201000133 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種遮蔽藥物之收斂性或澀味、刺激性、 苦味、辣味等異味之經口組合物及異味之遮蔽方法。 【先前技術】 藥物多數情況呈收斂性、刺激性、苦味、澀味或辣味等 異味，而無法直接服用，因此必須遮蔽口腔内之異味。遮 蔽藥物異味之方法大致分為控制藥物在口腔内溶解之方 ® 法、以及使用遮蔽劑來掩蔽藥物自身異味之方法。 作為控制藥物在口腔内溶解之方法，可列舉：藉由胃溶 性高分子、腸溶性高分子、水不溶性高分子、壤類等來施 以被覆之方法（專利文獻1〜6)，形成基質來遮蔽之方法（專 利文獻7、8)，使用包藏化合物來包藏之方法（專利文獻9) 等。但是，由於控制溶解，因此溶出性發生微小的變化， 亦會使藥物之效力表現變慢。又，在應用於水溶性較高之 这 藥物時，多數情況是必需大量的被膜劑或基質劑，或異味 之遮蔽不充分。反之，在應用於水溶性較低之藥物時，亦 有藥物之生物學利用能力降低而無法充分發揮效力之情 況。進而，存在以下缺點：服用時產生粗糙感，或者若形 成粗糙感較少之粒徑，則會由於殘留於齒間等口腔内之粒 子而在服用後暫時出現異味或刺激。又，亦有難以在液劑 或膠劑等半固形製劑中應用之缺點。 另一方面’作為使用遮蔽劑來掩蔽藥物自身異味之方 法，可列舉：添加乙醯磺胺酸鉀（專利文獻1〇)、阿斯巴甜 139873.doc 201000133 (aspartame)(專利文獻11Λ12)、甜菊萃取物（專利文獻⑼ 等同甜度甜味料之方法；添加篇枝油或檸檬油等精油（專 利文，14) ’ &壞血酸、檸檬酸、蘋果酸、富馬酸、酒石 酸單丁酸、縮合碟酸等酸（專利文獻i5〜i8卜甘油等多 一醇（專利文獻19及20)，界面活性劑（專利文獻2))等多種 物質之方法。該等方法對溶出性造成之影響較少，相反， 掩蔽效果較弱、或僅特定藥物有效果、或者對收斂性或刺 激性較強之藥物掩蔽效果較小，而未必容易使用，可應用 之藥物受到掩蔽劑限定之情況較Η了改良此種缺點， 亦嘗试以下方法：將芳香劑與甜味劑加以組合而添加之方 法（專利文獻22及23) ’將酸與甜味料加以組合而添加之方 法（專利文獻24)等將多種掩蔽劑加以組合之方法但現狀 是仍未對收斂性或刺激性較強之藥物或者水溶性較高之藥 物等多數藥物發揮充分的掩蔽效果。 ' [專利文獻1]日本專利特開2〇08_37863號公報 [專利文獻2]日本專利特開2〇〇6_232789號公報 [專利文獻3]日本專利特開2〇〇6 22〇39號公報 [專利文獻4]曰本專利特開2005 — 343800號公報 [專利文獻5]曰本專利特開平313〇214號公報 [專利文獻6]日本專利特開昭57_5863丨號公報 [專利文獻7]曰本專利特開2004-丨89758號公報 [專利文獻8]曰本專利特開平9_2〇8458號公報 [專利文獻9]日本專利特開平3_236316號公報 [專利文獻1〇]曰本專利特開2007-269716號公報 139873.doc 201000133 [專利文獻11]曰本專利特開2005-336078號公報 [專利文獻12]曰本專利特開2〇〇2_1287〇5號公報 [專利文獻13]曰本專利特開平2_56416號公報 [專利文獻14]日本專利特開之⑽弘丨328〇1號公報 [專利文獻15]日本專利特開2〇〇7·54〇〇1號公報 [專利文獻16]日本專利特開2〇〇1_213764號公報 [專利文獻17]日本專利特開平9_194356號公報 [專利文獻18]日本專利特開2〇〇〇_119175號公報 [專利文獻19]日本專利特開2〇〇2_363 1〇5號公報 [專利文獻20]曰本專利特開2002445764號公報 [專利文獻21]曰本專利特開2〇〇4_914〇8號公報 [專利文獻22]日本專利特開2〇〇7·217687號公報 [專利文獻23]日本專利特開2〇〇4_ΐ55781號公報 [專利文獻24]曰本專利特開2000-290199號公報 【發明内容】 [發明所欲解決之問題] 因此，本發明之目的在於提供一種不限於固形製劑還可 應用於液劑等多種劑形，並可防止藥物之收斂性或刺激 性苦味、澀味或辣味等異味而不會使溶出性發生變化的 經口組合物及方法。 [解決問題之技術手段] 馨於此種實際情況，本發明者等人對防止不僅應用於固 形製劑而且亦可應用於液劑之藥物異味的方法進行了各種 研究’結果發現’若使呈異味之藥物含有酸性物質作為遮 139873.doc 201000133 蔽劑’則由藥物自身引起之異味會較大減少，進而，若於 該組合物中添加鹼土金屬鹽及/或土族金屬鹽，則由酸性 物質引起之異味亦會較大減少，結果可獲得不呈異味之經 口組合物’從而完成本發明。 即’本發明提供一種遮蔽異味之經口組合物，其含有呈 異味之藥物、酸性物質以及鹼土金屬鹽及/或土族金屬 鹽。 又’本發明提供一種異味之遮蔽方法，其特徵在於：使 - 呈異味之藥物含有酸性物質以及鹼土金屬鹽及/或土族金 © 屬鹽。 [發明之效果] 根據本發明，可防止藥物之收斂性或刺激性、苦味、澀 味或辣味等異味而不會使溶出性發生變化。 【實施方式】 以下’對本發明進行詳細說明。 〇 於本發明中，所謂呈異味之藥物’係指在經口服用時， 於口腔内或喉嚨内引起收斂性、刺激性、苦味、澀味或辣 味等不舒適感覺的藥物。作為此種藥物，可列舉驗性藥 物γ兩性藥物、酸性藥物，進而亦可列舉生藥、草藥或中 草藥等源自生物之萃取物。於本發明組合物中，該等均有 效果並具有掩蔽效果。於本發明中，所謂驗性藥物，意 指游離體表現驗性之藥物’在形成鹽時未必為驗性。同 樣’所謂酸性藥物’意指游離體表現酸性之藥物，在形成 鹽時未必為酸性。X，所謂兩性藥物，係指溶解既可形成 139873.doc 201000133 鹼亦可形成酸之藥物。又，鹼性藥物、兩性藥物、酸性藥 物分別可為其本來狀態，亦可為其鹽酸鹽、硝酸鹽、硫酸 鹽、乙酸鹽、乳酸鹽、檸檬酸鹽、琥珀酸鹽、富馬酸鹽、 碳酸鹽、茶氯酸鹽、對甲苯磺酸鹽、酒石酸鹽、丁酸鹽、 氫溴酸鹽、磷酸鹽、海苯酸鹽、苯磺酸鹽、馬來酸鹽等酸 加成鹽，又可為鈉鹽、鉀鹽等鹼金屬鹽或鈣鹽、鎂鹽、鋁 鹽等鹼土金屬鹽等，還可為氣化物、溴化物、碘化物等。 ❹201000133 VI. Description of the Invention: [Technical Field] The present invention relates to an oral composition for masking the astringency of a drug or an odor, an irritating, a bitter taste, a spicy taste, and the like, and a method for masking an odor. [Prior Art] Most of the drugs are astringent, irritating, bitter, astringent or spicy, and cannot be taken directly, so the odor in the mouth must be masked. The method of masking the odor of a drug is broadly divided into a method of controlling the dissolution of a drug in the oral cavity, and a method of masking the odor of the drug itself using a masking agent. As a method of controlling the dissolution of the drug in the oral cavity, a method of applying a coating by a gastric-soluble polymer, an enteric polymer, a water-insoluble polymer, or a locus (Patent Documents 1 to 6) is used to form a matrix. A method of shielding (Patent Documents 7 and 8), a method of occluding a occlusion compound (Patent Document 9), and the like. However, due to the controlled dissolution, a slight change in the dissolution property also causes the efficacy of the drug to be slow. Further, when applied to a drug having a high water solubility, in many cases, a large amount of a filming agent or a matrix agent is required, or the shielding of the odor is insufficient. On the other hand, when applied to a drug having a low water solubility, there is also a case where the biological utilization ability of the drug is lowered and the effect is not sufficiently exerted. Further, there is a disadvantage that a rough feeling is generated when taken, or if a particle size having a small roughness is formed, odor or irritation temporarily occurs after taking the particles due to the particles remaining in the oral cavity such as the interdental space. Further, there are disadvantages in that it is difficult to apply to a semi-solid preparation such as a liquid preparation or a gel. On the other hand, as a method of masking the odor of the drug itself by using a masking agent, potassium sulfonate (Patent Document 1), aspartame 139873.doc 201000133 (aspartame) (patent document 11Λ12), stevia may be mentioned. Extract (Patent Document (9) Method equivalent to sweetness sweetener; add essential oil such as oil or lemon oil (patent text, 14) ' & ascorbic acid, citric acid, malic acid, fumaric acid, tartaric acid monobutyl A method of a plurality of substances such as an acid, a condensed acid, and the like (a patent document i5 to i8, a polyalcohol such as glycerin (Patent Documents 19 and 20), and a surfactant (Patent Document 2)). These methods are caused by dissolution. The effect is less. On the contrary, the masking effect is weaker, or only the specific drug has effect, or the convergent or irritating drug masking effect is small, but it is not easy to use, and the applicable drug is limited by the masking agent. In order to improve such a disadvantage, the following method is also employed: a method of adding a fragrance together with a sweetener (Patent Documents 22 and 23) 'Method of adding an acid and a sweetener in combination (Patent Document) (24) A method in which a plurality of masking agents are combined, but the current state of the art is that a sufficient masking effect is not exhibited for a drug having a strong astringency or irritancy or a drug having a high water solubility. [Patent Document 1] Japan [Patent Document 2] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. [Patent Document 5] Japanese Patent Laid-Open Publication No. SHO 57-5863 No. PCT Publication No. JP-A No. s [Patent Document 8] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. 2, No. Hei. Patent Special (10) Hongda 328〇1 [Patent Document 15] Japanese Patent Laid-Open Publication No. Hei No. Hei 9-194764 (Patent Document 17) Japanese Patent Laid-Open Publication No. Hei 9-194356 [Patent Document 19] Japanese Patent Laid-Open Publication No. Hei No. Hei. No. Hei. No. 2002-445764 [Patent Document 21] Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. SUMMARY OF THE INVENTION [Problem to be Solved by the Invention] Therefore, an object of the present invention is to provide a dosage form which is not limited to a solid preparation and can be applied to a liquid preparation and the like, and can prevent a drug. An oral composition and method which astringent or irritating bitterness, astringency or a pungent taste, and which does not change the dissolution property. [Technical means for solving the problem] In the actual situation, the inventors of the present invention conducted various studies on a method for preventing the odor of a drug not only applied to a solid preparation but also to a drug, and the result was found to be odorous. The drug contains an acidic substance as a mask 139873.doc 201000133, and the odor caused by the drug itself is greatly reduced. Further, if an alkaline earth metal salt and/or a metal salt is added to the composition, the acid substance is caused by the acidic substance. The odor is also greatly reduced, and as a result, an oral composition which does not exhibit an odor is obtained, thereby completing the present invention. Namely, the present invention provides an oral composition for masking an odor, which comprises an odor-producing drug, an acidic substance, and an alkaline earth metal salt and/or a terrigenous metal salt. Further, the present invention provides a method for masking odor, characterized in that the odor-producing drug contains an acidic substance and an alkaline earth metal salt and/or a Turkish gold source. [Effects of the Invention] According to the present invention, it is possible to prevent odor such as astringency or irritation, bitterness, astringency or spicy taste of a drug without changing the dissolution property. [Embodiment] Hereinafter, the present invention will be described in detail. In the present invention, the term "drug which is odorous" means a drug which causes an uncomfortable feeling such as astringency, irritation, bitterness, astringency or spicy taste in the oral cavity or throat when it is orally administered. Examples of such a drug include an injectable drug γ amphoteric drug and an acidic drug, and further, a biologically derived extract such as a crude drug, an herbal medicine or a Chinese herbal medicine. These are effective and have a masking effect in the compositions of the present invention. In the present invention, the term "intestinal drug" means that the drug exhibiting an inactive form is not necessarily inferior in forming a salt. Similarly, the term "acidic drug" means a drug in which the free body exhibits acidity and is not necessarily acidic when forming a salt. X, the so-called amphoteric drug, refers to a drug that can form an acid by forming a 139873.doc 201000133 alkali. Further, the basic drug, the amphoteric drug, and the acidic drug may be in their original state, or may be their hydrochloride, nitrate, sulfate, acetate, lactate, citrate, succinate, fumarate. Acid addition salts such as carbonates, tea chlorates, p-toluenesulfonates, tartrates, butyrates, hydrobromides, phosphates, sea phenates, besylates, maleates, etc. Further, it may be an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt, a magnesium salt or an aluminum salt, or may be a vapor, a bromide or an iodide. ❹
作為此種呈異味之藥物的具體例，可列舉：氮卓斯汀 (azelastine)、腺苦銘胺（adenosylcobalamin)、阿利馬 口井（alimemazine)、尿囊素銘（aldioxa)、氨漠索（ambroxol)、 氨來占諾（amlexanox)、異西喷地（isothipendyl)、艾芬地爾 (ifenprodil)、茚洛秦（indeloxazine)、依替福林（etilefrine)、 依匹斯汀（epinastine)、麻黃驗（ephedrine)、依美斯；丁 (emedastine)、奥沙米特（oxatomide)、奥托硫胺 (octotiamine)、奥美沙坦醋（olmesartan medoxomil)、η加弓卜 因（caffeine)、卡比沙明（carbinoxamine)、坎地沙垣賴 (candesartan cilexetil)、哌芬那辛（gUaifenesin)、氣馬斯汀 (clemastine)、氣哌斯汀（chloperastine)、氣笨那敏 (chlorpheniramine)、克羅赫斯汀（chl〇rhexidine)、可待因 (codeine)、鈷胺素（cobalamin)、氰鈷胺、世甲命 (dicethiamine)、二氫可待因（dihydrocodeine)、地芬尼多 (difenidol)、二苯拉林（diphenylpyraline)、二笨胺明 (diphenhydramine)、二羥丙茶鹼（diprophylline)、笨甲醯硫 胺明（dibenzoyl thiamine)、西咪替丁（cimetidine)、二 139873.doc 201000133 烧（dimemorfan)、地爾硫卓（diltiazem)、昔多芬（sildenafil)、 東笑菪驗（scopolamine)、硫糖銘（sucralfate)、甲續司特 (suplatast tosilate)、西曲酸醋（cetraxate)、西替利 11 井（cetirizine)、他達那非（tadalafil)、硫胺素（thiamine)、 二硫硫胺（thiamine disulfide)、氣匹定（ticlopidine)、替培 定（tipepidine)、右美沙芬（dextromethorphan)、替米沙坦 (telmisartan)、多西拉敏（doxylamine)、多奈0底齊（donepezil)、 曲尼司特（tranilast)、曲普立定（triprolidine)、特美奎諾 (trimetoquinol)、尼紮替丁（nizatidine)、那可汀（noscapine)、 罌粟驗（papaverine)、绳沙坦（valsartan)、伐地那非 (vardenafil)、生物素（biotin)、匹可硫酸鈉（sodium picosulfate)、雙異 丁硫胺（bisibuthiamine)、雙苯醯硫胺 (bisbentiamine)、經钻胺（hydroxocobalamin)、D比吟素 (pyridoxine)、°比 D多醇（pyridoxol)、D比0多胺（pyridoxamine)、 口底舍西平（pirenzepine)、法莫替丁（famotidine)、非那雄胺 (finasteride)、非尼拉敏（pheniramine)、去氧腎上腺素 (phenylephrine)、偽麻黃驗（pseudoephedrine)、丁 基東笑 菪驗、黃素腺嗓吟二核甘酸納（flavin adenin dinucleotide sodium)、普萘洛爾（propranolol)、異丙 p井（promethazine)、 溴己新（bromhexine)、撥皮皆（hesperidin)、癸煙醋 (hepronicate)、貝他斯汀（bepotastine)、黃連素（berberine)、 苯填硫胺（benfotiamine)、馬普替林（maprotiline)、美喧他 _(mequitazine)、美克利靜（meclizine)、甲基阿托品 (methylatropine)、甲基麻黃驗（methylephedrine)、曱姑胺 201000133 ❹Specific examples of such an odor-producing drug include azelastine, adenosylcobalamin, alimemazine, aldioxa, and ammonia-moistin ( Ambroxol), amlexanox, isothipendyl, ifenprodil, indeloxazine, etilefrine, epinastine, Ephedrine, Eames, emedastine, oxatomide, octotiamine, olmesartan medoxomil, η plus caffeine, Carbinoxamine, candesartan cilexetil, gUaifenesin, clemastine, chloperastine, chlorpheniramine, gram Chl〇rhexidine, codeine, cobalamin, cyanocobalamin, dicethiamine, dihydrocodeine, difenidol ), diphenylpyraline, diphenylamine (di) Phenhydramine), diprophylline, dibenzoyl thiamine, cimetidine, 139873.doc 201000133 dimemorfan, diltiazem, sildenafil , scopolamine, sucralfate, suplatast tosilate, cetraxate, cetirizine, tadalafil, Thiamine, thiamine disulfide, ticlopidine, tipepidine, dextromethorphan, telmisartan, doxylamine Doxylamine), donepezil, tranilast, triprolidine, trimetoquinol, nizatidine, noscapine, Papaverine, valsartan, vardenafil, biotin, sodium picosulfate, bisibuthiamine, bisbenzoquinone (bisbentiamine) Hydroxocobalamin, pyridoxine, pyridoxol, pyridoxamine, pirenzepine, famotidine, non Finasteride, pheniramine, phenylephrine, pseudoephedrine, butyl-tertine, flavin adenin Dinucleotide sodium), propranolol, promethazine, bromhexine, hesperidin, hepronicate, bepotastine, berberine Berberine, benfotiamine, maprotinline, mequitazine, meclizine, methylatropine, methylephedrine ), 曱姑amine 201000133 ❹
(methylcobalamin)、甲貝那替秦（methylbenactyzium)、甲 氧那明（methoxyphenamine)、核黃素（riboflavin)、核黃素 鈉、雷尼替丁（ranitidine)、拉°夫替丁（lafutidine)、羅沙替 丁 乙酸醋（roxatidine acetate)、氣沙坦（losartan)、洛派丁胺 (loperamide)、氣雷他定（loratadine)、阿司匹林（aspirin)、 乙酿胺紛（acetaminophen)、異丙安替比林（isopropylantipyrine)、 布洛芬（ibuprofen)、乙水揚胺（ethenzamide)、雙氯芬酸 (diclofenac)、水揚醯胺（salicylamide)、甲芬那酸 (mefenamic acid)、氟芬那酸（flufenamic acid)、美洛昔康 (meloxicam)、洛索洛芬（loxoprofen)、傳明酸（tranexamic acid)、依託度酸（etodolac)、塞來昔布（celecoxib)、羅非昔 布（rofecoxib)、伐地昔布（valdecoxib)、帕瑞昔布 (parecoxib)、依託昔布（etoricoxib)、魯米昔布（lumiracoxib)、 茶驗（theophylline)、非索非那定（fexofenadine)、西替利 井、異丙蛾胺（isopropamide iodide)、黃連素、棕網酸視黃 醋（retinol palmitate)、泛酸約（calcium pantothenate)、漠異 戊醯脈（bromovalerylurea)、氣徽素（chloramphenicol)、胺 基菲林（aminophyllin)、顛茄浸膏（belladonna total alkaloid)、烯丙異丙乙醯尿等。又，作為生藥、草藥或中 草藥等源自生物之萃取物，可列舉：野梧桐、兒茶、蘆 薈、黃檗、銀杏、茴香、黃苓、黃柏、薑黃、熊果葉（uva ursi)、烏藥、薔薇果、延胡索、延命草、黃柏、黃連、何 首烏、莪術、纈草、乾薑、甘草、桔梗、武靴葉、小球 藻、桂皮、龍膽、酵母、山藥、地黃、生薑、當藥、苦 139873.doc 201000133 蔘、紅花、大黃、棗、苟藥、山茱蔓、蒼求、大棗、澤 瀉、丁香、西番蓮、釣藤鉤、茯苓、炮附子、牡丹皮、啤 酒化、蘆薈、胡蘿蔔、葛根湯、驅風解毒湯、響聲破笛丸 料 '小柴胡湯、小青龍湯、酸棗仁湯、十味敗毒湯等之萃 取物。該等藥物可單獨使用，亦可將二以上加以組合而使 用。該等藥物中特別好的是二苯胺明、氨漠索、依匹斯 ’丁去氧腎上腺素、溴己新、依替福林、派余西平、偽麻 黃鹼、曱基麻黃鹼、洛派丁胺、或該等之鹽。 於本發明中，呈異味之藥物在經口組合物中較好的是含 有0.1〜95質量％，更好的是含有1〜90%質量％。 又’於本發明之組合物中，除了上述藥物外，可調配其 :藥物。例如，作為此種藥物，可列舉：解熱鎮痛消炎 樂、鎮靜催眠藥、抗睡眠劑、抗眩暈藥 '小兒鎮痛藥、健 胃藥、製酸藥、消化藥、強心藥、心律不齊用藥、降壓 藥、血管擴展藥、利尿藥、抗溃瘍藥、調整胃腸藥、骨質 疏鬆症治療藥、鎮咳去痰藥、平喘藥、抗菌劑、尿頻改善 劑、滋養強壯劑、維他命劑等中所用之藥理活性成分。 於本發明中，遮蔽劑係將酸性物質與鹼土金屬鹽及,或 土族金屬鹽加以組合而使用。此處所謂酸性物質，係指本 身表現酸性之醫藥品添加物之調味劍。作為其具體例可 :舉單寧酸、沒食子酸丙醋、捧檬酸、乙酸、及酒石酸 等’該等可使用-種或將二種以上加心合而使用。該等 就異味之遮蔽效果方面而言，更好的是單寧酸、沒 食子酸丙酯、乙酸。 139873.doc -10- 201000133 酸性物質之添加量亦會根據呈異味之藥物的種類而變 化’大體上相對於呈異味之藥物1質量份，較好的是 0.05-50質量份之範圍，更好的是〇1〜1〇質量份尤其好的 是0.5〜5質量份，特別好的是〇 8~2質量份。 於本發明中，進而添加鹼土金屬鹽及/或土族金屬鹽作 為k蔽劑作為驗土金屬鹽及/或土族金屬鹽，可列舉選 ； 自鎂鹽、鈣鹽及鋁鹽之一種或二種以上。 0 作為鹼土金屬鹽及/或土族金屬鹽之具體例，可列舉： 鋁偏矽酸鎂（magnesium alumin〇metasiUcate)、碳酸鈣、氣 化鈣水合物、氯化鎂、乾燥氫氧化鋁凝膠、檸檬酸鈣、甘 油磷酸鈣、葡萄糖酸鈣水合物、矽酸鈣、矽酸鎂、矽酸鎂 鋁、合成矽酸鋁、合成水滑石、乙酸鈣、氧化鎂、氫氧化 鋁鎂、氯氧化鋁凝膠、氫氧化鋁-碳酸氫鈉共沈澱物、氫 氧化鋁-碳酸鎂-碳酸鈣共沈澱物、氫氧化鎂、磷酸三鈣、 碳酸鎂、沈澱碳酸鈣、天然矽酸鋁、乳酸鈣水合物無水 〇 峨酸氫鈣、無水磷酸氫鈣造粒物、硫酸鋁、硫酸鈣、磷酸 一氫飼、磷酸氫鈣水合物、磷酸氫鈣造粒物、磷酸二氫約 水合物等，該等可使用一種或將二種以上加以組合而使 用。该等之中’就異味之遮蔽效果方面而言，特別好的是 紹偏矽酸鎂、碳酸鈣、矽酸鈣。 驗土金屬鹽及/或土族金屬鹽之添加量亦會根據呈異味 之藥物的種類或調配量、酸性物質之種類或添加量而變 化’大體上相對於酸性物質1質量份，較好的是〇 〇5〜50質 量伤’更好的是0.1〜50質量份’尤其好的是〇_25〜25質量 139873.doc 11 201000133 份，特別好的是0.5〜l〇質量份。 本發明之組合物特別好的是，使用二苯胺明、氨溴索、 依匹斯汀、去氧腎上腺素、$己新、依替福林、哌侖西 平、偽麻黃鹼、甲基麻黃鹼、洛派丁胺、卡比沙明馬來 酸、二氫可待因、異丙碘胺、無水咖啡因、茶鹼、乙醯胺 盼、布洛[右美沙芬或料之鹽、相花乾燥萃取物、 胡蘿蔔乾燥萃取物、野梧桐乾燥萃取物來作為呈異味之藥 物，使用單寧酸、沒食子酸丙醋或乙酸來作為酸性物質了 使用鋁偏矽酸鎂、碳酸鈣或矽酸鈣來作為鹼土金屬鹽及/ 或土族金屬鹽。 本發明之組合物係藉由在呈異味之藥物中調配作為遮蔽 劑的酸性物質以及驗土金屬鹽及/或土族金屬鹽而提供 的。於調配時，本發明之組合物係將呈異味之藥物與遮蔽 劑製成粉體再混合而得’亦可將該等之—部或全部溶解於 適當的溶劑，再藉由喷霧乾燥、加熱乾燥、冷;東乾燥、送 風乾燥、減壓乾燥等將該溶劑除去。χ，至於本發明之电 合物的劑形’可製成錠劑、顆粒劑、細粒劑、散劑、硬膠 囊劑、片劑（Cap⑻、軟膝囊劑、丸劑、内服液劑、縣浮 劑、乳劑、糖衆劑、乾糖漿劑”且嚼劑、發泡劑、滴劑、 口腔内崩解键、膜劑、膠劑等各種經口投予製劑後而使 用。又，在製成微膠囊、奈米膠囊、微球體、奈米球體、 脂質體等微小粒子後，再製成上述製劑。 該等製劑可視需要添加通常製劑學上可利㈣製劑添力 物、例如穩定化劑、穩定劑、界面活性劑、潤滑化劑； 139873.doc 201000133 滑劑、可溶（化）劑、緩衝劑、甜味劑、基劑、吸附劑、調 味劑、結合劑、懸浮（化）劑、硬化劑、抗氧化劑、光澤化 劑、香料、包衣劑、包衣、濕潤劑、濕潤調整劑、填充 劑、消泡劑、清涼（化）劑、哑嚼劑、抗靜電劑、芳香劑-香 料、著色劑、糖衣劑、等張劑、軟化劑、乳化劑、黏著 : 劑、增黏劑、黏調（化）劑、發泡劑、pH值調整劑、pH值調 ： 節劑、賦形劑、分散劑、崩解劑、崩解助劑、芳香劑、防 ❹ 濕劑、防腐劑、保存劑、溶解劑、溶解助劑、溶劑、流動 化劑等，藉由常法而製造。 作為製劑添加物之具體例，可列舉··精製白糖 '葡萄 糖、海藻糖（trehalose)、乳糖、麥芽糖、甘露醇 (mannitol)、山梨糖醇（s〇rbit〇1)、木糖醇（xyiit〇i)、赤藻糖 醇（erythritoi)、糖精鈉、阿斯巴甜、乙醯磺胺酸鉀、嚴糖 素（sucralose)'甘草萃取物、甜菊萃取物、羅漢果萃取 物、玉米澱粉（corn starch)、馬鈴薯澱粉、小麥澱粉、碳 〇 酸氫鈉、氣化鈉、結晶纖維素、甲基纖維素、乙基纖維 素、經丙基甲基纖維素、經丙基纖維素、m甲基纖維素、 叛曱基纖維素鈉、缓甲基纖維素軒、經丙基甲基纖維素鄰 : n酸g旨、乙酸鄰苯二甲酸纖維素、糊精、^凝粉、 - ~拉伯冑、明膠、海藻酸鈉、聚乙烯吡咯啶酮、聚乙烯 • si、羧乙烯聚合物、硬脂酸鎂、滑石、氫化植物油、聚乙 二醇（macrogol)、矽酮油、瓊脂、蟲膠、甘油、芳香性精 油類、水溶性食用色素、黃色氧化鐵、黃色三氧化二鐵： 三氧化二鐵、褐色氧化鐵、黑色氧化鐵、二氧化敛、色搬 139873.doc 13 201000133 色素、笨甲酸、苯甲酸鈉、對羥基苯曱酸、聚山梨醇酯 8〇、甘油脂肪酸酯、白蜂蠟、中鏈脂肪酸甘油三酯、抗壞 血k、生月酚、硫代硫酸鈉、依地酸鈉、橙或檸檬等柑橘 系香料或咖啡系香料、巧克力系香料、酸乳酪系香料、乳 系香料、或檸檬油、薄荷油、綠薄荷油、香辛料油等植物 精/由等。可用於本發明之組合物的製劑添加劑並不限定於 上述所列舉者，若為製劑學上可利用者，則並無特別限 定。 例如至於製劑，在需要利用錠劑、顆粒劑、細粒劑、散 劑、丸劑、乾糖漿劑等調整造粒末時，可藉由噴霧造粒 法、攪拌造粒法、流動造粒法、滾動造粒法、滾動流動造 粒法等濕式造粒法，壓密造粒法等乾式造粒法等通常所利 用的造粒法來製造。又，可將包含有效成分之粉末或造粒 末進行混合，細分成包而填充。錠劑係藉由將有效成分之 粉末、粉末劑、細粒劑、顆粒劑或丸劑與製劑添加物加以 混合、並壓縮成型而製造。糖衣錠、膜包衣錠、包衣顆粒 等包衣製劑係藉由鍋包衣法、流動包衣法、滾動包衣法、 以及該等之組合等常法而製造。 至於飲料劑、糖漿劑、酏劑、檸檬劑（lem〇nade)、萃取 物劑等内服液劑、以及填充有液狀或半固形物之軟膠囊 劑、硬膠囊劑等，通常係將各成分與純化水等溶劑等製劑 添加物之一部分加以混合、溶解、分散，並添加剩餘之溶 劑等製劑添加物來調整液量而進行製造。視需要可使用酸 或鹼來調整pH值。又，可藉由使用界面活性劑、可溶化 139873.doc -14- 201000133 劑、乳㈣、料料㈣添加㈣ 懸浮化。調整時視需要可實施加 ：,、礼化、 濾、滅菌處理等。 冷部、齓氣置換、過 進而視需要’可使用製劑 宗仆、螇键& 卿寻果賦予樂效成分之穩 盖、服用感u持續化、速崩化、速溶化、溶解性之改 ;使用之功能。賦予該等功能之方法可藉由通 节使用之方法來進行，例如可列舉以τ方法··將藥效成分(methylcobalamin), methylbenactyzium, methoxyphenamine, riboflavin, riboflavin sodium, ranitidine, lafutidine, Roxatidine acetate, losartan, loperamide, loratadine, aspirin, acetaminophen, isoproterenol Isopropyl antipyrine, ibuprofen, ethenzamide, diclofenac, salicylamide, mefenamic acid, flufenamic acid Acid), meloxicam, loxoprofen, tranexamic acid, etodolac, celecoxib, rofecoxib, Valdecoxib, parecoxib, etoricoxib, lumiracoxib, theophylline, fexofenadine, cetirizine Isopropanol Iodide), berberine, retinol palmitate, calcium pantothenate, bromovaleryryrerea, chloramphenicol, aminophyllin, belladonna dip Cream (belladonna total alkaloid), allyl isopropyl hydrazine and the like. Further, as biological extracts such as crude drugs, herbs, or Chinese herbal medicines, there are mentioned wild paulownia, catechin, aloe vera, scutellaria, ginkgo, fennel, scutellaria, cork, turmeric, uva ursi, and black medicinal herbs. , Rose hip, Yanhusuo, Yanmingcao, Phellodendron, Rhizoma Coptidis, Polygonum multiflorum, Rhizoma Curcumae, Valerian, Ginger, Licorice, Campanulaceae, Wushouye, Chlorella, Cinnamon, Gentian, Yeast, Yam, Rehmannia, Ginger, When medicine, bitter 139873.doc 201000133 蔘, safflower, rhubarb, jujube, peony, hawthorn, sage, jujube, diarrhea, clove, passionflower, vine hook, scorpion, cannon, peony , beer, aloe, carrot, pueraria soup, detoxification detoxification soup, sound of broken flute pills 'Xiaochaihu soup, Xiaoqinglong soup, Suanzaoren soup, Shiwei detoxification soup and other extracts. These drugs may be used singly or in combination of two or more. Particularly preferred among these drugs are diphenylamine, amoxime, epilis 'butoxyphenylephrine, bromhexine, etifeline, zuyuxiping, pseudoephedrine, decyl ephedrine, and loperidine. An amine, or a salt of these. In the present invention, the odor-producing drug is preferably contained in the oral composition in an amount of from 0.1 to 95% by mass, more preferably from 1 to 90% by mass. Further, in the composition of the present invention, in addition to the above-mentioned drugs, a drug can be formulated. For example, as such a drug, an antipyretic analgesic anti-inflammatory, a sedative hypnotic, an anti-sleeping agent, an anti-vertigo drug, a pediatric analgesic, a stomachic drug, an antacid, a digestive drug, a cardiotonic drug, an arrhythmia drug, Antihypertensive drugs, vasodilators, diuretics, antiulcer drugs, gastrointestinal drugs, osteoporosis treatment drugs, antitussive and expectorant drugs, antiasthmatic drugs, antibacterial agents, urinary frequency improvers, nourishing strongeners, vitamins, etc. Pharmacologically active ingredient. In the present invention, the masking agent is used by combining an acidic substance with an alkaline earth metal salt or a noble metal salt. The term "acidic substance" as used herein refers to a seasoning sword of a pharmaceutical additive which is acidic in nature. Specific examples thereof include tannin acid, gallic acid vinegar, citric acid, acetic acid, and tartaric acid. These may be used in combination or in combination of two or more kinds. In terms of the shielding effect of the odor, tannic acid, propyl gallate, and acetic acid are more preferable. 139873.doc -10- 201000133 The amount of the acidic substance to be added will also vary depending on the type of the odor-producing drug. Generally, it is preferably in the range of 0.05 to 50 parts by mass, more preferably 0.05 to 50 parts by mass, more preferably. It is particularly preferably 0.5 to 5 parts by mass, and particularly preferably 8 to 2 parts by mass. In the present invention, an alkaline earth metal salt and/or a soil metal salt is further added as a k-blocking agent as a soil-salt metal salt and/or a soil metal salt, which may be enumerated; one or two kinds of magnesium salt, calcium salt and aluminum salt. the above. 0 Specific examples of the alkaline earth metal salt and/or the earth metal salt include: magnesium aluminate magnesiumate (magnesium aluminium metasi Ucate), calcium carbonate, calcium carbonate hydrate, magnesium chloride, dried aluminum hydroxide gel, citric acid Calcium, calcium glycerophosphate, calcium gluconate hydrate, calcium citrate, magnesium citrate, magnesium aluminum silicate, synthetic aluminum citrate, synthetic hydrotalcite, calcium acetate, magnesium oxide, magnesium aluminum hydroxide, aluminum chloride gel , aluminum hydroxide-sodium bicarbonate coprecipitate, aluminum hydroxide-magnesium carbonate-calcium carbonate coprecipitate, magnesium hydroxide, tricalcium phosphate, magnesium carbonate, precipitated calcium carbonate, natural aluminum citrate, calcium lactate hydrate without water Calcium hydrogen citrate, anhydrous calcium hydrogen phosphate granules, aluminum sulfate, calcium sulfate, monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, dihydrogen phosphate hydrate, etc., can be used One type may be used in combination of two or more types. Among these, it is particularly preferable in terms of the shielding effect of the odor, such as magnesium citrate, calcium carbonate, and calcium citrate. The addition amount of the soil metal salt and/or the earth metal salt is also changed depending on the type or amount of the odor-producing drug, the type or amount of the acid substance, and is generally 1 part by mass relative to the acid substance, preferably 〇〇 5~50 mass injury 'better is 0.1~50 mass parts' especially good 〇 _25~25 mass 139873.doc 11 201000133 parts, particularly good is 0.5~l 〇 mass parts. The composition of the present invention is particularly preferably used, such as diphenylamine, ambroxol, eplesine, phenylephrine, hexaxin, ezetine, pirenzepine, pseudoephedrine, methylephedrine, Loperamide, carbitramine maleic acid, dihydrocodeine, isopropyl iodide, anhydrous caffeine, theophylline, acetaminophen, bulu [dextromethorphan or salt of the material, phase flower dry extraction Dry extract of carrot, wild sycamore, dried extract of wild paulownia as a odor-producing drug, using tannic acid, gallic vinegar or acetic acid as an acidic substance, using aluminum magnesium metasilicate, calcium carbonate or calcium citrate Comes as an alkaline earth metal salt and / or a soil metal salt. The composition of the present invention is provided by formulating an acidic substance as a masking agent and a soil-checking metal salt and/or a terrigenous metal salt in an odor-producing drug. When formulated, the composition of the present invention is obtained by mixing the odor-producing drug and the masking agent into a powder to obtain a part or all of the solvent dissolved in a suitable solvent, and then by spray drying, The solvent is removed by heating, drying, and cooling; drying in the east, drying in the air, drying under reduced pressure, or the like. χ, as for the dosage form of the electric compound of the present invention, it can be used as a tablet, granule, fine granule, powder, hard capsule, tablet (Cap (8), soft knee capsule, pill, oral liquid, county float Agents, emulsions, sugar collectors, dry syrups, and chewables, foaming agents, drops, intraoral disintegration bonds, films, gels, etc. are used after various oral administrations. After the microcapsules, nanocapsules, microspheres, nanospheres, liposomes, and the like, the above preparations are prepared. The preparations may be added as usual, and the preparations may be added to the preparations, such as stabilizers, Stabilizer, surfactant, lubricating agent; 139873.doc 201000133 slip agent, soluble agent, buffer, sweetener, base, adsorbent, flavoring agent, binding agent, suspending agent Hardeners, antioxidants, glossing agents, perfumes, coating agents, coatings, wetting agents, wetting regulators, fillers, defoamers, cooling agents, dulling agents, antistatic agents, fragrances - Perfume, coloring agent, sugar coating agent, isotonic agent, softener, emulsifier, sticky : agents, tackifiers, viscosity modifiers, foaming agents, pH adjusters, pH adjustments: agents, excipients, dispersants, disintegrants, disintegration auxiliaries, fragrances, Anti-mite agents, preservatives, preservatives, solubilizers, solubilizers, solvents, fluidizers, etc., are produced by a conventional method. Specific examples of the preparation additives include: refined white sugar 'glucose, seaweed Trehalose, lactose, maltose, mannitol, sorbitol (s〇rbit〇1), xylitol (xyiit〇i), erythritoi, sodium saccharin, aspartame , acetaminophen sulfamate, sucralose' licorice extract, stevia extract, mangosteen extract, corn starch, potato starch, wheat starch, sodium hydrogencarbonate, sodium carbonate, crystallization Cellulose, methylcellulose, ethylcellulose, propylmethylcellulose, propylcellulose, m-methylcellulose, ruthenium cellulose sodium, slow methylcellulose, propyl Methyl cellulose o: n acid g, cellulose acetate phthalate, dextrin, ^ powder, - ~ Raber, gelatin, sodium alginate, polyvinylpyrrolidone, polyethylene • si, carboxyvinyl polymer, magnesium stearate, talc, hydrogenated vegetable oil, macrogol, fluorenone oil, Agar, shellac, glycerin, aromatic essential oils, water-soluble food coloring, yellow iron oxide, yellow ferric oxide: ferric oxide, brown iron oxide, black iron oxide, oxidizing, color transfer 139873.doc 13 201000133 Pigment, benzoic acid, sodium benzoate, p-hydroxybenzoic acid, polysorbate 8 〇, glycerol fatty acid ester, white beeswax, medium chain fatty acid triglyceride, ascorbic acid k, raw phenol, sodium thiosulfate , citrus flavors such as sodium edetate, orange or lemon, coffee flavors, chocolate flavors, yoghurt flavors, milk flavors, or lemon oil, peppermint oil, spearmint oil, spice oil, etc. . The preparation additive which can be used in the composition of the present invention is not limited to the above-mentioned ones, and is not particularly limited as long as it is pharmaceutically acceptable. For example, as for the preparation, when it is necessary to adjust the granulation by using a tablet, a granule, a fine granule, a powder, a pill, a dry syrup, or the like, it can be spray granulated, stirred granulation, flow granulation, rolling It is produced by a granulation method generally used, such as a wet granulation method such as a granulation method or a rolling flow granulation method, or a dry granulation method such as a compact granulation method. Further, the powder or granules containing the active ingredient may be mixed and subdivided into a packet and filled. The tablet is produced by mixing a powder, a powder, a fine granule, a granule or a pill of an active ingredient with a formulation additive, and compression molding. The coating preparations such as sugar-coated tablets, film-coated tablets, and coated granules are produced by a usual method such as a pan coating method, a flow coating method, a roll coating method, and the like. As a beverage, a syrup, an elixir, a lemon (lem〇nade), an extracting agent, etc., and a soft capsule filled with a liquid or semi-solid, a hard capsule, etc., usually each component A part of the preparation additive such as a solvent such as purified water is mixed, dissolved, and dispersed, and a preparation additive such as a remaining solvent is added to adjust the amount of the liquid to be produced. Acid or base can be used to adjust the pH as needed. Further, it can be suspended (4) by using a surfactant, solubilizing 139873.doc -14-201000133, milk (4), and material (4). Adjustments can be implemented as needed: ,, ritual, filtration, sterilization, etc. The cold part, the hernia replacement, and the need to use the preparation of the servant, 螇 key &卿; fruit to give the effect of the composition of the ingredients, sustained susceptibility, rapid disintegration, rapid dissolution, solubility change ; the function used. The method of imparting such functions can be carried out by a method of general use, for example, a method of τ can be used.
調配至各顆粒中，製成多層顆粒，製成多層錠或有減， 製成各顆粒後it行打錠’製成微膠囊，製成糖衣錠 '膜包 衣錠、包衣顆粒等包衣製劑，製成發泡製劑，製成呕嚼製 劑，製成口腔内崩解製劑，製成基質製劑，進行共粉碎， 製成固溶體，添加甜味劑或清涼化劑，添加抗氧化劑或穩 定（化）劑，調整成特定pH值、黏度、滲透壓、鹽濃度等， 亦可將該等方法加以組合。 [實施例] 繼而，表示實施例及比較例，對本發明進行更具體說 明，但本發明並不限定於該等實施例及比較例。 實施例1 稱量二苯胺明鹽酸鹽（金剛化學製造）丨g、單寧酸（大曰 本住友製藥製造）1 g、及鋁偏矽酸鎂（富士化學工業製造）4 g ’並溶解、分散於純化水中，使總量達到100 mL，而獲 得實施例1之内服液劑。 比較例1 以與實施例1相同之方式，自實施例1除去單寧酸以及鋁 139873.doc •15- 201000133 偏矽酸鎂而獲得比較例la之内服液劑，自實施例1除去鋁 偏矽酸鎂而獲得比較例比之内服液劑，自實施例1除去單 寧酸而獲得比較例1 c之内服液劑。 實施例2 將實施例1之二苯胺明鹽酸鹽變更為氨溴索鹽酸鹽（陽進 堂製造）1 g，其他相同，而獲得實施例2之内服液劑。 比較例2 以與實施例2相同之方式，自實施例2除去單寧酸以及在呂 偏石夕酸鎂而獲得比較例2a之内服液劑，自實施例2除去紹 偏石夕酸鎂而獲得比較例2b之内服液劑，自實施例2除去單 寧酸而獲得比較例2c之内服液劑。 實施例3 將實施例1之二苯胺明鹽酸鹽變更為依匹斯汀鹽酸鹽 (Boehringer-Ingelheim製造）1 g，其他相同，而獲得實施例 3之内服液劑。 比較例3 以與實施例3相同之方式，自實施例3除去單寧酸以及铭 偏矽酸鎂而獲得比較例3a之内服液劑’自實施例3除去紹 偏矽酸鎂而獲得比較例3b之内服液劑，自實施例3除去單 寧酸而獲得比較例3c之内服液劑。 實施例4 將實施例1之二苯胺明鹽酸鹽變更為去氧腎上腺素鹽酸 鹽（Boehringer-Ingelheim製造）1 g’其他相同，而獲得實施 例4之内服液劑。 139873.doc -16 * 201000133 比較例4 以與實施例4相同之方式，自實施例4除去單寧酸以及鋁 偏矽酸鎂而獲得比較例4a之内服液劑，自實施例4除去鋁 偏矽酸鎂而獲得比較例4b之内服液劑，自實施例4除去單 寧酸而獲得比較例4c之内服液劑。 實施例5 將實施例1之二苯胺明鹽酸鹽變更為溴己新鹽酸鹽（岩城 製藥製造）1 g，其他相同，而獲得實施例5之内服液劑。 比較例5 以與實施例5相同之方式，自實施例5除去單寧酸以及鋁 偏矽酸鎂而獲得比較例5a之内服液劑，自實施例5除去鋁 偏矽酸鎂而獲得比較例5b之内服液劑，自實施例5除去單 寧酸而獲得比較例5 c之内服液劑。 實施例6 將實施例1之二苯胺明鹽酸鹽變更為依替福林鹽酸鹽 (Boehringer-Ingelheim製造）1 g，其他相同，而獲得實施例 6之内服液劑。 比較例6 以與實施例6相同之方式，自實施例6除去單寧酸以及鋁 偏矽酸鎂而獲得比較例6a之内服液劑，自實施例6除去鋁 偏矽酸鎂而獲得比較例6b之内服液劑，自實施例6除去單 寧酸而獲得比較例6c之内服液劑。 實施例7 將實施例1之二苯胺明鹽酸鹽變更為哌侖西平鹽酸鹽 17 139873.doc 201000133 (Boehringer-Ingelheim製造）1 g，其他相同，而獲得實施例 7之内服液劑。 比較例7 以與實施例7相同之方式，自實施例7除去單寧酸以及鋁 偏矽酸鎂而獲得比較例7a之内服液劑，自實施例7除去鋁 偏矽酸鎂而獲得比較例7b之内服液劑，自實施例7除去單 寧酸而獲得比較例7c之内服液劑。 實施例8 將實施例1之二苯胺明鹽酸鹽變更為偽麻黃鹼鹽酸鹽（阿 爾卑斯藥品工業（ALPS Pharmaceutical Ind.)製造）1 g，其 他相同，而獲得實施例8之内服液劑。 比較例8 以與實施例8相同之方式，自實施例8除去單寧酸以及鋁 偏石夕酸鎮而獲得比較例8 a之内服液劑，自實施例8除去铭 偏石夕酸鎮而獲得比較例8b之内服液劑，自實施例8除去單 寧酸而獲得比較例8c之内服液劑。 實施例9 將實施例1之二笨胺明鹽酸鹽變更為dl-甲基麻黃鹼鹽酸 鹽（阿爾卑斯藥品工業製造）1 g，其他相同，而獲得實施例 9之内服液劑。 比較例9 以與實施例9相同之方式，自實施例9除去單寧酸以及鋁 偏矽酸鎂而獲得比較例9a之内服液劑，自實施例9除去鋁 偏石夕酸鎂而獲得比較例9b之内服液劑，自實施例9除去單 139873.doc 18· 201000133 寧酸而獲得比較例9c之内服液劑。 實施例10 將實施例1之二苯胺明鹽酸鹽變更為洛派丁胺鹽酸鹽 (ICFI製造）1 g，其他相同’而獲得實施例1 〇之内服液劑。 比較例10 以與實施例10相同之方式，自實施例10除去單寧酸以及 ί呂偏石夕酸鎂而獲得比較例1 〇a之内服液劑，自實施例丨〇除 去銘偏矽酸鎂而獲得比較例l〇b之内服液劑，自實施例1〇 除去單寧酸而獲得比較例1 〇c之内服液劑。 試驗例1 5名健康被試驗者將實施例之内服液劑及比較例 1〜10之内服液劑約〇·5 mi含於口中，以不咽下之方式加以 留心並使之遍布舌頭，約15秒後吐出。按下述所示之5個 等級對此時之收斂性、刺激性、苦味、澀味、辣味等異味 之程度進行評價。Formulated into individual granules, made into multi-layered granules, made into multi-layered ingots or reduced, and made into individual granules, then made into ingots to make microcapsules, and made into coating preparations such as sugar-coated tablets' film-coated tablets and coated granules. , made into a foaming preparation, made into a chew preparation, made into an orally disintegrating preparation, made into a matrix preparation, co-pulverized, made into a solid solution, added with a sweetener or cooling agent, added with antioxidant or stabilized The agent can be adjusted to a specific pH, viscosity, osmotic pressure, salt concentration, etc., and these methods can also be combined. [Examples] Hereinafter, the present invention will be more specifically described by showing examples and comparative examples, but the present invention is not limited to the examples and comparative examples. Example 1 Weighed diphenylamineamine hydrochloride (manufactured by King Kong Chemical Co., Ltd.) 丨g, tannic acid (manufactured by Otsuka Sumitomo Pharmaceutical Co., Ltd.) 1 g, and aluminum magnesium metasilicate (manufactured by Fuji Chemical Industry Co., Ltd.) 4 g 'dissolved The liquid solution of Example 1 was obtained by dispersing in purified water to a total amount of 100 mL. Comparative Example 1 In the same manner as in Example 1, tannic acid and aluminum 139873.doc •15-201000133 magnesium metasilicate were removed from Example 1 to obtain an internal liquid of Comparative Example la, and aluminum was removed from Example 1. Magnesium citrate was used to obtain a comparative example of an internal liquid solution, and tannic acid was removed from Example 1 to obtain an internal liquid preparation of Comparative Example 1c. Example 2 The diphenylamine hydrochloride salt of Example 1 was changed to 1 g of ambroxol hydrochloride (manufactured by Yangjintang), and the others were the same, and the liquid preparation of Example 2 was obtained. Comparative Example 2 In the same manner as in Example 2, the tannic acid was removed from Example 2 and the internal solution of Comparative Example 2a was obtained by removing the magnesium sulphate, and the magnesium sulphate was removed from Example 2. The internal solution of Comparative Example 2b was obtained, and tannic acid was removed from Example 2 to obtain the internal solution of Comparative Example 2c. Example 3 The diphenylamine salt hydrochloride of Example 1 was changed to 1 g of Epstein salt hydrochloride (manufactured by Boehringer-Ingelheim), and the others were the same, and the liquid preparation of Example 3 was obtained. Comparative Example 3 In the same manner as in Example 3, tantalum acid and magnesium citrate were removed from Example 3 to obtain an internal liquid preparation of Comparative Example 3a, and a comparative example was obtained by removing magnesium bismuth citrate from Example 3. The liquid solution was taken in 3b, and the tannic acid was removed from Example 3 to obtain the internal solution of Comparative Example 3c. Example 4 The diphenylamine hydrochloride salt of Example 1 was changed to phenylephrine hydrochloride (manufactured by Boehringer-Ingelheim) 1 g', and the internal solution of Example 4 was obtained. 139873.doc -16 * 201000133 Comparative Example 4 In the same manner as in Example 4, tannic acid and aluminum magnesium metasilicate were removed from Example 4 to obtain an internal liquid preparation of Comparative Example 4a, and aluminum was removed from Example 4. The internal solution of Comparative Example 4b was obtained by magnesium citrate, and the tannic acid was removed from Example 4 to obtain the internal solution of Comparative Example 4c. Example 5 The diphenylamine hydrochloride salt of Example 1 was changed to 1 g of bromohexyl neohydrochloride (manufactured by Iwa City Pharmaceutical Co., Ltd.), and the others were the same, and the liquid preparation of Example 5 was obtained. Comparative Example 5 In the same manner as in Example 5, tannic acid and aluminum magnesium metasilicate were removed from Example 5 to obtain an internal liquid preparation of Comparative Example 5a, and aluminum aluminum metasilicate was removed from Example 5 to obtain a comparative example. The liquid solution was taken in 5b, and the tannic acid was removed from Example 5 to obtain the internal solution of Comparative Example 5c. Example 6 The diphenylamine hydrochloride salt of Example 1 was changed to ezetine hydrochloride (manufactured by Boehringer-Ingelheim) 1 g, and the others were the same, and the liquid preparation of Example 6 was obtained. Comparative Example 6 In the same manner as in Example 6, tannic acid and aluminum magnesium metasilicate were removed from Example 6 to obtain an internal liquid preparation of Comparative Example 6a, and aluminum aluminum metasilicate was removed from Example 6 to obtain a comparative example. The liquid solution of 6b was removed from the solution of Example 6 to obtain the internal solution of Comparative Example 6c. Example 7 The diphenylamine hydrochloride salt of Example 1 was changed to pirenzepine hydrochloride 17 139873.doc 201000133 (manufactured by Boehringer-Ingelheim) 1 g, and the others were the same, and the liquid preparation of Example 7 was obtained. Comparative Example 7 In the same manner as in Example 7, tantalum acid and aluminum magnesium metasilicate were removed from Example 7 to obtain an internal liquid preparation of Comparative Example 7a, and aluminum aluminum metasilicate was removed from Example 7 to obtain a comparative example. The liquid solution in 7b was obtained by removing tannic acid from Example 7 to obtain the internal solution of Comparative Example 7c. Example 8 The diphenylamine salt hydrochloride of Example 1 was changed to 1 g of pseudoephedrine hydrochloride (manufactured by ALPS Pharmaceutical Ind.), and the same was obtained, and the liquid preparation of Example 8 was obtained. Comparative Example 8 In the same manner as in Example 8, the tannic acid and aluminum bismuth acid acid were removed from Example 8 to obtain the internal liquid preparation of Comparative Example 8a, and the etched stone was removed from Example 8 The internal solution of Comparative Example 8b was obtained, and tannic acid was removed from Example 8 to obtain the internal solution of Comparative Example 8c. Example 9 The alicyclic amine hydrochloride salt of Example 1 was changed to 1 g of dl-methylephedrine hydrochloride (manufactured by Alpine Pharmaceutical Industries), and the others were the same, and the liquid preparation of Example 9 was obtained. Comparative Example 9 In the same manner as in Example 9, the tantalum acid and aluminum magnesium metasilicate were removed from Example 9 to obtain the inner liquid preparation of Comparative Example 9a, and the aluminum magnesium garnet was removed from Example 9 to obtain a comparison. In the liquid solution of Example 9b, the internal solution of Comparative Example 9c was obtained by removing the single 139873.doc 18·201000133 from Example 9. Example 10 The diphenylamine hydrochloride salt of Example 1 was changed to 1 g of loperamide hydrochloride (manufactured by ICFI), and the same was employed to obtain the internal solution of Example 1. Comparative Example 10 In the same manner as in Example 10, tannic acid and magnesium lanthanide were removed from Example 10 to obtain an internal liquid preparation of Comparative Example 1 〇a, and yttrium acid was removed from the Example 丨〇 The internal solution of Comparative Example 1b was obtained by magnesium, and the tannic acid was removed from Example 1 to obtain the internal solution of Comparative Example 1 〇c. Test Example 1 Five healthy subjects were placed in the mouth with the liquid medication of the examples and the liquid medication of Comparative Examples 1 to 10, and were placed in the mouth so as not to be swallowed and spread over the tongue. Spit out after 15 seconds. The degree of astringency, irritation, bitterness, astringency, spicy taste, and the like was evaluated at five levels as shown below.
1 :感覺到非常強異味 2 :感覺到異味 3 :感覺到較少異味 4 :似乎有異味 5 :什麼都未感覺到 將此時之得分的平始伯— μ 士， 值不於表1。實施例之本發明组合 物如表1所示，可遮蔽輯 蚊特別疋吉味、澀味、收斂性等非當 強之驗之鹽酸鹽的各藥物之非常 物質以及驗土金屬+ * ㈣此1含有酸性 屬孤及/或土族金屬鹽之任一種、 139873.doc -19· 201000133 種的比較例之組合物的異味未被遮蔽。 [表1] 實施例1 比較例la 比較例lb 比較例lc 藥物 4.8 1.0 1.6 1.0 二苯胺明鹽酸鹽 實施例2 比較例2a 比較例2b 比較例2c 5.0 1.8 2.6 1.8 氨溴索鹽酸鹽 實施例3 比較例3a 比較例3b 比較例3c 4.8 1.4 2.3 1.4 依匹斯汀鹽酸鹽 實施例4 比較例4a 比較例4b 比較例4c 4.8 1.6 2.4 1.6 去氧腎上腺素鹽酸鹽 實施例5 比較例5a 比較例5b 比較例5c 5.0 2.2 2.8 2.0 溴己新鹽酸鹽 實施例6 比較例6a 比較例6b 比較例6c 4.6 1.4 2.2 1.6 依替福林鹽酸鹽 實施例7 比較例7a 比較例7b 比較例7c 4.8 1.2 2.4 1.4 〇底余西平 實施例8 比較例8a 比較例8b 比較例8c 4.6 1.6 2.6 1.6 偽麻黃鹼鹽酸鹽 實施例9 比較例9a 比較例9b 比較例9c 4.8 2.0 2.8 2.0 dl-甲基麻黃鹼鹽酸鹽 實施例10 比較例10a 比較例10b 比較例10c 4.6 2.0 2.6 2.2 洛派丁胺鹽酸鹽 實施例11 稱量卡比沙明馬來酸鹽（金剛化學製造）1 g、單寧酸（大 曰本住友製藥製造）1 g、及鋁偏矽酸鎂（富士化學工業製 造）4 g，並溶解、分散於純化水中，使總量達到100 mL， 而獲得實施例11之内服液劑。 比較例11 以與實施例11相同之方式，自實施例11除去單寧酸以及 鋁偏矽酸鎂而獲得比較例11 a之内服液劑，自實施例11除 去鋁偏矽酸鎂而獲得比較例1 lb之内服液劑，自實施例11 除去單寧酸而獲得比較例11 c之内服液劑。 139873.doc •20- 201000133 實施例12 將實施例11之卡比沙明馬來酸鹽變更為二氫可待因磷酸 鹽(第一三共製造)1 g，其他相同’而獲得實施例!2之内服 液劑。 比較例121 : I feel very strong odor 2 : I feel odor 3 : I feel less odor 4 : I seem to have odor 5 : I don't feel anything I will score the score at this time - the value is not in Table 1. The composition of the present invention of the present invention, as shown in Table 1, can mask the extraordinary substances of the respective chemicals of the hydrochloride which are not the strong test of the mosquito, the astringency, the astringency, and the like, and the soil test metal + * (4) The odor of the composition of the comparative example containing 139873.doc -19·201000133 of any of the acid genus and/or the earth metal salt was not masked. [Table 1] Example 1 Comparative Example la Comparative Example lb Comparative Example lc Drug 4.8 1.0 1.6 1.0 Diphenylamineamine hydrochloride Example 2 Comparative Example 2a Comparative Example 2b Comparative Example 2c 5.0 1.8 2.6 1.8 Ambroxol hydrochloride implementation Example 3 Comparative Example 3a Comparative Example 3b Comparative Example 3c 4.8 1.4 2.3 1.4 Epsteinine hydrochloride Example 4 Comparative Example 4a Comparative Example 4b Comparative Example 4c 4.8 1.6 2.4 1.6 phenylephrine hydrochloride Example 5 Comparative Example 5a Comparative Example 5b Comparative Example 5c 5.0 2.2 2.8 2.0 Bromohexine hydrochloride Example 6 Comparative Example 6a Comparative Example 6b Comparative Example 6c 4.6 1.4 2.2 1.6 Etifolin hydrochloride Example 7 Comparative Example 7a Comparative Example 7b Comparison Example 7c 4.8 1.2 2.4 1.4 〇底余西平 Example 8 Comparative Example 8a Comparative Example 8b Comparative Example 8c 4.6 1.6 2.6 1.6 Pseudoephedrine hydrochloride Example 9 Comparative Example 9a Comparative Example 9b Comparative Example 9c 4.8 2.0 2.8 2.0 dl-methyl Ephedrine hydrochloride Example 10 Comparative Example 10a Comparative Example 10b Comparative Example 10c 4.6 2.0 2.6 2.2 Loperamide hydrochloride Example 11 Weighing of carbamine maleate (manufactured by King Kong Chemicals) 1 g, single Ning Acid (Otsuka Sumitomo) Manufacturing) 1 g, and the biasing aluminum magnesium silicate (manufactured by Fuji Chemical Co.) 4 g, and dissolved and dispersed in purified water to make total volume of 100 mL, internal liquid obtained in Example 11 of the embodiment. Comparative Example 11 In the same manner as in Example 11, tannic acid and aluminum magnesium metasilicate were removed from Example 11 to obtain an internal liquid preparation of Comparative Example 11a, and aluminum aluminum metasilicate was removed from Example 11 to obtain a comparison. Example 1 lb of the solution was taken and the tannic acid was removed from Example 11 to obtain the internal solution of Comparative Example 11c. 139873.doc • 20- 201000133 Example 12 The carbazomin maleate salt of Example 11 was changed to dihydrocodeine phosphate (first three co-manufactured) 1 g, the other identical 'to obtain an example! 2 Take the liquid agent. Comparative Example 12
. 以與實施例12相同之方$，ώ杳_ — & μ A J心乃式，自實施例12除去單寧酸以及 - 叙偏石夕酸鎮而獲得比較例12a夕ιλι HB .¾無丨^ . 平乂椚12a之内服液劑，自實施例12除 去IS偏石夕酸鎮而獲得比較例^ 9 h夕Λΐ BE Ά念丨 ❹ 权例12b之内服液劑’自實施例12 除去單寧酸而獲得比較例12e之内服液劑。 實施例13 將實施例11之卡比沙明馬來酸鹽變更為異丙碘胺 (NiPP〇nBulk Yakuhin製造}1 g，其他相同而獲得實施例 13之内服液劑。 比較例13 以與實施例13相同之方式，自實施例13除去單寧酸以及 〇 鋁偏矽酸鎂而獲得比較例13a之内服液劑，自實施例13除 去鋁偏矽酸鎂而獲得比較例13b之内服液劑，自實施例13 除去單寧酸而獲得比較例1 3c之内服液劑。 • 實施例14 將實施例11之卡比沙明馬來酸鹽變更為無水咖啡因（靜 岡吻》徘因工業所製造）1 g，其他相同，而獲得實施例14之 内服液劑。 比較例14 以與實施例14相同之方式，自實施例μ除去單寧酸以及 139873.doc -21- 201000133 鋁偏矽酸鎂而獲得比較例14a之内服液劑，自實施例14除 去鋁偏矽酸鎂而獲得比較例14b之内服液劑，自實施例14 除去單寧酸而獲得比較例14c之内服液劑。 實施例15 將實施例11之卡比沙明馬來酸鹽變更為茶鹼（白鳥製藥 製造）1 g ’其他相同，而獲得實施例15之内服液劑。 比較例15 以與實施例I5相同之方式，自實施例I5除去單寧酸以及 銘偏矽酸鎂而獲得比較例15a之内服液劑，自實施例15除 去銘偏石夕酸鎂而獲得比較例1 5b之内服液劑，自實施例1 5 除去單寧酸而獲得比較例1 5C之内服液劑。 實施例16 將實施例11之卡比沙明馬來酸鹽變更為乙醯胺酚（山本 化學工業製造）1 g，其他相同，而獲得實施例16之内服液 劑0 比較例1 6 以與實施例16相同之方式，自實施例Μ除去單寧酸以及 銘偏石夕酸鎮而獲得比較例16a之内服液劑，自實施例16除 去銘偏石夕酸鎂而獲得比較例16b之内服液劑，自實施例16 除去單争酸而獲得比較例16 c之内服液劑。 實施例1 7 將實施例11之卡比沙明馬來酸鹽變更為布洛芬（BASF製 造）1 g ’其他相同’而獲得實施例17之内服液劑。 比較例17 139873.doc 201000133 以與實施例17相同之方式，自實施例17除去單寧酸以及 銘偏石夕酸鎮而獲得比較例17 a之内服液劑，自實施例17除 去鋁偏矽酸鎂而獲得比較例17b之内服液劑，自實施例17 除去單寧酸而獲得比較例17c之内服液劑。 實施例18 將實施例11之卡比沙明馬來酸鹽變更為右美沙芬氫溴酸 鹽水合物（DSM NUTRITION JAPAN製造）1 g，其他相同， 而獲得實施例18之内服液劑。 比較例18 以與實施例18相同之方式，自實施例18除去單寧酸以及 紹偏石夕酸鎮而獲得比較例18a之内服液劑，自實施例18除 去鋁偏矽酸鎂而獲得比較例18b之内服液劑，自實施例18 除去單寧酸而獲得比較例1 8 c之内服液劑。 實施例19 將實施例11之卡比沙明馬來酸鹽變更為啤酒花乾燥萃取 物（阿爾卑斯藥品工業製造）1 g，其他相同，而獲得實施例 19之内服液劑。 比較例19 以與實施例19相同之方式，自實施例19除去單寧酸α及 銘偏石夕酸鎮而獲得比較例19a之内服液劑，自實施例19除 去鋁偏矽酸鎂而獲得比較例19b之内服液劑，自實施例i9 除去單寧酸而獲得比較例19c之内服液劑。 實施例20 將實施例11之卡比沙明馬來酸鹽變更為野梧桐乾燥萃取 139873.doc -23- 201000133 物（日本粉末藥品工業製造）i g，其他相同，而獲得實施例 20之内服液劑。 比較例20 以與實施例20相同之方式，自實施例20除去單寧酸以及 鋁偏矽酸鎂而獲得比較例20a之内服液劑，自實施例20除 去鋁偏矽酸鎂而獲得比較例20b之内服液劑，自實施例20 除去單寧酸而獲得比較例20c之内服液劑。 實施例21 將實施例11之卡比沙明馬來酸鹽變更為胡蘿蔔乾燥萃取 物（日本粉末藥品工業製造）丨g，其他相同，而獲得實施例 21之内服液劑。 比較例21 以與實施例21相同之方式，自實施例21除去單寧酸以及 紹偏矽酸鎂而獲得比較例21 a之内服液劑，自實施例21除 去銘偏矽酸鎂而獲得比較例21 b之内服液劑，自實施例21 除去單寧酸而獲得比較例21 c之内服液劑。 試驗例2 5名健康被試驗者使用實施例丨丨〜21之内服液劑及比較例 11〜2 1之内服液劑，以與試驗例i相同之方式，按5個等級 對異味之程度進行評價。 將此時之得分的平均值示於表2。實施例之本發明組合 物可遮蔽表2所示之各種性質之藥物的異味，相對於此， 不含有酸性物質以及鹼土金屬鹽及/或土族金屬鹽之任一 種、或其兩種的比較例之組合物的異味未被遮蔽。 139873.doc -24· 201000133 [表2] 實施例11 比較例11a 比較例lib 比較例11c 藥物 5.0 1.4 2.2 1.4 卡比沙明馬來酸鹽 實施例12 比較例12a 比較例12b 比較例12c 4.8 1.6 1.8 1.6 二氫可待因磷酸鹽 實施例13 比較例13a 比較例13b 比較例13c 4.6 1.2 1.6 1.2 異丙破胺 ΐ施例14 比較例14a 比較例14b 比較例14c 5.0 2.0 2.8 2.0 無水咖啡因 實施例15 比較例15a 比較例15b 比較例15c 5.0 1.4 3.2 1.6 茶鹼 實施例16 比較例16a 比較例16b 比較例16c 4.8 1.8 2.4 2.0 乙醯胺酚 實施例17 比較例17a 比較例17b 比較例17c 4.4 1.0 2.2 1.0 七备芬 實施例18 比較例18a 比較例18b 比較例18c 4.4 1.2 1.8 1.4 右美沙芬氫溴酸鹽水合物 貪施例19 比較例19a 比較例19b 比較例19c 5.0 1.4 2.6 1.6 啤酒花乾燥萃取物 實施例20 比較例20a 比較例20b 比較例20c 5.0 1.6 2.8 1.8 野梧桐乾燥萃取物 實施例21 比較例21a 比較例2 lb 比較例21c 5.0 1.4 2.4 1.4 胡蘿15乾燥萃取物 實施例22 ❹ 實施例22a :稱量二苯胺明鹽酸鹽（金剛化學製造）丨g、單 寧酸（大曰本住友製藥製造）0.05 g、以及鋁偏矽酸鎂（富士 化學工業製造）40 g，於純化水中混練後，將水分加熱乾燥 而除去。以每包50 mg二苯胺明鹽酸鹽之方式，將所得乾 燥粉末分包而獲得實施例22a之分包劑。 ’ 實施例22b :將實施例22a之單寧酸變更為〇.1 g，其他相 同，而獲得實施例22b之分包劑。 實施例22c :將實施例22a之單寧酸變更為〇.5 g，其他相 同，而獲得實施例2 2 c之分包劑。 139873.doc -25- 201000133 實施例22d :將實施例22a之單寧酸變更為0·8 g，其他相 同，而獲得實施例22d之分包劑。 實施例22e :將實施例22a之單寧酸變更為lg，其他相同， 而獲得實施例22e之分包劑。 實施例22f :將實施例22a之單寧酸變更為1.5 g，其他相 同，而獲得實施例22f之分包劑。 實施例22g :將實施例22a之單寧酸變更為2g，其他相 ， 同’而獲得實施例22g之分包劑。 · 實施例22h :將實施例22a之單寧酸變更為5 g，其他相 ❹ 同，而獲得實施例22h之分包劑。 實施例22i :將實施例22a之單寧酸變更為10 g，其他相 同’而獲得實施例22i之分包劑。 比較例22 除去實施例22a之單寧酸，其他相同，而獲得比較例22 之分包劑。 試驗例3 5名健康被試驗者將實施例22a 〜i及比較例22之分包劑含 〇 於口中，以不咽下 <方式加以留心並使之遍布舌頭，約15 &後吐出&下述所示5個等級對此時之收斂性、刺激 性、苦味、澀味、玆此& _ · 禪味專異味之程度進行評價。 1 :感覺到非常強異味 - 2 :感覺到異味 . 3 :感覺到較少異味 4 :似乎有異味 139873.doc -26 - 201000133 5 :什麼都未感覺到 將此時之得分的平均值示於表3。實施例之本發明組合 物如表3所示，相對於藥物1質量份，而利用0_05質量份以 上之調味劑即開始遮蔽藥物之異味，利用0.8質量份以上 之酸性物質則幾乎完全遮蔽異味。 [表3] 得分 酸性物質相對於藥物1之比 實施例22a 1.8 0.05 實施例22b 2.6 0.1 實施例22c 3.8 0.5 實施例22d 4.8 0.8 實施例22e 5.0 1.0 實施例22f 5.0 1.5 實施例22g 5.0 2.0 實施例22h 5.0 5.0 實施例22i 5.0 10.0 比較例22 1.0 0 實施例23a :稱量二苯胺明鹽酸鹽（金剛化學製造）1 g、單 寧酸（大日本住友製藥製造）1 g、及鋁偏矽酸鎂（富士化學 工業製造）0.05 g，並溶解、分散於純化水中，使總量達到 500 mL，而獲得實施例23a之内服液劑。 實施例23b :將實施例23a之鋁偏矽酸鎂變更為0.25 g，其 他相同，而獲得實施例2 3 b之内服液劑。 實施例23c :將實施例23a之鋁偏矽酸鎂變更為0.5 g，其他 相同，而獲得實施例23c之内服液劑。 實施例23d :將實施例23a之鋁偏矽酸鎂變更為1 g，其他 相同，而獲得實施例23d之内服液劑。 實施例23e :將實施例23a之鋁偏矽酸鎂變更為2 g，其他相 139873.doc -27- 201000133 同，而獲得實施例23e之内服液劑。 實施例23f :將實施例23a之鋁偏矽酸鎂變更為5 g，其他相 同，而獲得實施例23f之内服液劑。 實施例23g :將實施例23a之鋁偏矽酸鎂變更為10 g，其他 相同，而獲得實施例23g之内服液劑。 實施例23h :將實施例23a之鋁偏矽酸鎂變更為25 g，其他 相同，而獲得實施例23h之内服液劑。 實施例23i :將實施例23a之鋁偏矽酸鎂變更為50 g，其他 相同，而獲得實施例23i之内服液劑。 試驗例4 5名健康被試驗者使用實施例23a〜i之内服液劑，以與試 驗例1相同之方式，按5個等級對異味之程度進行評價。 此時之得分的平均值示於表4。實施例之本發明組合物 如表4所示，相對於酸性物質1質量份，而利用0.1質量份 以上之鹼土金屬鹽及/或土族金屬鹽即可遮蔽藥物之異 味。 [表4] 得分 鹼土金屬鹽及/或土族金屬鹽相對於 酸性物質之比 實施例23a 3.2 0.1 實施例23b 3.8 0.25 實施例23c 4.0 0.5 實施例23d 4.4 1.0 實施例23e 4.8 2.0 實施例23f 5.0 5.0 實施例23g 5.0 10.0 實施例23h 5.0 25.0 實施例23i 5.0 50.0 139873.doc •28- 201000133 實施例24 稱量二苯胺明鹽酸鹽（金剛化學製造）丨g、沒食子酸丙酯 (大曰本住友製藥製造）1 g、及銘偏;ε夕酸鎮（富士化學工業 製造）3 g，並溶解、分散於純化水中’使總量達到1 〇〇 mL，而獲得實施例24之内服液劑。 ； 實施例25 ； 將實施例24之沒食子酸丙酯變更為乙酸（日本合成化學 製造）1 g ’其他與實施例24相同’而獲得實施例25之内服 ^ 液劑。 實施例26 將實施例24之沒食子酸丙酯變更為酒石酸（昭和化工製 造）1 g，其他與實施例24相同，而獲得實施例26之内服液 劑。 實施例27 將實施例2 4之沒食子酸丙酯變更為檸檬酸（昭和化工製 ❹ 造）1 g，其他與實施例24相同，而獲得實施例27之内服液 劑。 實施例28 : 將實施例24之沒食子酸丙酯變更為單寧酸（大日本住友 1藥製造）1 g’其他與實施例24相同，而獲得實施例28之 内服液劑。 試驗例5 5名健康被試驗者使用實施例24〜28之内服液劑，以與試 驗例1相同之方式，按5個等級對異味之程度進行評價。 139873.doc -29· 201000133 此時之得分的平均值示於表5。實施例之本發明組合物 可利用表5所示之各種酸性物質來遮蔽異味。 [表5] 得分 酸性物質 實施例24 4.6 沒食子酸丙醋 實施例25 4.8 乙酸 實施例26 4.2 酒石酸 實施例27 4.2 檸檬酸 實施例28 4.8 單寧酸 實施例29 稱量二苯胺明鹽酸鹽（金剛化學製造）1 g、單寧酸（大曰 本住友製藥製造）1 g、碳酸鈣（日東粉化王製造）5 g，於純 化水中混練後，將水分加熱乾燥而除去，進而添加D-甘露 醇（Mitsubishi Shoji Foodtech製造）33 g、玉米澱粉（日本食 品化工製造）10 g，以每包50 mg二苯胺明鹽酸鹽之方式將 所得粉末進行分包而獲得實施例29之分包劑。 實施例30 將實施例29之碳酸鈣變更為矽酸鈣（德山（TOKUYAMA) 製造）5 g，其他與實施例29相同，而獲得實施例30之分包 劑。 實施例3 1 將實施例29之碳酸鈣變更為乾燥氫氧化鋁凝膠（協和化 學工業製造）5 g，其他與實施例29相同，而獲得實施例3 1 之分包劑。 實施例32 將實施例29之碳酸鈣變更為鋁偏矽酸鎂（富士化學工業 139873.doc -30- 201000133 製& )5 g，其他與實施例29相肖而獲得實施例^之分包 劑。 試驗例6 5名健康被試驗者❹實施例29〜32之分包劑，以與試驗 例3相同之方式，按5個等級對異味之程度進行評價。 口此時之仔分的平均值示於表6。實施例之本發明組合物 〇 表6所示之各種驗土金屬鹽及/或土族金屬鹽來遮蔽 異味。 [表6] 得分 鹼土金屬鹽及/或土族金屬鹽 實施例29 4.8 碳酸約 實施例30 4.6 矽酸鈣 實施例31 4.4 乾燥氫氧化鋁凝膠 實施例32 5.0 鋁偏矽酸鎂 [產業上之可利用性] 本發明之經口組合物可對呈異味之多數藥物遮蔽該藥物 特有的收斂性、刺激性、苦味、澀味或辣味等異味。該經 口組合物亦可廣泛用於固形製劑、液劑、半固形製劑之任 意劑形。進而，本發明之經口組合物一面遮蔽異味，一面 在服用後之遲延時間内立即釋放藥物，因此可應用於多數 速釋製劑。而且’本發明之經口固形組合物不僅容易服 用，而且多數患者可長期服用，係可實實在在發揮各種藥 物效果之製劑。 服用性優異，患者之依從性可期待得到提高， QOL(quality of life，生活品質）亦提高。 139873.doc •31 ·In the same way as in Example 12, ώ杳__ & μ AJ, the tannin acid was removed from Example 12, and the symmetry was obtained to obtain Comparative Example 12a 夕 λ λ HB .3⁄4丨^. The liquid solution of the flat 乂椚12a, the IS yttrium acid acid was removed from Example 12 to obtain a comparative example ^ 9 h Λΐ Ά Ά Ά 丨❹ 权 权 12 12 12 12 12 12 12 12 ' ' ' ' The liquid solution of Comparative Example 12e was obtained by tannic acid. Example 13 The carbissamin maleate salt of Example 11 was changed to isopropyl iodide (manufactured by NiPP〇n Bulk Yakuhin) 1 g, and the others were obtained to obtain the internal liquid agent of Example 13. Comparative Example 13 and Examples In the same manner, the tantalum acid of the comparative example 13a was obtained by removing tannic acid and bismuth aluminum ferrocyanate from Example 13, and the aluminum metasilicate was removed from Example 13, to obtain the internal liquid of Comparative Example 13b. The internal solution of Comparative Example 1 3c was obtained by removing tannic acid from Example 13. Example 14 The carbissamin maleate salt of Example 11 was changed to anhydrous caffeine (Shizuoka Kiss) manufactured by the Industrial Co., Ltd. 1 g, the others were the same, and the liquid preparation of Example 14 was obtained. Comparative Example 14 In the same manner as in Example 14, tannic acid was removed from Example μ and 139873.doc -21 - 201000133 aluminum magnesium metasilicate The liquid solution of Comparative Example 14a was obtained, and aluminum aluminum metasilicate was removed from Example 14 to obtain the internal liquid preparation of Comparative Example 14b, and tannic acid was removed from Example 14 to obtain the internal liquid preparation of Comparative Example 14c. 15 Change the carbissamin maleate salt of Example 11 to Theophylline (manufactured by Shiraishi Pharmaceutical Co., Ltd.) 1 g was otherwise the same, and the liquid preparation of Example 15 was obtained. Comparative Example 15 In the same manner as in Example I5, tannic acid and magnesium citrate were removed from Example I5. The liquid preparation of Comparative Example 15a was obtained, and the internal solution of Comparative Example 1 5b was obtained by removing magnesium magnesium sulphate from Example 15, and the tannic acid was removed from Example 15 to obtain the internal solution of Comparative Example 1 5C. Example 16 The carbiumamine maleate salt of Example 11 was changed to acetaminophen (manufactured by Yamamoto Chemical Industry Co., Ltd.) 1 g, and the others were the same, and the internal liquid agent of Example 16 was obtained. Comparative Example 1 6 and Example 16 In the same manner, the internal solution of Comparative Example 16a was obtained by removing the tannic acid and the smectic acid from the Example ,, and the internal liquid solution of Comparative Example 16b was obtained by removing the magnesium sulphate from Example 16. The liquid preparation of Comparative Example 16c was obtained by removing the acid from Example 16. Example 1 7 The carbissamin maleate salt of Example 11 was changed to ibuprofen (manufactured by BASF) 1 g 'Others identical' The liquid solution of Example 17 was obtained. Comparative Example 17 1398 73.doc 201000133 In the same manner as in Example 17, the tantalum acid was removed from Example 17, and the inner liquid of Comparative Example 17a was obtained by removing the tannic acid and the aluminum bismuth citrate from Example 17. The internal solution of Comparative Example 17b was obtained, and the tannic acid was removed from Example 17 to obtain the internal solution of Comparative Example 17c. Example 18 The carbissamin maleate salt of Example 11 was changed to dextromethorphan hydrobromide. The salt hydrate (manufactured by DSM NUTRITION JAPAN) was 1 g, and the others were the same, and the liquid preparation of Example 18 was obtained. Comparative Example 18 In the same manner as in Example 18, tannic acid and saponin were removed from Example 18 to obtain an internal liquid preparation of Comparative Example 18a, and aluminum aluminum metasilicate was removed from Example 18 to obtain a comparison. The liquid solution of Example 18b was obtained by removing tannic acid from Example 18 to obtain the internal liquid of Comparative Example 18 c. Example 19 The carbissamin maleate salt of Example 11 was changed to 1 g of a hop dried extract (manufactured by Alpine Pharmaceutical Industries), and the others were the same, and the liquid preparation of Example 19 was obtained. Comparative Example 19 In the same manner as in Example 19, tannic acid α and erbium acid were removed from Example 19 to obtain the internal liquid of Comparative Example 19a, and aluminum aluminum metasilicate was removed from Example 19. The liquid solution of Comparative Example 19b was obtained by removing tannic acid from Example i9 to obtain the internal solution of Comparative Example 19c. Example 20 The carbissamin maleate salt of Example 11 was changed to the wild paulownia dry extract 139873.doc -23- 201000133 (manufactured by Japan Powder Pharmaceutical Industry) ig, the others were the same, and the liquid solution of Example 20 was obtained. . Comparative Example 20 In the same manner as in Example 20, tannic acid and aluminum magnesium metasilicate were removed from Example 20 to obtain an internal liquid preparation of Comparative Example 20a, and aluminum aluminum metasilicate was removed from Example 20 to obtain a comparative example. The liquid solution in the solution of 20b was obtained by removing tannic acid from Example 20 to obtain the liquid preparation of Comparative Example 20c. Example 21 The carbissamin maleate salt of Example 11 was changed to a carrot dried extract (manufactured by Japan Powder Pharmaceutical Industry Co., Ltd.), and the others were the same, and the liquid preparation of Example 21 was obtained. Comparative Example 21 In the same manner as in Example 21, tannic acid and magnesium bismuth citrate were removed from Example 21 to obtain an internal liquid preparation of Comparative Example 21a, and a magnesium citrate was removed from Example 21 to obtain a comparison. The liquid solution of Example 21b was obtained by removing tannic acid from Example 21 to obtain the internal solution of Comparative Example 21c. Test Example 2 Five healthy subjects were treated with the liquid preparations of Examples 丨丨 to 21 and the internal liquid preparations of Comparative Examples 11 to 2, and the degree of odor was measured in five levels in the same manner as in Test Example i. Evaluation. The average value of the scores at this time is shown in Table 2. The composition of the present invention of the present invention can mask the odor of the drug of various properties shown in Table 2, and does not contain any of an acidic substance, an alkaline earth metal salt and/or a noble earth metal salt, or a comparative example thereof. The odor of the composition is not obscured. 139873.doc -24· 201000133 [Table 2] Example 11 Comparative Example 11a Comparative Example lib Comparative Example 11c Drug 5.0 1.4 2.2 1.4 Carbium samine maleate Example 12 Comparative Example 12a Comparative Example 12b Comparative Example 12c 4.8 1.6 1.8 1.6 Dihydrocodeine phosphate Example 13 Comparative Example 13a Comparative Example 13b Comparative Example 13c 4.6 1.2 1.6 1.2 Isopropylamine Example 14 Comparative Example 14a Comparative Example 14b Comparative Example 14c 5.0 2.0 2.8 2.0 Anhydrous Caffeine Example 15 Comparative Example 15a Comparative Example 15b Comparative Example 15c 5.0 1.4 3.2 1.6 Theophylline Example 16 Comparative Example 16a Comparative Example 16b Comparative Example 16c 4.8 1.8 2.4 2.0 Acetaminophen Example 17 Comparative Example 17a Comparative Example 17b Comparative Example 17c 4.4 1.0 2.2 1.0 Seven Preparation Example 18 Comparative Example 18a Comparative Example 18b Comparative Example 18c 4.4 1.2 1.8 1.4 Dexmesenil Hydrobromide Hydrate Formulation Example 19 Comparative Example 19a Comparative Example 19b Comparative Example 19c 5.0 1.4 2.6 1.6 Hop Extract Samples 20 Comparative Example 20a Comparative Example 20b Comparative Example 20c 5.0 1.6 2.8 1.8 Wild Sycamore Dry Extract Example 21 Comparative Example 21a Comparative Example 2 lb Comparative Example 21c 5.0 1.4 2.4 1. 4 Carrot 15 dry extract Example 22 实施 Example 22a: Weighing of diphenylamineamine hydrochloride (manufactured by King Kong Chemicals) 丨g, tannic acid (manufactured by Otsuka Sumitomo Pharmaceutical Co., Ltd.) 0.05 g, and aluminum hexanoic acid 40 g of magnesium (manufactured by Fuji Chemical Industry Co., Ltd.), after kneading in purified water, the water was dried by heating and removed. The resulting dry powder was sub-packaged in the form of 50 mg of diphenylamine hydrochloride hydrochloride to obtain the sub-packaging agent of Example 22a. Example 22b: The tannic acid of Example 22a was changed to 〇.1 g, and the others were the same, and the sub-packaging agent of Example 22b was obtained. Example 22c: The tannic acid of Example 22a was changed to 〇.5 g, and the others were identical to obtain the sub-packaging agent of Example 2 2 c. 139873.doc -25- 201000133 Example 22d: The tannic acid of Example 22a was changed to 0.8 g, and the others were identical to obtain the sub-packaging agent of Example 22d. Example 22e: The tannic acid of Example 22a was changed to lg, and the others were identical, and the sub-packaging agent of Example 22e was obtained. Example 22f: The tannic acid of Example 22a was changed to 1.5 g, and the others were identical to obtain the sub-packaging agent of Example 22f. Example 22g: The tannic acid of Example 22a was changed to 2 g, and the other phases were the same, and the sub-packaging agent of Example 22g was obtained. Example 22h: The tannic acid of Example 22a was changed to 5 g, and the other phases were the same to obtain the sub-packaging agent of Example 22h. Example 22i: The tannic acid of Example 22a was changed to 10 g, and the same was used to obtain the sub-packaging agent of Example 22i. Comparative Example 22 The tannic acid of Example 22a was removed, and the others were identical, and the sub-packaging agent of Comparative Example 22 was obtained. Test Example 3 Five healthy subjects were placed in the mouth with the sub-packaging agents of Examples 22a to i and Comparative Example 22, and were carefully placed in the mouth without swallowing <<>>, and sprinkled & The five grades shown below are evaluated for the degree of astringency, irritation, bitterness, astringency, and the degree of odor of the scent. 1 : I feel very strong odor - 2 : I feel odor. 3 : I feel less odor 4 : I seem to have odor 139873.doc -26 - 201000133 5 : Nothing is felt to show the average value of the score at this time table 3. As shown in Table 3, the composition of the present invention of the present invention starts to mask the odor of the drug with 0 to 5 parts by mass or more with respect to 1 part by mass of the drug, and almost completely shields the odor with 0.8 parts by mass or more of the acidic substance. [Table 3] Ratio of Scoring Acid to Drug 1 Example 22a 1.8 0.05 Example 22b 2.6 0.1 Example 22c 3.8 0.5 Example 22d 4.8 0.8 Example 22e 5.0 1.0 Example 22f 5.0 1.5 Example 22g 5.0 2.0 Example 22h 5.0 5.0 Example 22i 5.0 10.0 Comparative Example 22 1.0 0 Example 23a: Weighing of diphenylamineamine hydrochloride (manufactured by King Kong Chemicals) 1 g, tannic acid (manufactured by Dainippon Sumitomo Pharmaceutical Co., Ltd.) 1 g, and aluminum hemiplegia Magnesium acid (manufactured by Fuji Chemical Industry Co., Ltd.) was 0.05 g, dissolved and dispersed in purified water to a total amount of 500 mL, and the liquid preparation of Example 23a was obtained. Example 23b: The aluminum meta-magnesium silicate of Example 23a was changed to 0.25 g, and the other was the same, and the internal liquid of Example 2 3 b was obtained. Example 23c: The aluminum meta-magnesium silicate of Example 23a was changed to 0.5 g, and the others were the same, and the liquid preparation of Example 23c was obtained. Example 23d: The aluminum meta-magnesium silicate of Example 23a was changed to 1 g, and the others were the same, and the liquid preparation of Example 23d was obtained. Example 23e: The aluminum metasilicate of Example 23a was changed to 2 g, and the other phases 139873.doc -27-201000133 were the same, and the liquid preparation of Example 23e was obtained. Example 23f: The aluminum meta-magnesium silicate of Example 23a was changed to 5 g, and the others were the same, and the liquid preparation of Example 23f was obtained. Example 23g: The aluminum meta-magnesium silicate of Example 23a was changed to 10 g, and the others were the same, and the liquid preparation of Example 23g was obtained. Example 23h: The aluminum meta-magnesium silicate of Example 23a was changed to 25 g, and the others were identical, and the liquid preparation of Example 23h was obtained. Example 23i: The aluminum meta-magnesium silicate of Example 23a was changed to 50 g, and the others were the same, and the liquid preparation of Example 23i was obtained. Test Example 4 Five healthy subjects were evaluated for the degree of odor by five grades in the same manner as in Test Example 1, using the liquid medications of Examples 23a to i. The average value of the score at this time is shown in Table 4. In the composition of the present invention, as shown in Table 4, the odor of the drug can be masked by using 0.1 part by mass or more of the alkaline earth metal salt and/or the earth metal salt with respect to 1 part by mass of the acidic substance. [Table 4] Scoring ratio of alkaline earth metal salt and/or earth metal salt to acid substance Example 23a 3.2 0.1 Example 23b 3.8 0.25 Example 23c 4.0 0.5 Example 23d 4.4 1.0 Example 23e 4.8 2.0 Example 23f 5.0 5.0 Example 23g 5.0 10.0 Example 23h 5.0 25.0 Example 23i 5.0 50.0 139873.doc •28- 201000133 Example 24 Weighing of diphenylamine hydrochloride (manufactured by King Kong Chemicals) 丨g, propyl gallate (大曰This Sumitomo Pharmaceutical Manufacturing Co., Ltd.) 1 g, and Ming Bi; ε ̄ acid (manufactured by Fuji Chemical Industry Co., Ltd.) 3 g, and dissolved and dispersed in purified water 'to make the total amount of 1 〇〇 mL, and the internal solution of Example 24 was obtained. Agent. Example 25; The propyl gallate of Example 24 was changed to acetic acid (manufactured by Nippon Synthetic Chemical Co., Ltd.) 1 g 'Others as in Example 24' to obtain the liquid preparation of Example 25. Example 26 The propyl gallate of Example 24 was changed to 1 g of tartaric acid (manufactured by Showa Chemical Co., Ltd.), and the same as in Example 24, to obtain the internal liquid of Example 26. (Example 27) The propyl galate of Example 24 was changed to 1 g of citric acid (manufactured by Showa Chemical Co., Ltd.), and the same as in Example 24, except that the internal liquid of Example 27 was obtained. Example 28: The propyl gallate of Example 24 was changed to tannic acid (manufactured by Dainippon Sumitomo 1) 1 g' Others were the same as in Example 24, and the internal liquid preparation of Example 28 was obtained. Test Example 5 Five healthy subjects were evaluated for the degree of odor by five grades in the same manner as in Test Example 1, using the liquid medications of Examples 24 to 28. 139873.doc -29· 201000133 The average value of the scores at this time is shown in Table 5. The composition of the present invention of the examples can utilize various acidic substances shown in Table 5 to mask odor. [Table 5] Scoring Acids Example 24 4.6 Gallic acid vinegar Example 25 4.8 Acetic acid Example 26 4.2 Tartaric acid Example 27 4.2 Citric acid Example 28 4.8 Tannic acid Example 29 Weighing of diphenylamine hydrochloride 1 g of salt (manufactured by King Kong Chemical Co., Ltd.), 1 g of tannic acid (manufactured by Otsuka Sumitomo Pharmaceutical Co., Ltd.), and 5 g of calcium carbonate (manufactured by Nitto Powder Chemical Co., Ltd.). After mixing in purified water, the water is dried by heating and removed, and then added. D-mannitol (manufactured by Mitsubishi Shoji Foodtech) 33 g, corn starch (manufactured by Nippon Food Chemical Co., Ltd.) 10 g, and the obtained powder was sub-packaged in the form of 50 mg of diphenylamine hydrochloride hydrochloride to obtain the score of Example 29. Bag. Example 30 The calcium carbonate of Example 29 was changed to 5 g of calcium citrate (manufactured by Tokuyama), and the same as Example 29, and the sub-packaging agent of Example 30 was obtained. Example 3 1 The calcium carbonate of Example 29 was changed to 5 g of a dry aluminum hydroxide gel (manufactured by Kyowa Chemical Industry Co., Ltd.), and the same procedure as in Example 29 was carried out to obtain a sub-packaging agent of Example 31. Example 32 The calcium carbonate of Example 29 was changed to aluminum magnesium metasilicate (Fuji Chemical Industry 139873.doc -30-201000133, &) 5 g, and other examples were obtained in the same manner as in Example 29, and the sub-package of Example ^ was obtained. Agent. Test Example 6 Five healthy subjects were subjected to the sub-packaging agents of Examples 29 to 32, and the degree of odor was evaluated in five levels in the same manner as in Test Example 3. The average value of the mouth at this time is shown in Table 6. The composition of the present invention of the examples 各种 various soil metal salts and/or earth metal salts shown in Table 6 to mask odor. [Table 6] Scoring alkaline earth metal salt and/or earth metal salt Example 29 4.8 Carbonic acid About Example 30 4.6 Calcium citrate Example 31 4.4 Dry aluminum hydroxide gel Example 32 5.0 Aluminum magnesium metasilicate [Industrial Availability The oral composition of the present invention can mask the odor such as astringency, irritation, bitterness, astringency or spicy taste peculiar to the drug to most drugs having an odor. The oral composition can also be widely used in any form of a solid preparation, a liquid preparation, or a semi-solid preparation. Further, the oral composition of the present invention can be applied to most immediate release preparations while masking the odor and releasing the drug immediately after the delay period after administration. Further, the oral solid composition of the present invention is not only easy to use, but also can be used for a long period of time in most patients, and is a preparation which can exert various drug effects. Excellent patient use, patient compliance can be expected to improve, and QOL (quality of life) is also improved. 139873.doc •31 ·