)以打錠壓15kN進行打錠，獲得直徑11mm之積層錠(製劑2)。將該製劑2每錠之組成表示於表2。 Weighing the yttrium salicylic acid premix (Ethyl salicylic acid: corn starch = 90:10, dry granulated product, Rodi 2312 manufactured by Rodia) 1800g, mannitol (Pearlitol manufactured by Rockdale) 200 SD) 1540 g, 400 g of carboxymethylcellulose, 36.0 g of anhydrous citric acid, 40.0 g of aspartame, and 184.0 g of hardened oil were mixed as pellet D. 604.9 g of mannitol (Pearlitol 200SD manufactured by Rockford) and 71.5 g of crystalline cellulose were weighed in a fluidized bed dryer (MP-01 manufactured by Parek), and 5% hydroxypropylcellulose solution 811.2 g spray, granulation. It is then dried to obtain granule E. Weighing granules E 298.9 g, lansylazole enteric fine 675 g, crospovidone 74.75 g, aspartame 13.52 g, crystalline cellulose 108 g (Asahi Kasei Co., Ltd. Kia-KG-1000) 27.48 g of Nixil (manufactured by Fuji Chemical Co., Ltd., trade name) and 12.5 g of magnesium stearate were mixed and used as pellet F. The pellets D and the pellets F were tableted by a tableting machine (Piccola manufactured by RIVA Co., Ltd.) at a tableting pressure of 15 kN to obtain a laminated ingot having a diameter of 11 mm (formulation 2). The composition of each of the preparations 2 was shown in Table 2.

實施例3 Example 3

秤取乙醯水楊酸預混品(乙醯水楊酸：玉米澱粉=90：10，乾式造粒品，羅迪亞公司製造之羅迪2312)900g、甘露糖醇(羅克德公司製造之Pearlitol 200SD)760g、羧甲基纖維素200g、無水檸檬酸17.93g、阿斯巴甜20.0g、輕質無水矽酸10.0g、硬化油91.99g，予以混合，作為顆粒G。將甘胺酸鋁550.3g、碳酸鎂1100.2g、甘露糖醇(羅克德公司製造之Pearlitol 200SD)2545.5g、結晶纖維素298.0g在流動層乾燥機(佛洛因德公司製造之FLO-5M)中秤取，將7%羥丙基纖維素溶液2414g噴霧，進行造粒。然後乾燥，獲得顆粒。另外，將以相同地反覆操作而獲得之顆粒與先前製造之顆粒混合，作為顆粒H。秤取顆粒H 1091.7g、蘭素拉唑腸溶性細粒2025.2g、交聯聚維酮224.3g、阿斯巴甜40.5g、結晶纖維素323.8g(旭化成公司製造之協歐拉斯KG-1000)、鈕西林(富士化學公司製造，商品名)82.5g、硬脂酸鎂37.5g，混合，作為顆粒I。將顆粒G及顆粒I使用打錠機(RIVA公司製造之Piccola)以打錠壓8.6kN進行打錠，獲得直徑10mm之積層錠(製劑3)。將該製劑3每錠之組成表示於表3。 Weighing the yttrium salicylic acid premix (acetonitrile salicylic acid: corn starch = 90:10, dry granulated product, Rodi 2312 manufactured by Rodia) 900 g, mannitol (Pearlitol manufactured by Rockdale) 200 SD) 760 g, carboxymethylcellulose 200 g, anhydrous citric acid 17.93 g, aspartame 20.0 g, light anhydrous citric acid 10.0 g, and hardened oil 91.99 g were mixed as granule G. 550.3 g of aluminum glycinate, 1100.2 g of magnesium carbonate, 2545.5 g of mannitol (Pearlitol 200SD manufactured by Rockford), and 298.0 g of crystalline cellulose were used in a fluidized bed dryer (FLO-5M manufactured by Freund Corporation). After weighing, 2414 g of a 7% hydroxypropylcellulose solution was sprayed and granulated. It is then dried to obtain granules. Further, the particles obtained by the same operation in the same manner were mixed with the previously produced particles as the particles H. Weighing 109 H of granule H, 2025.2 g of lansile-carbazole enteric-coated fine granules, 224.3 g of crospovidone, 40.5 g of aspartame, and 323.8 g of crystalline cellulose (Co-Olas KG-1000 manufactured by Asahi Kasei Corporation) ), button Xilin (manufactured by Fuji Chemical Co., Ltd., trade name) 82.5 g, magnesium stearate 37.5 g, and mixed as pellet I. The pellets G and pellets I were tableted using a tableting machine (Piccola manufactured by RIVA Co., Ltd.) at a tableting pressure of 8.6 kN to obtain a laminated ingot having a diameter of 10 mm (formulation 3). The composition of the preparation 3 per ingot is shown in Table 3.

實施例4 Example 4

秤取乙醯水楊酸1214.6g、玉米澱粉135.0g、甘露糖醇(羅克德公司製造之Pearlitol 200SD)1140.2g、羧甲基纖維素300.0g、無水檸檬酸27.0g、阿斯巴甜30.0g、輕質無水矽酸14.93g、硬化油138.2g，予以混合，作為顆粒J。將顆粒J及上述顆粒I使用打錠機(RIVA公司製造之Piccola)以打錠壓10kN進行打錠，獲得直徑10.5mm(形狀：2段R)之積層錠(製劑4)。將該製劑4每錠之組成表示於表4。 Weighed 1214.6 g of acetyl salicylic acid, 135.0 g of corn starch, 1140.2 g of mannitol (Pearlitol 200SD manufactured by Rockford), 300.0 g of carboxymethylcellulose, 27.0 g of anhydrous citric acid, and 30.0 g of aspartame. 14.93 g of light anhydrous citric acid and 138.2 g of hardened oil were mixed and used as granule J. The pellet J and the pellet I described above were tableted at a tableting pressure of 10 kN using a tableting machine (Piccola manufactured by RIVA Co., Ltd.) to obtain a laminated ingot (formulation 4) having a diameter of 10.5 mm (shape: two-stage R). The composition of the preparation 4 per ingot is shown in Table 4.

實施例5 Example 5

秤取乙醯水楊酸預混品(乙醯水楊酸：玉米澱粉=90：10，乾式造粒品，羅迪亞公司製造之羅迪2312)31500g、甘露糖醇(羅克德公司製造之Pearlitol 200SD)28420g、羧甲基纖維素7000g、無水檸檬酸630g、阿斯巴甜700g、輕質無水矽酸(日本艾羅西爾(Aerosil)股份有限公司製造之氧相二氧化矽)350g、硬化油1400g，用轉鼓混合機混合，作為顆粒K。將甘胺酸鋁4840g、碳酸鎂9680g、甘露糖醇(羅克德公司製造之Pearlitol 200SD)22180g、結晶纖維素(旭化成公司製造之協歐拉斯PH-101)2622g、交聯聚維酮6578g、阿斯巴甜1188g、結晶纖維素9504g(旭化成公司製造之協歐拉斯KG-1000)、鈕西林(富士化學公司製造，商品名)2420g在流動層乾燥機(帕雷克公司製造之WSG-60型)中秤取，將6%羥丙基纖維素溶液24785g噴霧，進行造粒。然後乾燥，獲得顆粒L。將顆粒L使用動力混煉機(power mill)進行整粒後，秤取34380g，與蘭素拉唑腸溶性細粒33750g、硬脂酸鎂625g一起用轉鼓混合機混合，作為顆粒M。將顆粒K及顆粒M使用打錠機(畑鐵公所公司製造之HT-CVX54LS-UW/C&3L)以打錠壓11Kn進行打錠，獲得直徑10.5mm之積層錠。將該積層錠真空乾燥，獲得製劑5。將該製劑5每錠之組成表示於表5。 Weighing the yttrium salicylic acid premix (acetonitrile salicylic acid: corn starch = 90:10, dry granulated product, Rodi 2312 manufactured by Rodia), 3,500 g, mannitol (Pearlitol, manufactured by Rockdale) 200SD) 28820g, carboxymethyl cellulose 7000g, anhydrous citric acid 630g, aspartame 700g, light anhydrous citric acid (Oxygen cerium oxide manufactured by Aerosil Co., Ltd.) 350g, hardened 1400 g of oil was mixed with a tumbler mixer as pellet K. 4840 g of aluminum glycinate, 9680 g of magnesium carbonate, 22180 g of mannitol (Pearlitol 200SD manufactured by Rockford), 2622 g of crystalline cellulose (Co-Olas PH-101 manufactured by Asahi Kasei Co., Ltd.), crospovidone 6576 g, 1188g of spartan, 9504g of crystalline cellulose (Co-Olas KG-1000 manufactured by Asahi Kasei Co., Ltd.), 2420g of Nisshin (manufactured by Fuji Chemical Co., Ltd.) in a fluidized layer dryer (WSG-60 manufactured by Parek) In the middle of the scale, 24,785 g of a 6% hydroxypropylcellulose solution was sprayed and granulated. It is then dried to obtain particles L. After the pellet L was granulated using a power mill, 34,380 g of the pellet L was weighed and mixed with lansalazole enteric fine granules 33,725 g and magnesium stearate 625 g together as a pellet M. The pellets K and the pellets M were subjected to tableting using a tableting machine (HT-CVX54LS-UW/C&3L manufactured by Nippon Steel Co., Ltd.) at a spindle pressure of 11 Kn to obtain a laminated ingot having a diameter of 10.5 mm. The laminated ingot was vacuum dried to obtain Formulation 5. The composition of the preparation 5 per ingot is shown in Table 5.

評估 Evaluation 試驗例1 Test example 1

將實施例1、實施例5獲得之錠劑放入乾燥劑，予以密栓，於40℃下1個月後，經由高速液體層析法定量製劑中之乙醯水楊酸之含量。從經定量之值算出乙醯水楊酸之殘存率%(=經過後之乙醯水楊酸含量/初期之乙醯水楊酸含量×100)。評估係乙醯水楊酸之殘存率在95%以上且100%以下為○，在90%以上且未達95%為△，未達90%為×。評估結果表示於表6。 The tablets obtained in Example 1 and Example 5 were placed in a desiccant, and they were tightly sealed, and after 1 month at 40 ° C, the content of acetaminosalicylic acid in the preparation was quantified by high-speed liquid chromatography. From the quantified value, the residual ratio of acetaminophenic acid was calculated as % (= the content of acetaminolic acid after the passage / the content of the initial hydrazine salicylic acid × 100). The residual rate of the acetaminophen acid was 95% or more and 100% or less was ○, and 90% or more and 95% was Δ, and less than 90% was ×. The results of the evaluation are shown in Table 6.

試驗例2 Test example 2

測定實施例1、實施例5獲得之錠劑之口腔內崩解時間。又，口腔內崩解時間係指將錠劑含在健康正常人中之口中後，完全不用牙齒咬而直到溶解為止的時間(n=2之平均值)。結果表示於表7。 The intraoral disintegration time of the tablets obtained in Example 1 and Example 5 was measured. Further, the intraoral disintegration time refers to the time (n=2 of the average value) after the tablet is contained in the mouth of a healthy normal person, and the tooth is not bitten until dissolved. The results are shown in Table 7.

試驗例3 Test Example 3

使用錠劑測定裝置(Pharmatest公司製造)，測定實施 例1、實施例5獲得之錠劑最初(initial)之錠劑硬度。試驗係對於實施例1進行5次，對於實施例5進行10次，其平均值表示於表8。 Using a tablet measuring device (manufactured by Pharmatest), measurement was carried out Example 1, the tablet obtained in Example 5, the initial tablet hardness. The test was carried out 5 times for Example 1, and 10 times for Example 5, and the average value thereof is shown in Table 8.

[產業上利用之可能性] [Possibility of industrial use]

根據本發明之口腔內崩解錠，由於含有具有強力抑制酸分泌作用之PPI、以及屬於NSAIDs之一種之乙醯水楊酸，故在為了繼續投予NSAIDs且治療或抑制胃潰瘍或十二指腸潰瘍之發病時，可進行投予。又，本發明之口腔內崩解錠係活性成分之安定性高，投予後活性成分之藥理效果會安定且迅速地表現。又，本發明之口腔內崩解錠亦具有在無水狀況下可輕易地在任何時間、任何地方隨時容易地服用之便利性。 The orally disintegrating tablet according to the present invention contains a PPI having a strong inhibitory effect on acid secretion and an acetyl salicylic acid belonging to one of NSAIDs, and is used for treating or inhibiting the onset of gastric ulcer or duodenal ulcer in order to continue administering NSAIDs. At the time, it can be administered. Further, the orally disintegrating tablet active ingredient of the present invention has high stability, and the pharmacological effect of the active ingredient after administration is stable and rapid. Further, the orally disintegrating tablet of the present invention also has the convenience of being easily taken at any time and anywhere at any time in the absence of water.

以上，將數個本發明之具體態樣加以詳細說明，惟只要是本發明所屬技術領域中具有通常知識者，即可對所示之特定態樣，以實質上不超出本案之教示與優點之範圍的方式，作各種修正及變更。因此，該等修正及變更，都包含於申請專利範圍所請之本發明之精神及範圍內。 In the above, a plurality of specific aspects of the present invention will be described in detail, but as long as it is a person having ordinary knowledge in the technical field of the present invention, the specific aspects shown can be substantially eliminated from the teachings and advantages of the present invention. Various modifications and changes are made to the scope of the scope. Therefore, these modifications and variations are intended to be included within the spirit and scope of the invention as claimed.

Claims (16)

一種積層之口腔內崩解錠，係具有：(1)含有包含氫離子幫浦抑制劑之腸溶性細粒的層、以及(2)含有乙醯水楊酸的層；包含氫離子幫浦抑制劑之腸溶性細粒係將含有氫離子幫浦抑制劑之組成物以腸溶性包覆層包覆而成的細粒，前述氫離子幫浦抑制劑為蘭素拉唑或其光學活性體或是其鹽，在前述含有腸溶性細粒的層中，於腸溶性細粒以外之部分含有制酸劑，該制酸劑之含量為約10mg至約100mg，該口腔內崩解錠在口腔內崩解之時間係在約60秒以內，並且該口腔內崩解錠之硬度為約20至約100N。 A laminated intraoral disintegrating tablet comprising: (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor; and (2) a layer containing acetaminophen salicylic acid; The enteric fine particle of the agent is a fine particle containing a composition of a hydrogen ion pump inhibitor coated with an enteric coating layer, and the hydrogen ion pump inhibitor is lansile or its optically active substance or Is a salt thereof, and in the layer containing the enteric fine particles, an acid generator is contained in a portion other than the enteric fine particles, and the content of the acid generator is from about 10 mg to about 100 mg, and the orally disintegrating ingot is in the oral cavity. The time for disintegration is within about 60 seconds, and the hardness of the orally disintegrating ingot is from about 20 to about 100N. 如申請專利範圍第1項所述之口腔內崩解錠，其中，制酸劑為選自由金屬氧化物、金屬氫氧化物、鹼土金屬之碳酸鹽及甘胺酸鋁所成群組之至少一種成分。 The orally disintegrating tablet according to claim 1, wherein the antacid is at least one selected from the group consisting of metal oxides, metal hydroxides, alkaline earth metal carbonates, and aluminum glycinate. ingredient. 如申請專利範圍第2項所述之口腔內崩解錠，其中，金屬氧化物為選自由氧化鎂、矽酸鎂、乾燥氫氧化鋁凝膠及偏矽酸鋁鎂(magnesium aluminometasilicate)所成群組之至少一種。 The orally disintegrating tablet of claim 2, wherein the metal oxide is selected from the group consisting of magnesium oxide, magnesium citrate, dried aluminum hydroxide gel, and magnesium aluminometasilicate. At least one of the groups. 如申請專利範圍第2項所述之口腔內崩解錠，其中，金屬氫氧化物為選自由氫氧化鎂、氫氧化鋁、合成水滑石、氫氧化鋁與氫氧化鎂之共沉澱物、氫氧化鋁與 碳酸鎂與碳酸鈣之共沉澱物、以及氫氧化鋁與碳酸氫鈉之共沉澱物所成群組之至少一種。 The orally disintegrating ingot according to claim 2, wherein the metal hydroxide is selected from the group consisting of magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite, coprecipitate of aluminum hydroxide and magnesium hydroxide, and hydrogen. Alumina and At least one of a coprecipitate of magnesium carbonate and calcium carbonate, and a coprecipitate of aluminum hydroxide and sodium hydrogencarbonate. 如申請專利範圍第2項所述之口腔內崩解錠，其中，鹼土金屬之碳酸鹽為碳酸鈣或碳酸鎂。 The orally disintegrating ingot according to claim 2, wherein the alkaline earth metal carbonate is calcium carbonate or magnesium carbonate. 如申請專利範圍第1項所述之口腔內崩解錠，其中，制酸劑為碳酸鎂及甘胺酸鋁之混合物。 The orally disintegrating ingot according to claim 1, wherein the antacid is a mixture of magnesium carbonate and aluminum glycinate. 如申請專利範圍第1項所述之口腔內崩解錠，其中，乙醯水楊酸之含量為每錠約70mg至約120mg。 The orally disintegrating tablet of claim 1, wherein the content of acetaminosalicylic acid is from about 70 mg to about 120 mg per ingot. 如申請專利範圍第1項所述之口腔內崩解錠，其中，在含有乙醯水楊酸的層中含有羧甲基纖維素。 The orally disintegrating tablet according to claim 1, wherein the layer containing acetaminosalicylic acid contains carboxymethylcellulose. 如申請專利範圍第1項所述之口腔內崩解錠，其係在含有包含氫離子幫浦抑制劑之腸溶性細粒的層中，於腸溶性細粒以外之部分含有選自交聯聚維酮及偏矽酸鋁鎂之至少1種崩解劑。 The orally disintegrating ingot according to claim 1, which is contained in a layer containing enteric fine particles containing a hydrogen ion pump inhibitor, and is selected from the group consisting of cross-linked polycondensation in a portion other than the enteric fine particles. At least one disintegrant of ketene and aluminum magnesium metasilicate. 如申請專利範圍第1項所述之口腔內崩解錠，其係在含有乙醯水楊酸的層中含有潤滑劑。 The orally disintegrating ingot according to claim 1, which contains a lubricant in a layer containing acetyl salicylic acid. 如申請專利範圍第10項所述之口腔內崩解錠，其中，潤滑劑為硬化油。 The orally disintegrating ingot according to claim 10, wherein the lubricant is a hardened oil. 如申請專利範圍第1項所述之口腔內崩解錠，其為雙層錠。 The orally disintegrating ingot according to claim 1, which is a two-layer ingot. 如申請專利範圍第1項所述之口腔內崩解錠，其係在(1)含有包含氫離子幫浦抑制劑之腸溶性細粒的層及(2)含有乙醯水楊酸的層之間，具有中間層。 The orally disintegrating ingot according to claim 1, which is characterized in that (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) a layer containing acetaminosalicylic acid. Between, with an intermediate layer. 如申請專利範圍第1項所述之口腔內崩解錠，其中， 乙醯水楊酸係不經腸溶包覆。 The orally disintegrating ingot according to claim 1, wherein Acetylsalicylic acid is not enteric coated. 如申請專利範圍第1項所述之口腔內崩解錠，其中，錠劑重量為約300mg至約800mg，且(1)含有包含氫離子幫浦抑制劑之腸溶性細粒的層與(2)含有乙醯水楊酸的層之重量比為約10：1至約1：10。 The orally disintegrating tablet according to claim 1, wherein the tablet has a weight of about 300 mg to about 800 mg, and (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) The weight ratio of the layer containing acetyl salicylic acid is from about 10:1 to about 1:10. 如申請專利範圍第1項所述之口腔內崩解錠，其係在打錠面具有曲面。 The orally disintegrating ingot according to claim 1, which has a curved surface on the ingot surface.