JPH09509669A

JPH09509669A - Granular product or tablet containing effervescent system and pharmaceutically active substance and preparation method thereof

Info

Publication number: JPH09509669A
Application number: JP7522671A
Authority: JP
Inventors: ゲルゲリイ、ゲルハルト; ゲルゲリイ、イルムガルト; ゲルゲリイ、トーマス; ゲルゲリイ、シュテファン
Original assignee: Individual
Current assignee: Individual
Priority date: 1994-03-01
Filing date: 1995-02-23
Publication date: 1997-09-30
Also published as: RU2153331C2; CN1142182A; HU9602380D0; DE670160T1; CZ251996A3; HUT75677A; TW403658B; BR9506964A; NZ281228A; NO315308B1; FI963385L; AU681256B2; CA2183952A1; FI118033B; PL181714B1; PL316113A1; WO1995023594A1; NO963588L; HU228147B1; NO963588D0

Abstract

(57)【要約】本発明により、制酸作用を妨げるのに特に有益であり、約1.6 〜約2.3 g 当たり5 meq 未満の酸結合能力を有する酸に敏感な製剤学的活性物質、例えばβ-カロテン、シメチジン、ラニチジン又はシサプリドを含む、発泡系を備えた顆粒生成物を提供する。この発泡性顆粒は、少なくとも１種の食用に適した固体有機酸、好ましくはクエン酸の担体結晶から作られ、製剤学的活性物質とは別の顆粒生成物として存在し、水及び／又はアルコールに可溶で酸の顆粒の表面の融点降下の可能な中性物質、例えば水溶性ポリマー、高級アルコール、炭水化物及び／又はヒドロコロイドの少なくとも１つの層で被覆されている。第二の被覆は、全調剤のために備えられるアルカリ金属又はアルカリ土類金属の炭酸塩又は炭酸水素塩の少なくとも一部を含んでいる。 (57) [Summary] According to the present invention, acid-sensitive pharmaceutically active substances, such as β-carotene, cimetidine, ranitidine, which are particularly useful for preventing antacid action and have an acid binding capacity of less than 5 meq per about 1.6 to about 2.3 g. Alternatively, there is provided a granular product with an effervescent system comprising cisapride. The effervescent granules are made from carrier crystals of at least one edible edible solid organic acid, preferably citric acid, which is present as a granulated product separate from the pharmaceutically active substance, and is water and / or alcohol. Of the acid granules are soluble in water and capable of lowering the melting point on the surface of the granules, for example at least one layer of a water-soluble polymer, higher alcohols, carbohydrates and / or hydrocolloids. The second coating contains at least part of the alkali metal or alkaline earth metal carbonate or bicarbonate provided for the entire preparation.

Description

【発明の詳細な説明】発泡系及び製剤学的活性物質を含む顆粒状生成物又は錠剤並びにその調製方法発明の分野本発明は、顆粒状製剤学的調合剤(granular pharmaceutical preparation)に関し、更に詳しくは、発泡系(effervescent system)、− 好ましくは酸に敏感な − 例えばシサプリド、β-カロテンのような製剤学的物質、例えばシメチジン又はラニチジンのような H2-遮断剤、及び／又は、比較的少量の発泡性成分又は比較的少ない酸結合能力を有する発泡性の製剤学的調合剤に添加すべき物質を含む錠剤に関する。発明の背景従来、酸に敏感な薬剤を発泡性錠剤又は発泡性インスタント顆粒状生成物に安定な形で混合することは、困難であった。そのような成分は、発泡系の酸に触れると加水分解し又は分解し、そのために、安定な保存ができない。更に、このような物質が水の表面張力に影響する場合には、必ず、発泡性溶液を服用する場合に極めて好ましくない泡立ちが生ずるか、或いは、いずれにせよ、薬剤中の疎水性粒子がガラス壁をはい上がる傾向がある。他方では、発泡性錠剤の制酸副作用が多くの薬剤にとって好ましくないこともある。従って、本発明の目的は、上記の欠点のない発泡系を用意し、疎水性又は水の表面張力に影響する性質を有する酸に敏感な物質を含む製剤学的物質を飲用しやすい発泡性溶液として患者に投与する可能性を提供することにある。更に、本発明の目的は、望ましくない制酸作用を避けるために酸結合能力が５ meq（ミリ当量）未満の発泡性錠剤又は発泡性インスタント顆粒状生成物を得ることにあり、この点は、全ての H2-遮断剤にとって特に有利である。最後に、錠剤又は顆粒状生成物が約15〜20℃の水に約２分未満の時間で速やかに溶解することは、望ましいことである。本発明の要約本発明によれば、前記の問題は、次の方法で簡単に、効果的な経費で有効に解決することができる。即ち、その方法は、先ず、酸の顆粒表面の融点降下に有効な少なくとも一種の中性物質を含む成分で酸の粒子を実質的に被覆し、続いて、アルカリ金属及び／又はアルカリ土類金属の炭酸塩又は炭酸水素塩並びに場合によっては、炭酸塩又は炭酸水素塩と同じ有機酸又は異なる有機酸との部分反応生成物、を含む少なくとも１層の第二の被覆をその上に付着するというものである。次に、本発明を詳細な検討と幾つかの好ましい実施例とにより更に詳しく説明する。発明の詳細本発明の意味する中性物質とは、水及び／又はアルコールに可溶のポリマー、例えばポリビニルピロリドン、炭水化物、例えばサッカロース、ペンタエリトリトール、グルコース及びフラクトース（但し最後の二つは炭酸水素塩の被覆による微アルカリ性の発泡性顆粒の表面の影響でメイラード反応を受け黄変しやすいのでここでは余り好ましくない）、ヒドロコロイド、例えばマルトデキストリン、デキストリンなどである。特に、高級アルコール、例えば、キシリトール、マンニトール及びソルビトールが好ましい。本発明の種々の実施態様は従属請求の範囲の限定事項に記載してある。 W093/00886 号には、確かに、異なる酸、恐らくグルコン酸に加水分解するグルコン酸δ-ラクトンを酸性賦形剤結晶の表面に導入して結晶格子に欠陥をもたらし、その融点を下げる方法が公表されている。しかし、このような方法では、勿論酸に敏感な活性物質を適切に保護することはできない。従って、これまで W 093/00886 の発明を酸に敏感な活性物質に対して実際に使用することは不可能であった。更に、発泡性錠剤用の酸性賦形剤結晶を、例えば、ポリビニルピロリドン、カルボキシメチルセルロースなどの薄いポリマー層で被覆することが提案された（英国特許第 1 270 781号）。しかし、この方法では、好ましくない溶解時間の遅れを招き、更に、その実施例に記載の１〜５重量% のポリビニルピロリドンを使用した場合には、泡立ちの問題が生ずる。更に、被覆をエタノール溶液又は水溶液で実施した場合には、酸の種類によっては、これが結晶賦形剤から層の溶液に移行し、そのため、酸に敏感な物質が充分保護されなくなる。更に、このような技術をもってしても、酸に敏感な活性物質を発泡系に添加する場合の問題を、貯蔵安定性に関してのみならず、非常に低い酸結合能力と短い溶解時間とを備えた比較的小さい錠剤に関しても、20年以上の間満足に解決することができなかった。一般に、発泡性錠剤が 120秒以内、好ましくは90秒以内に溶解（又は完全に懸濁）した場合に、これを特に急速であると定義する。しかし、本発明によれば、（好ましくは少量の）中性物質を酸の顆粒に塗布してから、酸と活性物質との間の相互作用を防ぐために、アルカリ金属及び／又はアルカリ土類金属の炭酸塩及び／又は炭酸水素塩の粒子を顆粒の表面に付着する。更に、EP-A1-415 326 には、酸性賦形剤結晶を一定量の砂糖で炭酸水素塩と組み合わせて数回被覆して、チュアブル錠又は菱形錠に僅かの炭酸の剌激効果を与える方法が提案されているが、この方法では、問題又は課題の組合せを解決することはできなかった。このようなシステムは適当な時間内に発泡性錠剤を水に溶解できるほど充分活性ではない。この欧州特許 EP- A1 の発明は、口の中で望ましくない強い発泡効果が生じないように酸と炭酸塩との間の反応を遅らせるのがその目的であった。従来技術（US A-4 127 645）に記載のように、酸、炭酸水素塩及び炭酸塩を含む芯を有する錠剤を中性物質、例えば水溶液、アルコール溶液又は水／アルコール混合溶液に溶かしたソルビトールで被覆したとしても、芯の中に含まれた酸に敏感な活性物質を確実に保護することはできない。しかし、もし混合物を中性物質（例えば、モルトデキストリン、必要ならば、砂糖との混合物、US A-4 650 6 69; ソルビトールとビタミン、US A-5 223 264、刺激性チュアブル錠にのみ適する）と共に圧縮して錠剤にすれば、両方の反応成分が一緒に被覆されるか、或いは、好ましくない塊状顆粒が生ずる。どちらの場合にも、錠剤の溶解反応は遅くなって、溶解時間が掛かりすぎるか、或いは、溶液が望ましくないほど多量の砂糖を含むようになる。更に、塊状顆粒の場合、その表面に酸の粒子も又保護されずに存在する可能性が大きい。そうなれば、酸に敏感な活性物質は更に不安定となる。米国特許第 4 867 942号には、食用に適する固体有機酸の賦形剤結晶の表面を、緩衝剤として作用する前反応させた溶液により被覆する方法が記載されている。その後、更に多くの酸性結晶及び炭酸塩又は炭酸水素塩の相当量をこの被覆の上に並べて付着する。種々の中和部分反応の際に生ずる水分は、アルコールによる最終処理と真空乾燥により除かれる。しかし、このような方法は、酸の結晶の表面で追加の酸が同時に炭酸アルカリと反応を始め、この反応が非常に速く進行するので充分均一には行われない、という点で、酸に敏感な薬剤にとって不利である。そのため、この方法で製造された製剤では、顆粒の表面に存在する酸の結晶のために、この製剤の中に混合した、酸に敏感な薬剤の反応を完全に防ぐことができない。これとは反対に、本発明の発泡系の構造は、酸に敏感な薬剤と酸の結晶との直接の接触を防止して発泡性の錠剤又は顆粒状生成物の貯蔵安定性を向上するのみならず、充分小さい錠剤の調製、即ち、溶解した時に緩衝系となる発泡成分の量の更に少ない錠剤の調製を可能にする。このようにして、本発明によるこの錠剤は、制酸性発泡性製剤の緩衝系とは対照的に、酸結合能力を５ meq より遙かに少ない量にすることができる。また、製剤調製の場合、反応の遅延と錠剤への圧縮性の向上とが達成される。本発明によって、シサプリドのような酸に敏感な薬剤やシメチジンのような H2 遮断剤を含み、錠剤（又は顆粒剤）の重量が僅か 1 .6〜2.3 g に対して５ meq 未満の酸結合能力を有する発泡性錠剤の調製が始めて可能になる。更に、本発明の特に有利な実施例によれば、酸の結晶を中性物質の被膜で覆った後で、一回の用量に予定した炭酸塩及び／又は炭酸水素塩の少なくとも一部をこの被覆に加えて、発泡性顆粒を中性物質の最初の被覆とその上に炭酸塩及び／又は炭酸水素塩（その一部はある場合には酸と部分的に反応する）の第二の被覆とを設けた酸の結晶から形成する。本発明は、例えばEP B1-76 340、US A- 4 867 942 及びW093/00886号に記載の製剤又は方法に特に有利に使用することができ、これらの記述と請求の範囲とはここで公表されたものとみなす。中性物質、特にソルビトール溶液の塗布により、例えば、クエン酸結晶の表面の融点が下がる。こうして、一方では、アルカリ金属又はアルカリ土類金属の炭酸塩及び／又は炭酸水素塩を含む第二の被覆に対する付着力が増加し、同時に、このことはクエン酸結晶表面の反応が更にゆっくり、従って、更に均一に行われ、不動態化が向上し、酸に敏感な薬剤への発泡性顆粒の影響が少なくなることを意味する。他方では、融点降下により、クエン酸又は生成したクエン酸塩の再結晶時間が長くなり、従って、より長い時間にわたっての発泡性顆粒の圧縮性が向上する。酸性賦形剤結晶に塗布する中性物質の量は、水溶液には最大50〜70重量% 溶解することができるので、酸を湿らせるのに使用しうる溶剤の量によって決まる。従って、酸に対して好ましくは0.05〜1.0 重量%、特に、0.07〜0.8 重量% 加えられる。0.07% 未満の添加量では、僅かの効果しか得られず、0.05% 未満では、本発明による効果がみられなくなり、酸に敏感な活性物質の貯蔵安定性が低下する。0.8%を超えると一般に阻害の影響が始まり、1.0%以上でクエン酸の反応性と発泡系の反応性とが著しく低下する。しかし、顆粒の場合には、顆粒を水に入れたときに、先ず、沈んでその後で始めて溶解反応に入るようにするために、より長い溶解時間が望ましい傾向があるので、上記の点は、この場合余り問題ではない。しかし、他方では、中性物質は、実際に溶液として塗布され、50乃至最高70% の溶液を作ることができるので、例えばクエン酸に塗布しうる中性物質の量は、クエン酸を湿らすのに使用しうる溶剤の量によって決まる。クエン酸の結晶を無限に大量の水で濡らすことはできず、それゆえ、溶剤でも濡らすことはできない。場合によっては、中性の被覆に、特にその上に炭酸塩及び／又は炭酸水素塩の粒子が付着していれば、少量の食用に適する固体の有機酸及び場合によって賦形剤結晶を形成する酸とは異なる酸 − それ自体は他の関連で公表された −をここでは融点降下を促進し及び／又は発泡反応と溶解速度を制御するために含ませることができる。そのような発泡性顆粒は、それだけで実際に小さな発泡性『錠剤』であり、それ自体で発泡する。従って、必要ならば、短い溶解時間、少しの量及び僅かの酸結合能力とすることができる。クエン酸の代わりにクエン酸一ナトリウムを使用して迅速に作用する小さい発泡性錠剤を取得しようとしたが、クエン酸一ナトリウムの反応が炭酸水素ナトリウムに比べて遅く、そのため、得られる錠剤の発泡反応が非常に遅くなり、又そのような錠剤の酸消費能力が５ meq を超えるので、そのようなこれまでの実験は失敗に終わった。一方では、本発明による非常に薄いクエン酸一ナトリウムの被覆は、１モルのクエン酸一ナトリウムが１モルの結晶水と結合し、乾燥又は乾燥度の維持に寄与するので、特に三番目又は四番目の層として有効であり、この層は必要ならば追加の中性物質を含んでもよい。更に、いずれにせよ被覆されていないクエン酸の表面を更に炭酸水素塩で再度又はもっと完全に覆うことができる。更に、多くの物質には、ある種の味があり、その多くが不快であり、特にその多くがにがみを呈するので、最終の発泡溶液、特に、それは飲料であるから、pH を 3.8〜4.6 の範囲に保つことが望ましい。この範囲が特ににがい物質を効果的に隠すことが実験により判明した。必須の条件ではないが、反応顆粒から残留水分をその調製の過程中にアルコールを用いた最終処理により除去することが望ましい。乾燥の際に、残留水分は、アルコールと共に蒸発して除去されるので、アルコールは、結晶水の結合を妨げているようである。最終製品の錠剤の溶解を促進するために、アルコールに少量の消泡剤を加えてもよい。前述の薬剤の多く、特にシメチジンとシサプリドは発泡性錠剤の泡立ちを起こしやすい。しかし、これは界面活性剤によって生ずる泡立ちではない。即ち、界面活性剤だけを水の中に撹拌しても泡立ちしないが、錠剤中の発泡性粒子を溶かせば二酸化炭素の気泡を生ずる。これらの気泡は、はじけて表面に二酸化炭素を残す。ここで、もし、溶解度の低いか疎水性の高い物質が存在していれば、溶けなかった粒子が二酸化炭素の気泡を包み、そのような薄膜の形成が気泡の急速な破裂を防ぐので、気泡はこの薄膜と共に表面に集まって『泡』となる。しかし、既に発泡性顆粒の間に形成されたこの『泡』が反応の継続とそれによる錠剤や顆粒の急速な溶解とを妨げる。この状況は、本発明によれば、少なくとも一種の消泡剤を微量加えることにより対処でき、その結果、発泡反応によって形成された『泡』の全てが直ちに崩壊し始める。消泡剤は、好ましくは、充填剤、香味料などを含めた全量に対して 0.005〜0. 5 重量%、或いは、活性物質に対して0.05〜2.0 重量% 加えられる。0.005%未満の添加では、発明による効果は、得られない。添加量が0.5%を超えると、障害や好ましくない副作用が生ずる。シミチジンのように可溶性ではあるが溶解限度のある活性物質の場合には、活性物質に対して 0.1〜0.3 重量 % のシメチコンを使用する。これは錠剤全量に対して 0.016〜0.028 重量%(約0.03%)に相当する。シサプリド（一水和物を使用）のような不溶性の疎水性活性物質の場合にはこの状況が幾らか異なっており、活性物質に対して１% のシメチコンが用いられるが、これは錠剤重量 1.6 gに対しては 0.006% の量である。シサプリドは、僅かに可溶性の疎水性活性物質であるので、泡立ち防止のために多量の消泡剤を必要とするが、必要な充填剤や発泡ベース(efferverscent base)により錠剤に対するシメチコンの量が遙かに少なくなるので、その比率が逆になるということがわかる。シメチジン、ラニチジンのような可溶性活性物質の場合には、発泡錠剤の溶解の際の局部的反応での泡立ちの傾向は少ないので、この泡立ちを抑えるために、必要なシメチコンの必要量は、少なくてすむが、一方、シサプリドの場合には− 前述のように − 泡立ちの傾向は遥かに大きく、従って、その原理もいくらか異なっている。使用量が多くなると、シメチコンが発泡溶剤の溶解後に表面に薄膜を形成する。これは − 特に不溶性活性物質の場合に − 活性物質の粒子が集まって表面に浮かぶためで、好ましくない溶解現象である。この薄膜は、更に硝子の壁にリングを形成する傾向がある。しかし、場合によっては、界面活性剤、例えば、ドクセートナトリウム（ジオクチルスルホコハク酸ナトリウム）を微量加えることがある。その湿潤性によって、上記のような薬剤粒子は速く溶解し、気泡に付着することがなくなる。そのような物質の量は、希望する溶解特性が得られるように極めて正確に定める必要がある。消泡剤を発泡系及び／又は薬剤に塗布できる場合もあるがこれは本発明によれば好ましくはない。第一の場合、所要の効果を達成するのに充分な非常に少量の消泡剤を用いた場合は別として、発泡系への塗布が発泡性成分の溶解と反応とを遅らせるので望ましくない。第二の場合は、消泡剤をある溶剤（例えばメチルエチルケトンとアセトン）に溶かした溶液から40℃で薬剤に加えた場合に、その溶解度や安定性が損なわれないような薬剤にのみ適用可能である。更に、細かく粉砕した薬剤を用いた製造の過程で消泡剤を添加すると、薬剤粒子が消泡剤の小滴に付着するため薬剤の分散が悪くなる可能性もある。従って、本発明によれば、最初に消泡剤と中性物質とから成る普通の顆粒状生成物を作るようにして、この顆粒状生成物に発泡系と薬剤、必要ならば更に助剤（例えば香料、甘味剤など）を加えてから、混合物を錠剤の形に圧縮するのが好ましい。発泡系の調製の際に中和反応によって発生し、加熱処理及び／又は真空処理によっては完全には除去できない水分、並びに貯蔵の際に空気から吸収した水分は、吸湿剤、特に無水の炭酸ナトリウム（１モル当たり10モルの水分を吸収できる）又は硫酸ナトリウムを加えてこれとうまく結合させることができる。吸湿剤は賦形剤結晶の被覆の一つ又は幾つかに加えるか、或いは全体の混合物に加えるようにする。この方法で、酸に敏感な活性物質と酸との反応が水分の減少によって更に抑えられるか、或いは、完全に阻止されて、貯蔵性が向上する。但しそのような吸湿剤、例えば炭酸ナトリウムを過剰に加えると発泡反応を遅らせるので好ましくない。従って、乾燥剤としての炭酸ナトリウムは、発泡性顆粒を完全に覆う程使用してはならない。なぜなら、単に残留水分を除去するために、又は製造中の反応を遅らせるために、或いは錠剤の溶解時間が不当に長くならないために、有効な少量のみで処理するのが好ましいからである。従って、炭酸ナトリウムの最後の添加には、顆粒の量と大きさ(約0.1 〜0.05 mm)の両方によって定まる完全な被覆（又は錠剤コーティング）のための量を使用すべきではない。従って、既に存在している炭酸水素塩の上に連続した被覆を形成することは適当でない。しかし、発泡性顆粒の上に部分的に付着させることは可能である。しかしながら、乾燥操作の終わるまで炭酸ナトリウムを加えないことも可能である。原理的には、錠剤当たりの炭酸ナトリウムの量は、例えば使用した発泡ベースの量、使用した充填剤の量と種類、例えば炭酸カルシウムのような他の炭酸塩の存在などのいくつかの要因によって左右される。吸湿剤、特に炭酸ナトリウムを（充填剤、風味剤などを含む全量に対して）１〜10重量%、特に４〜６重量% 加えるのが好ましい。４% 未満の添加では効果が充分でなく、１% 未満では乾燥効果と安定性の向上があまりに少なく、本発明による効果は得られない。また、炭酸ナトリウムの溶解と反応が遅いために添加量が６% を超えると、一般に好ましくない効果があらわれるようになり、10% を超えると発泡性錠剤の溶解の際に炭酸ナトリウムがまず水分（10モルまでの結晶水）を吸収し、即ち、残留水分を除去してからクエン酸と反応するので、溶解時間がそれだけで著しく長くなる。ここで強調すべきことは、結晶水の１モルをソルビトールの層の中又は上に生成したクエン酸ナトリウムの１モルだけで結合することができ、どのような量の残留水分が存在していてもソルビトールの層が薬剤に対する酸の悪影響を防止し又は妨げる、ということである。本発明により規定される全ての手順によれば、前述の厄介な物質を使用した場合でも、錠剤重量が例えば 1.6 gで溶解時間が 100秒未満の発泡性錠剤を作ることができる。但し、特にシメチジンの場合には、その疎水性のために、他の条件が同じ場合でも他の薬剤に比べて溶解時間が長くなることに注意する必要がある。ソルビトール溶液を加えた顆粒は、例えば W093/00886 により必要とされた他の酸を添加しなくとも迅速に溶解することができる。更に、本発明の発泡系の調製の際に、また、錠剤自体の全ての場合に、本発明により採られる各手順により、個々の結晶又は顆粒の表面で行われる反応を制御して、局部的機構(local mechanism)を構成することができ、溶解の際にも前述の望ましい特徴が残りなく達成される。このシステムは、酸に敏感でしかも水に溶けにくい物質の処理に特に良く適している。そのような物質、例えばシサプリドは、懸濁液の中で、前述のように沸騰システムと共に泡立ちを生じやすく、ガラス壁に付着し、醜いリングを形成し、飲み物の表面で塊をつくるなどの非常に厄介な挙動を示す。前述の全ての問題は、別々の顆粒を調製することにより効果的に解決できる。本発明のもう一つの実施例に、この目的のための方法が記載してあり、それによれば、エアロジル及び／又は中性物質から構成しうる賦形剤を用意し、その上に薬剤を加え、その際好ましくはその顆粒の表面を部分的に溶解し、及び／又は必要ならば結合剤及び／又は界面活性剤を使用し、乾燥し、或いは結合剤により賦形剤の表面に結合する。懸濁物質の量が多いと錠剤の溶解後の顆粒粒子の沈降が増加するので、例えばシサプリドの場合、その量は最高８重量%、好ましくは 4.5重量%(混合物全体に対して)に限られる。一方、使用する結合剤の量も同様に１重量% 迄で、それを超えると活性物質、懸濁物質及び結合剤が凝集するようになり、凝集した塊は溶解し難く底に沈降して所要の懸濁液の生成を妨げるので好ましくない。次に、好ましい実施例により、本発明をよく理解されるように更に詳しく説明する。しかし、これらの実施例は単に例示のためのものであり、本技術に堪能な人にはその他の多くの実施態様や変更が容易に思い浮かぶ筈であり、従って、発明又は請求の範囲又はその要旨をこれらの実施例が決して限定するものでないことを理解される必要がある。例えば、薬剤をメチルエチルケトン又はアセトンに溶解してマンニトール、ア実施例１：シメチジン 200 mg を含む発泡性錠剤の調製 a) 発泡系の調製粗製のクエン酸 102重量部と微細粉末のクエン酸又は酒石酸25重量部（粉体は約 30%までの炭酸水素塩が付着できる粗い面を形成するので賦形剤結晶の上での発泡性顆粒の形成を改善するために好ましい）を予熱した真空タンクの中に吸引し撹拌しながら約60℃に加熱する。次に水とソルビトール各36重量部、クエン酸 21重量部及び炭酸水素ナトリウム７重量部から調製した溶液１の0.85重量部を吸引して撹拌によりクエン酸の上に分配(distributed)する。続いて炭酸水素ナトリウム52.5重量部とアスパルテーム 4.4重量部とを上記の混合物に加えて撹拌しながら200 mbar迄の真空下で乾燥し、更に炭酸ナトリウム 1.9重量部を吸引して撹拌により混合物の中に分散し、得られた混合物を 15 mbar迄の真空下で乾燥する。次に前記溶液の 0.6重量部を吸引して撹拌により混合物の中に分配する。生成した発泡性顆粒を撹拌しながら 20 mbar迄の真空下で乾燥する。必要ならば混合物を乾燥するために 96%エタノール0.25重量部を吸引使用する。次に再度炭酸ナトリウム 9.3重量部を発泡性顆粒の表面に付着させる。再度乾燥してから製品をふるいを通して取り出す。 b) 粒状の消泡剤の調製 80℃のジャケット付き真空混合タンクの中にソルビトール粉末 7.7 重量部を加えて50℃に加熱する。次にシメチコンのブタノン/アセトン混合物(5:3)の30% 溶液 0.2重量部を吸引し、振動混合法により撹拌し、15mbar迄の真空下で少なくとも45℃の温度で乾燥する。 c) 全混合物の調製ミキサーの中で、シメチジン20重量部と必要ならばソルビトール粉末21.1重量部とを a) で調製した発泡系178.4 重量部と共に10分間６rpm の回転数で混合する。次に b) で調製し 0.6 mm のふるいを通した消泡剤顆粒７重量部とレモンの香味料 4.5重量部とを加えて、更に、５分間６rpm で混合する。得られた混合物を圧縮して錠剤にする。この錠剤は重量2.3 g でシメチジン 200 mg を含み、その硬さは６〜８ kp である。実施例２：シメチジン 200 mg と発泡性顆粒の中にクエン酸とリンゴ酸とを含む発泡性錠剤の調製粗製のクエン酸 102重量部とクエン酸粉末25重量部とリンゴ酸 1.1 重量部とを予熱した真空タンクの中で撹拌しながら60℃に加熱する。水 0.4重量部、ソルビトール0.22重量部及びリンゴ酸0.22重量部から成る溶液を吸引し、混合してクエン酸の上に分布する。次に炭酸水素ナトリウム52.5重量部とアスパルテーム 4 .4重量部とを上記の混合物に加えて撹拌しながら200 mbar迄の真空下で乾燥し、更に炭酸ナトリウム 1.9重量部を吸引して撹拌により混合物の中に分布し 15 mb ar迄の真空下で乾燥する。最後にエタノールにより最終的に乾燥してもよい。更に炭酸ナトリウム 9.3重量部を混合物に加え、その後の工程を実施例１に準じて実施する。実施例３：シメチジン 400 mg と中性物質としてマンニトールとを含む発泡性錠剤の調製クエン酸49重量部を予熱した真空タンクの中に吸引し撹拌しながら60℃に加熱する。次に水0.25重量部とマンニトール0.20重量部とから成る溶液１の0.45重量部を吸引し、混合してクエン酸の上に分布し、その上に炭酸水素ナトリウム14.7 重量部とアスパルテーム 3.2 重量部とを加える。反応を撹拌により開始し、乾燥を200 mbar迄の真空下で実施する。続いて炭酸ナトリウム 0.5重量部を吸引して撹拌により混合物の中に分布し 15 mbar迄の真空下で乾燥する。次に、溶液１にクエン酸一ナトリウム0.16重量部を加えて調製した溶液２の0.5 重量部を混合物中に吸引し混合により分布する。こうして得られた発泡性顆粒を 20 mbarの真空中で撹拌しながら乾燥し、最後に炭酸ナトリウム 2.8重量部を加える。この混合物にシメチジン17.3重量部、マンニトール 4.3重量部、ソルビトール８重量部、香味料0.9 重量部及び実施例 1 b) により調製した消泡剤顆粒 0.9重量部を添加し均一に分布するまで混合する。実施例４：シメチジン 300 mg と中性物質としてマルトデキストリンとを含む発泡性錠剤の調製実施例３と同様に、300 mg シメチジン発泡性錠剤に対してマルトデキストリンの50％溶液を選び、これを400 mg の錠剤の場合と同じ量使用した。錠剤が100〜400 mg のシメチジンを含有する実施例の全てに於いて、錠剤の重量を2.3 g にすることができる。これらの錠剤の溶解時間は好ましくは60〜15 0 秒で緩衝能は 5 meq未満である。この緩衝能は USP（米国薬局法）XXIIに準じて発泡性錠剤を水７０mlに溶解し、これに１．０Ｎ塩酸を３０ml添加した溶液を（0.5 N 水酸化ナトリウム）逆滴定して測定する。表１に示した数字は、例示した好ましい実施例のそれぞれの全体の混合物に対する個々の成分の百分率で、従ってそれぞれの成分の好ましい範囲を示す。シメチジン 100，200，300及び 400 mg を含む、重量 2.31 g のシメチジン発泡性錠剤又は顆粒の袋の好ましい組成を表２に纏めた。実施例５：シサプリド発泡性錠剤 a) 発泡性顆粒の調製結晶性クエン酸 655重量部、クエン酸粉末70重量部及びサッカリンナトリウム８重量部を60℃に加熱しながら混合する。これに、ソルビトール 0.6重量部、クエン酸三ナトリウム 0.3重量部、クエン酸 0.5重量部及び水 1.6重量部から成る溶液 2.8重量部を前記混合物に吸引して混合により分配する。次に炭酸水素ナトリウム 340重量部とアスパルテーム２重量部とを加えて反応させる。炭酸ナトリウム77重量部を加えてから、混合物をゆっくり撹拌しながら15mbarの真空下で乾燥する。 b) 薬剤顆粒の調製不溶性で疎水性のシサプリドを次のようにして結合剤と少量の界面活性剤とにより懸濁物質に付着する: シサプリド10重量部、ポリビニルピロリドン２重量部及びドクセートナトリウム 0.8重量部をエタノール１重量部及びアセトン40重量ら乾燥する。得られた顆粒を0.1 〜0.3 mmのふるいに通す。 c) 最終混合物の調製発泡性顆粒1152重量部にマルトデキストリン50重量部、ラクトース 100重量部、マンニトール 184重量部、香味料40重量部、消泡顆粒50.2重量部（マンニトール50重量部をシメチコン 0.2重量部で被覆）及び b) で調製した薬剤顆粒を加え、均一に分布するまで15分間混合し、混合物を圧縮して 1.6 gの錠剤を作る。この錠剤の酸結合能力は僅か２ meqである。このような低い酸結合能力のシサプリド発泡性錠剤はこれまで知られていない。実施例６: β-カロテン発泡性錠剤この特に酸及び酸化に敏感な物質の場合には、酸の被覆に特に注意を払う必要がある。β-カロテンの表面及び接触範囲はアルカリ性に保たなければならない。従って発泡性性顆粒の少なくとも一部は炭酸カルシウムで覆って、アルカリ性の表面を確保する。しかしながら、このため溶解時間がいくらか長くなる。この場合、錠剤が溶けてからβ-カロテンが懸濁するまでに時間が掛かるので、長くなった溶解時間はむしろ好ましい。US A-5 223 264の最初に記載のような大量のソルビトールは、水に溶解又は懸濁する目的のβ-カロテン発泡性錠剤にとって決して好ましくはない。 a) 発泡性顆粒の調製クエン酸1315重量部、サッカリンナトリウム７重量部及びシクラミン酸ナトリウム45重量部を真空タンクの中で50℃に加熱する。これに炭酸カルシウム 3.6重量部、クエン酸19重量部、ソルビトール12重量部及び水45重量部から調製した溶液16.8重量部を撹拌しながら加え、混合によりクエン酸の上に分配する。次に、炭酸カルシウム400 重量部とクエン酸190 重量部とを加え、混合物を撹拌しながら60℃に加熱する。更に上記の溶液44重量部により第二の顆粒化を実施し、分配（bistributing）と混合後、炭酸水素ナトリウム403 重量部を加え、更に乾燥の前に炭酸ナトリウム52重量部を加える。次に混合物を緩く撹拌しながら 15 mbar の真空下で乾燥する。 b) 最終混合物の調製ソルビトール 130重量部、マンニトール 540重量部、香味料50重量部、100%β -カロテンの２〜15重量部に相当する、水に懸濁可能のカプセル入りβ-カロテン、必要ならばビタミンＣ及び／又は水に懸濁可能の固体のトコフェリルアセタート50〜 250重量部（100%トコフェリルアセタートの10〜75重量部に相当）、更に必要ならばその他のビタミン類を、a)で調製した沸騰顆粒2415重量部と共に、混合する。この生成物は、重量 3.3 gの錠剤重量を有し、その溶解時間は、60〜90 秒である。実施例７: ラニチジン発泡性錠剤 a) 発泡性顆粒の調製結晶性クエン酸 840重量部、クエン酸粉末 210重量部、シクラミン酸ナトリウム45重量部及びサッカリンナトリウム４重量部を60℃の真空混合タンクの中で加熱する。その後、水６重量部、クエン酸ナトリウム１重量部及びソルビトール３重量部から成る溶液を吸引、そして混合により分配する。続いて、炭酸水素ナトリウム 500重量部を加えて反応させる。更に、クエン酸一ナトリウム 370重量部を加えてこれも反応させる。最後に、炭酸ナトリウム 100重量部を加えてから、顆粒をゆっくり撹拌しながら15 mbar までの真空下で乾燥する。 b) 最終混合物の調製このように調製した発泡性顆粒に塩酸ラニチジン 167重量部、マンニトール 1 25重量部、顆粒化した消泡剤 100.4重量部（マンニトール 100重量部とシメチコン 0.4重量部の構成）及び香味料を加える。この混合物を均一に分布するように 15分間混合し、2.5 g の錠剤に圧縮する。この錠剤は、溶解時間60〜80秒及び酸結合能力約２meq を有し、そして、（重量% で表して）塩酸ラニチジン 6.8、クエン酸42.0、クエン酸一ナトリウム14.8、炭酸水素ナトリウム20.0、炭酸ナトリウム 4.0、甘味剤 2.0、マンニトール 5.0、ソルビトール 0.1、顆粒化消泡剤 4 .0（ジメチルポリシロキサン0.016 を含む）及び香味料 1.2を含有する。実施例８: 結晶性クエン酸 545重量部及びクエン酸又は酒石酸の粉末 133重量部を60℃に加熱しながら混合する。次に、第一の被覆として水６重量部とソルビトール４重量部とから成る溶液を撹拌しながら前記混合物の表面に分布する。次に炭酸水素ナトリウム 222重量部をクエン酸の表面で反応させ、最後に炭酸水素ナトリウム 80重量部を加える。生成物をゆっくり撹拌しながら乾燥する。得られた顆粒を 1 .5 mm のふるいに通し、これを塩酸ラニチジン 167重量部、消泡剤顆粒（シメチコン 0.4重量部及びラクトース 100重量部を含む） 100重量部、甘味剤54重量部並びに香味料40重量部と共に一様な分布が得られるように10rpm の回転数で10 分間混合する。この混合物を圧縮して1.43 gの重量の錠剤を作る。この錠剤は、溶解時間65〜70秒、硬度８、酸結合能力約 1.5 meqを有する。このように低い酸結合能力を有するラニチジン発泡性錠剤は、これまで公表されたことがない。実施例９: クエン酸38.2% をサッカリンナトリウム0.26% と共に60℃に加熱し、これに最終混合物に対して水0.6%、ソルビトール0.18% 及びクエン酸ナトリウム0.12% から成る溶液の2/3 を加えて、10rpm の回転数で５分間混合して分配する。次に炭酸水素ナトリウム16.2% 及びアスパルテーム2.9%を加えて、中性物質の被覆膜の上の反応により、クエン酸の表面に付着させる。続いて前記溶液の1/3 で第二の湿潤を行う。次に、クエン酸一ナトリウム12.9%、最後に、炭酸ナトリウム 5.2 %をそれぞれ加える。得られた発泡性顆粒をゆっくり混合しながら少なくとも50 ℃の温度で15 mbar の真空下で乾燥する。このベースとなる発泡性顆粒生成物1. 5 mmのふるいを通してから、これに塩酸ラニチジン11.0%、マンニトール6.5%、消泡剤顆粒6.5%及び香味料0.2%を混合し、この混合物を圧縮して1.55 gの重量の錠剤を作る。この錠剤は、溶解時間50秒、硬度7.3 及び酸結合能力２ meq未満を有する。実施例10: 中性物質のみで被覆した賦形剤結晶顆粒例えば、シサプリドは、ラニチジンと比較して酸との反応性が同じほど高くはないので、やはりシサプリドを後述の方法によって酸に対して保護することも可能であり、この場合、薬剤が顆粒中に埋められるのでそれだけなお有効である。 a) 中性物質で被覆した酸結晶の調製結晶性クエン酸 593重量部及びクエン酸粉末70重量部を60℃に加熱し、これにソルビトール４重量部を水４重量部に溶かした溶液を加え、混合してクエン酸の表面に分配する。このように被覆したクエン酸を最後に50〜60℃で真空乾燥する。ここで述べた形態の発泡性製剤及び第二のアルカリ又はアルカリ土類金属の炭酸塩の被覆を含む形態の発泡性顆粒の両方の場合において、炭酸水素ナトリウムを添加して、シサプリドを薬剤顆粒中のクエン酸の作用から保護することが可能である。 b) 薬剤顆粒の調製マニトール 160重量部、シサプリド10重量部、アエロジル５重量部及び炭酸水素ナトリウム10重量部を混合しながら60℃に加熱する。メチルエチルケトン27重量部（又はアセトン45重量部）、アルコール２重量部、ポリ(ビニルピロリドン) K30 ２重量部、プロピレングリコール１重量部及びドクセートナトリウム 0.8重量部から成る溶液の半分を加えて、一様に濡らすように５分間分配する。混合物を 0.8 barで乾燥し、溶液の残りの半分を吸引し、５〜10分撹拌して再度分配し、最後に乾燥する。得られた活性物質の顆粒を 0.3 mm のふるいを通す。これは、この状態で既に含有する炭酸水素ナトリウムにより、酸の作用に対して向上した保護作用を有する。この顆粒を前記の中性物質で被覆した酸結晶、残りの炭酸塩及び炭酸水素塩、並びに他の錠剤成分と混合し、混合物を圧縮して錠剤にすることができる。 c) 最終混合物の調製 a)により乾燥被覆したクエン酸を b) により調製した薬剤顆粒、甘味剤50重量部、炭酸ナトリウム80重量部、炭酸水素ナトリウム 430 重量部、マルトデキストリン50重量部、ラクトース100重量部、マンニトール 150重量部、消泡剤顆粒5 0重量部及び香味料20重量部と混合し、圧縮して約 1.6 gの錠剤にする。この硬度７の錠剤は60〜70秒で溶解する。実施例11: シサプリド発泡性錠剤 a) 発泡性顆粒の調製顆粒 300重量部、微細顆粒80重量部及び粉末40重量部から成るクエン酸をサッカリンナトリウム５重量部と共に、ソルビトール 0.4重量部、炭酸水素ナトリウム0.15重量部、クエン酸0.45重量部及び水 1.2重量部から成る溶液 2.2重量部により60℃で均一に濡らす。次に、リンゴ酸12重量部を吸引し、クエン酸結晶の上に形成したソルビトールの層に均一に付着させる。最後に、炭酸水素ナトリウム 205重量部及びアスパルテーム 1.2重量部を吸引して再度均一に分配する。最後にこの材料を炭酸ナトリウム46重量部で被覆し、真空乾燥してから 1.2 mm のふるいを通す。 b) 活性成分顆粒の調製ポリビニルピロリドン12重量部をエタノール12重量部に溶かす。そして、プロピレングリコール６重量部及びドクセートナトリウム６重量部を加え、得られた混合物をエチルメチルケトン 165重量部で希釈する。この溶液の半分を、マンニサプリド61重量部からなる混合物の上に分配し、60℃に加熱する。真空下で部分的に乾燥してから残りの半分の溶液で濡らし、完全に乾燥して 0.3 mm のふるいを通す。最終混合物は実施例５に準じて調製する。DETAILED DESCRIPTION OF THE INVENTION Granular products or tablets containing an effervescent system and a pharmaceutically active substance and a process for their preparation. Field of the invention The present invention relates to a granular pharmaceutical preparation, more particularly an effervescent system, preferably acid sensitive-for example a pharmaceutical substance such as cisapride, β-carotene. , A tablet comprising an H2-blocking agent such as cimetidine or ranitidine and / or a substance to be added to a relatively small amount of an effervescent component or an effervescent pharmaceutical formulation having a relatively low acid binding capacity . Background of the Invention Traditionally, it has been difficult to mix acid sensitive drugs into effervescent tablets or effervescent instant granular products in a stable form. Such components hydrolyze or decompose on contact with the foaming acid, which prevents stable storage. Furthermore, when such substances influence the surface tension of water, there is always a very unfavorable bubbling when taking effervescent solution, or in any case the hydrophobic particles in the drug are glass. Tends to climb up the wall. On the other hand, the antacid side effects of effervescent tablets may be unfavorable for many drugs. Therefore, an object of the present invention is to prepare a foaming system which does not have the above-mentioned drawbacks, and to prepare a foamable solution containing a substance sensitive to an acid having a property of affecting hydrophobicity or surface tension of water. To provide the possibility to administer to the patient. Furthermore, it is an object of the present invention to obtain effervescent tablets or effervescent instant granular products with an acid binding capacity of less than 5 meq (milliequivalents) in order to avoid undesired antacid action. Particularly advantageous for all H2-blockers. Finally, it is desirable for the tablet or granular product to dissolve rapidly in water at about 15-20 ° C in less than about 2 minutes. SUMMARY OF THE INVENTION According to the present invention, the above-mentioned problems can be solved simply, effectively and cost effectively by the following method. That is, the method comprises first substantially coating the acid particles with a component containing at least one neutral substance effective for lowering the melting point of the surface of the acid granules, and subsequently, applying an alkali metal and / or alkaline earth metal. Of a carbonate or hydrogen carbonate and optionally a partial reaction product of the carbonate or hydrogen carbonate with the same organic acid or a different organic acid, said second coating being deposited thereon. It is a thing. The invention will now be described in more detail by means of a detailed examination and some preferred embodiments. Details of the Invention Neutral substances within the meaning of the invention are water- and / or alcohol-soluble polymers such as polyvinylpyrrolidone, carbohydrates such as saccharose, pentaerythritol, glucose and fructose, with the last two being coated with bicarbonate. Hydrocolloids such as maltodextrins and dextrins are not preferable here because they easily undergo yellowing due to the Maillard reaction due to the influence of the surface of the slightly alkaline effervescent granules). Particularly, higher alcohols such as xylitol, mannitol and sorbitol are preferable. Various embodiments of the invention are described in the dependent claims. W093 / 00886 does indeed introduce a method of introducing a different acid, probably gluconic acid δ-lactone, which hydrolyzes into gluconic acid, into the surface of acidic excipient crystals, causing defects in the crystal lattice and lowering its melting point. It has been announced. However, such a method cannot, of course, adequately protect active substances sensitive to acids. Therefore, it has hitherto been impossible to actually use the invention of W 093/00886 for active substances sensitive to acids. Furthermore, it has been proposed to coat acidic excipient crystals for effervescent tablets with a thin polymer layer, eg polyvinylpyrrolidone, carboxymethylcellulose etc. (GB 1 270 781). However, this method causes an unfavorable dissolution time delay and further causes a problem of foaming when 1 to 5% by weight of polyvinylpyrrolidone described in the examples is used. Furthermore, when the coating is carried out in ethanolic or aqueous solutions, depending on the type of acid, it migrates from the crystalline excipient into the solution in the layer, so that the acid-sensitive substances are not well protected. Furthermore, even with such a technique, the problem of adding acid-sensitive active substances to the foaming system is not only in terms of storage stability, but also with very low acid binding capacity and short dissolution time. Even relatively small tablets could not be solved satisfactorily for over 20 years. It is generally defined as particularly rapid when the effervescent tablet dissolves (or completely suspends) within 120 seconds, preferably within 90 seconds. However, according to the present invention, a neutral substance (preferably a small amount) is applied to the granules of the acid and then alkali metal and / or alkaline earth metal is added to prevent the interaction between the acid and the active substance. Particles of carbonate and / or hydrogen carbonate are attached to the surface of the granules. Furthermore, EP-A1-415 326 describes a method in which chewy tablets or lozenges are given a slight carbon dioxide-stimulating effect by coating an acidic excipient crystal with a certain amount of sugar in combination with hydrogen carbonate several times. However, this method could not solve the problem or the combination of problems. Such systems are not active enough to dissolve effervescent tablets in water within a reasonable time. The invention of this European patent EP-A1 was aimed at delaying the reaction between the acid and the carbonate so that no undesirably strong effervescent effect was produced in the mouth. Sorbitol, as described in the prior art (US A-4 127 645), in which a tablet having a core containing an acid, a hydrogen carbonate and a carbonate is dissolved in a neutral substance such as an aqueous solution, an alcohol solution or a water / alcohol mixed solution. However, even if it is coated with, it cannot reliably protect the acid-sensitive active substance contained in the core. However, if the mixture is neutral (eg, maltodextrin, if necessary with sugar, US A-4 650 6 69; sorbitol and vitamins, US A-5 223 264, suitable only for irritating chewable tablets) When compressed together into tablets, both reactive components are coated together or undesired agglomerates are produced. In both cases, the dissolution reaction of the tablets is slowed down, either taking too long to dissolve or the solution contains undesirably high amounts of sugar. Furthermore, in the case of agglomerated granules, it is likely that acid particles will also be present unprotected on the surface. If this happens, the acid-sensitive active substance becomes even more unstable. US Pat. No. 4,867,942 describes a method of coating the surface of excipient crystals of edible edible solid organic acids with a pre-reacted solution which acts as a buffer. Thereafter, more acidic crystals and a substantial amount of carbonate or bicarbonate are deposited side by side on this coating. Moisture generated during the various neutralization partial reactions is removed by final treatment with alcohol and vacuum drying. However, such a method is not sensitive to the acid in that the additional acid starts to react with the alkali carbonate at the same time on the surface of the acid crystal, and the reaction proceeds so fast that it is not sufficiently homogeneous. Are disadvantageous to various drugs. Therefore, in the preparation produced by this method, the reaction of the acid-sensitive drug mixed in the preparation cannot be completely prevented due to the acid crystals existing on the surface of the granule. In contrast, the structure of the effervescent system of the present invention only prevents direct contact between acid-sensitive drugs and acid crystals and improves the storage stability of effervescent tablets or granular products. However, it allows the preparation of sufficiently small tablets, that is, tablets with a lower amount of effervescent component which, when dissolved, serve as a buffer system. In this way, the tablets according to the invention can have an acid binding capacity of much less than 5 meq, in contrast to the buffer system of antacid effervescent formulations. Further, in the case of formulation preparation, delay of reaction and improvement of compressibility into tablets are achieved. According to the present invention, an acid-binding ability of less than 5 meq for a tablet (or granule) containing only 1.6 to 2.3 g of a tablet (or granule) containing an acid-sensitive drug such as cisapride or an H 2 blocker such as cimetidine. The preparation of effervescent tablets with is possible for the first time. Furthermore, according to a particularly advantageous embodiment of the invention, after the acid crystals have been coated with a coating of neutral substances, at least a portion of the carbonate and / or hydrogen carbonate intended for a single dose is In addition to the coating, the effervescent granules are provided with a first coating of a neutral substance and a second coating of a carbonate and / or hydrogencarbonate thereon, some of which partially reacts with the acid. Formed from acid crystals with and. The invention can be used particularly advantageously in the formulations or methods described, for example, in EP B1-76 340, US A-4 867 942 and W093 / 00886, whose description and claims are hereby published. It is considered that it was done. Application of a neutral substance, especially a sorbitol solution, lowers the melting point of the surface of, for example, citric acid crystals. Thus, on the one hand, the adhesion to a second coating comprising alkali metal or alkaline earth metal carbonates and / or hydrogencarbonates is increased, which at the same time leads to a slower reaction of the citric acid crystal surface, and , More evenly performed, which means improved passivation and less effect of effervescent granules on acid sensitive drugs. On the other hand, the melting point depression increases the recrystallization time of the citric acid or the citrate salt formed and thus improves the compressibility of the effervescent granules over a longer period of time. The amount of neutral substance applied to the acidic excipient crystals is determined by the amount of solvent that can be used to moisten the acid, as it can dissolve up to 50-70% by weight in aqueous solution. Therefore, it is preferably added in an amount of 0.05 to 1.0% by weight, especially 0.07 to 0.8% by weight, based on the acid. If it is less than 0.07%, only a small effect is obtained, and if it is less than 0.05%, the effect of the present invention is not observed and the storage stability of the acid-sensitive active substance is lowered. When it exceeds 0.8%, the influence of inhibition generally begins, and when it is 1.0% or more, the reactivity of citric acid and the reactivity of the foaming system remarkably decrease. However, in the case of granules, a longer dissolution time tends to be desirable when the granules are placed in water, so that they first settle and then only go into the dissolution reaction, so the above point is In this case, it does not matter so much. However, on the other hand, neutrals can actually be applied as a solution to make a solution of 50 to up to 70%, so that the amount of neutrals that can be applied to citric acid, for example, will wet the citric acid. It depends on the amount of solvent that can be used. Crystals of citric acid cannot be wetted with infinitely large amounts of water and therefore also with solvents. In some cases, neutral coatings form small amounts of edible solid organic acids and, optionally, excipient crystals, especially if carbonate and / or bicarbonate particles are deposited thereon. Acids other than acids—as published in other contexts per se—can be included here to promote melting point depression and / or to control foaming reactions and dissolution rates. Such effervescent granules are, in and of themselves, actually small effervescent "tablets" that effervesce themselves. Thus, if desired, shorter dissolution times, lower amounts and lower acid binding capacity can be used. I tried to obtain a fast acting small effervescent tablet by using monosodium citrate instead of citric acid, but the reaction of monosodium citrate was slower than that of sodium bicarbonate, so the effervescence of the resulting tablets Such previous experiments failed because the reaction was very slow and the acid consumption capacity of such tablets exceeded 5 meq. On the one hand, the very thin coating of monosodium citrate according to the invention is especially the third or fourth, since 1 mol of monosodium citrate binds with 1 mol of water of crystallization and contributes to the maintenance of drying or dryness. Effective as a second layer, this layer may contain additional neutrals if desired. Furthermore, the surface of the uncoated citric acid in any case can be covered again or more completely with bicarbonate. In addition, many substances have a certain taste, many of which are unpleasant, especially many of which are bitter, which makes the final effervescent solution, in particular, a pH of 3.8 to 3.8, since it is a beverage. It is desirable to keep it within the range of 4.6. Experiments have shown that this range effectively masks bitter substances. Although not an essential requirement, it is desirable to remove residual water from the reaction granules by a final treatment with alcohol during the process of its preparation. Upon drying, residual water is removed by evaporation with the alcohol, so the alcohol appears to interfere with the binding of water of crystallization. A small amount of antifoaming agent may be added to the alcohol to facilitate dissolution of the final product tablet. Many of the aforementioned agents, particularly cimetidine and cisapride, are susceptible to effervescent tablet effervescence. However, this is not the foam created by the surfactant. That is, even if only the surfactant is stirred in water, it does not foam, but when the expandable particles in the tablet are dissolved, bubbles of carbon dioxide are generated. These bubbles pop, leaving carbon dioxide on the surface. Here, if a low-solubility or highly-hydrophobic substance is present, the undissolved particles wrap the carbon dioxide bubbles, and the formation of such a thin film prevents rapid bursting of the bubbles, Gather together on the surface with this thin film to form "bubbles". However, this "foam" already formed between the effervescent granules prevents the reaction from continuing and thus the rapid dissolution of the tablets and granules. This situation can be dealt with according to the invention by the addition of a trace amount of at least one antifoaming agent, so that all of the "foam" formed by the foaming reaction immediately begins to collapse. The antifoaming agent is preferably added in an amount of 0.005 to 0.5% by weight based on the total amount including fillers, flavors and the like, or 0.05 to 2.0% by weight based on the active substance. If it is less than 0.005%, the effect of the invention cannot be obtained. If the amount added exceeds 0.5%, damage and undesirable side effects occur. For active substances with a limited solubility such as cimitidine, 0.1-0.3% by weight of active substance of simethicone is used. This corresponds to 0.016 to 0.028% by weight (about 0.03%) based on the total amount of tablets. In the case of insoluble hydrophobic active substances such as cisapride (using monohydrate), this situation is somewhat different, with 1% simethicone being used for the active substance, which has a tablet weight of 1.6. The amount is 0.006% for g. Since cisapride is a slightly soluble hydrophobic active substance, it requires a large amount of antifoaming agent to prevent foaming, but the amount of simethicone in the tablet is much higher due to the required filler and efferverscent base. It can be seen that the ratio is reversed because it is significantly less. In the case of soluble active substances such as cimetidine and ranitidine, the tendency of foaming in the local reaction during dissolution of the effervescent tablet is small, and therefore the amount of simethicone required is small in order to suppress this foaming. However, on the other hand, in the case of cisapride-as mentioned above-the tendency of bubbling is much greater and therefore its principle is somewhat different. When used in large amounts, simethicone forms a thin film on the surface after the foaming solvent is dissolved. This is an undesirable dissolution phenomenon-particularly in the case of insoluble active substances-because particles of the active substance collect and float on the surface. This film also tends to form a ring on the glass wall. However, in some cases, a trace amount of a surfactant such as sodium doxate (sodium dioctylsulfosuccinate) may be added. Due to its wettability, drug particles as described above dissolve quickly and do not adhere to air bubbles. The amount of such a substance must be very precisely determined in order to obtain the desired dissolution properties. In some cases an antifoaming agent can be applied to the effervescent system and / or the drug, which is not preferred according to the invention. In the first case, unless a very small amount of defoamer sufficient to achieve the desired effect is used, application to the foam system delays the dissolution and reaction of the foamable component, which is undesirable. In the second case, the antifoaming agent can be applied only to a drug that does not impair its solubility or stability when added to the drug at 40 ° C from a solution prepared by dissolving it in a solvent (for example, methyl ethyl ketone and acetone). is there. Furthermore, if an antifoaming agent is added during the manufacturing process using a finely pulverized drug, the drug particles may adhere to the droplets of the antifoaming agent, which may result in poor drug dispersion. Therefore, according to the present invention, a conventional granular product consisting of an antifoaming agent and a neutral substance is first prepared, and this granular product is provided with an effervescent system and a drug, and if necessary further auxiliaries ( It is preferred to add the flavors, sweeteners etc.) and then press the mixture into tablet form. Moisture generated during the preparation of the foaming system due to neutralization reaction and not completely removed by heat treatment and / or vacuum treatment, and moisture absorbed from the air during storage are hygroscopic agents, especially anhydrous sodium carbonate. (Can absorb 10 moles of water per mole) or sodium sulfate can be added to bind well with this. The hygroscopic agent is added to one or several of the coatings of excipient crystals, or to the entire mixture. In this way, the reaction between the acid-sensitive active substance and the acid is either further suppressed by the reduction of the water content or completely prevented and the storability is improved. However, it is not preferable to add an excessive amount of such a hygroscopic agent, for example, sodium carbonate, because the foaming reaction is delayed. Therefore, sodium carbonate as a desiccant should not be used to completely cover the effervescent granules. This is because it is preferred to treat with only small effective amounts, simply to remove residual moisture, or to delay the reaction during manufacture, or to prevent unduly lengthening the dissolution time of the tablet. Therefore, the final addition of sodium carbonate should not use an amount for complete coating (or tablet coating), which is determined by both the amount and size of the granules (about 0.1-0.05 mm). Therefore, it is not appropriate to form a continuous coating on the already existing bicarbonate. However, it is possible to partially deposit it on the effervescent granules. However, it is also possible not to add sodium carbonate until the end of the drying operation. In principle, the amount of sodium carbonate per tablet depends on several factors, such as the amount of effervescent base used, the amount and type of filler used, the presence of other carbonates such as calcium carbonate. It depends. It is preferred to add a moisture absorbent, especially sodium carbonate (based on the total amount including fillers, flavors, etc.) in an amount of 1 to 10% by weight, particularly 4 to 6% by weight. If it is less than 4%, the effect is not sufficient, and if it is less than 1%, the drying effect and the improvement in stability are too small, and the effect of the present invention cannot be obtained. In addition, since the dissolution and reaction of sodium carbonate are slow, if the addition amount exceeds 6%, an unfavorable effect generally appears, and if the addition amount exceeds 10%, sodium carbonate is the first to absorb water when dissolving the effervescent tablet ( It dissolves up to 10 moles of water of crystallization), ie, removes residual water before reacting with citric acid, so that the dissolution time by itself increases significantly. It should be emphasized here that 1 mol of water of crystallization can be bound only by 1 mol of sodium citrate formed in or on the layer of sorbitol, and there is no residual amount of water present. It also means that the layer of sorbitol prevents or prevents the adverse effects of acid on the drug. By all the procedures defined by the present invention, it is possible to make effervescent tablets with a tablet weight of, for example, 1.6 g and a dissolution time of less than 100 seconds, even when using the aforesaid troublesome substances. However, it should be noted that, especially in the case of cimetidine, the hydrophobicity thereof causes a longer dissolution time than other drugs even under the same conditions. Granules to which the sorbitol solution has been added can be rapidly dissolved without the addition of the other acids required for example by W093 / 00886. Furthermore, during the preparation of the effervescent system of the present invention, and in all cases of the tablets themselves, each procedure taken according to the present invention controls the reaction taking place on the surface of the individual crystals or granules in a localized manner. A local mechanism can be configured, and upon melting, the desired features mentioned above are achieved without residue. This system is particularly well suited for the treatment of substances which are sensitive to acids and sparingly soluble in water. Such substances, e.g. cisapride, are prone to foaming with the boiling system in the suspension, as mentioned above, sticking to the glass walls, forming ugly rings and forming lumps on the surface of the drink. Shows awkward behavior. All the problems mentioned above can be effectively solved by preparing separate granules. Another embodiment of the invention describes a method for this purpose, according to which an excipient, which may consist of aerosol and / or a neutral substance, is provided on which the drug is added. Preferably, the surface of the granules is then partially dissolved and / or if necessary binders and / or surfactants are used, dried or bound to the surface of the excipient by means of a binder. For example, in the case of cisapride, the amount is limited to a maximum of 8% by weight, preferably 4.5% by weight (based on the total mixture), since a large amount of suspended solids increases the settling of the granule particles after dissolution of the tablets. . On the other hand, the amount of binder used is also up to 1% by weight. Above that amount, the active substance, suspended substance and binder start to agglomerate, and the agglomerated lumps are difficult to dissolve and settle to the bottom. This is not preferable because it hinders the formation of a suspension of. The invention will now be described in more detail by means of preferred embodiments so that it may be better understood. However, these examples are merely for illustrative purposes, and many other embodiments and modifications should readily occur to those skilled in the art, and thus the invention or claims or its scope. It should be understood that the gist of these examples is in no way limiting. For example, the drug is dissolved in methyl ethyl ketone or acetone to dissolve mannitol, Example 1: Preparation of effervescent tablets containing 200 mg cimetidine a) Preparation of effervescent system 102 parts by weight of crude citric acid and 25 parts by weight of finely powdered citric acid or tartaric acid (powder up to about 30% bicarbonate) Is preferred to improve the formation of effervescent granules on the excipient crystals, as it forms a rough surface to which can be attached) is sucked into a preheated vacuum tank and heated to about 60 ° C. with stirring. Then 0.85 parts by weight of solution 1 prepared from 36 parts by weight each of water and sorbitol, 21 parts by weight citric acid and 7 parts by weight sodium hydrogen carbonate are sucked in and distributed on citric acid by stirring. Subsequently, 52.5 parts by weight of sodium hydrogen carbonate and 4.4 parts by weight of aspartame were added to the above mixture and dried with stirring under a vacuum up to 200 mbar, and further 1.9 parts by weight of sodium carbonate was sucked into the mixture by stirring. Disperse and dry the resulting mixture under vacuum up to 15 mbar. Then 0.6 part by weight of the above solution is aspirated and dispensed into the mixture by stirring. The effervescent granules formed are dried with stirring and under a vacuum of up to 20 mbar. Aspirate 0.25 part by weight of 96% ethanol to dry the mixture if necessary. Next, 9.3 parts by weight of sodium carbonate is again adhered to the surface of the effervescent granules. Dry again and remove product through sieve. b) Preparation of granular antifoaming agent Add 7.7 parts by weight of sorbitol powder to a vacuum mixing tank with a jacket at 80 ℃ and heat to 50 ℃. 0.2 parts by weight of a 30% solution of the butanone / acetone mixture of simethicone (5: 3) are then sucked in, stirred by the vibration mixing method and dried at a temperature of at least 45 ° C. under a vacuum of up to 15 mbar. c) Preparation of the total mixture 20 parts by weight of cimetidine and if necessary 21.1 parts by weight of sorbitol powder are mixed with 178.4 parts by weight of the foaming system prepared in a) for 10 minutes at 6 rpm in a mixer. Next, add 7 parts by weight of antifoam granules prepared in b) through a 0.6 mm sieve and 4.5 parts by weight of lemon flavor and further mix for 5 minutes at 6 rpm. The resulting mixture is compressed into tablets. The tablets weigh 2.3 g and contain 200 mg cimetidine and have a hardness of 6-8 kp. Example 2: Preparation of effervescent tablets containing 200 mg cimetidine and citric acid and malic acid in effervescent granules 102 parts by weight of crude citric acid, 25 parts by weight of citric acid powder and 1.1 parts by weight of malic acid were used. Heat to 60 ° C with stirring in a preheated vacuum tank. A solution consisting of 0.4 parts by weight of water, 0.22 parts by weight of sorbitol and 0.22 parts by weight of malic acid is sucked in, mixed and distributed over citric acid. Next, 52.5 parts by weight of sodium hydrogen carbonate and 4.4 parts by weight of aspartame are added to the above mixture and dried with stirring under a vacuum of up to 200 mbar, and further 1.9 parts by weight of sodium carbonate are sucked in and the mixture is stirred. Distribute in and dry under vacuum up to 15 mb ar. Finally it may be finally dried with ethanol. Further, 9.3 parts by weight of sodium carbonate is added to the mixture, and the subsequent steps are carried out according to Example 1. Example 3: Preparation of an effervescent tablet containing 400 mg cimetidine and mannitol as a neutral substance 49 parts by weight of citric acid are sucked into a preheated vacuum tank and heated to 60 ° C. with stirring. Next, 0.45 part by weight of Solution 1 consisting of 0.25 part by weight of water and 0.20 part by weight of mannitol is sucked, mixed and distributed on citric acid, and 14.7 parts by weight of sodium hydrogencarbonate and 3.2 parts by weight of aspartame are added onto the solution. Add. The reaction is started by stirring and the drying is carried out under vacuum up to 200 mbar. Then 0.5 part by weight of sodium carbonate is sucked in, distributed by stirring in the mixture and dried under vacuum up to 15 mbar. Next, 0.56 parts by weight of solution 2 prepared by adding 0.16 parts by weight of monosodium citrate to solution 1 is sucked into the mixture and distributed by mixing. The effervescent granules thus obtained are dried in a vacuum of 20 mbar with stirring and finally 2.8 parts by weight of sodium carbonate are added. To this mixture are added 17.3 parts by weight of cimetidine, 4.3 parts by weight of mannitol, 8 parts by weight of sorbitol, 0.9 parts by weight of flavor and 0.9 parts by weight of antifoam granules prepared according to Example 1 b), and mixed until homogeneously distributed. Example 4 Preparation of Effervescent Tablets Containing 300 mg Cimetidine and Maltodextrin as Neutral Substance As in Example 3, a 50% solution of maltodextrin was selected for 300 mg cimetidine effervescent tablets, which was 400 The same amount was used as for the mg tablet. In all of the examples where the tablet contains 100-400 mg cimetidine, the tablet weight can be 2.3 g. The dissolution time of these tablets is preferably 60 to 150 seconds and the buffer capacity is less than 5 meq. This buffering capacity is measured according to USP XXII by dissolving effervescent tablets in 70 ml of water and adding 30 ml of 1.0 N hydrochloric acid thereto to back titrate (0.5 N sodium hydroxide). The numbers shown in Table 1 are the percentages of the individual components relative to the total mixture of each of the illustrated preferred examples, and thus indicate the preferred range of each component. A preferred composition of a bag of cimetidine effervescent tablets or granules containing cimetidine 100, 200, 300 and 400 mg and weighing 2.31 g is summarized in Table 2. Example 5: Cisapride effervescent tablet a) Preparation of effervescent granules 655 parts by weight of crystalline citric acid, 70 parts by weight of citric acid powder and 8 parts by weight of sodium saccharin are mixed while heating to 60 ° C. To this, 2.8 parts by weight of a solution consisting of 0.6 parts by weight of sorbitol, 0.3 parts by weight of trisodium citrate, 0.5 parts by weight of citric acid and 1.6 parts by weight of water is sucked into the mixture and distributed by mixing. Then, 340 parts by weight of sodium hydrogen carbonate and 2 parts by weight of aspartame are added and reacted. 77 parts by weight of sodium carbonate are added and then the mixture is dried under vacuum at 15 mbar with slow stirring. b) Preparation of drug granules Insoluble, hydrophobic cisapride is attached to the suspended substance by means of a binder and a small amount of surfactant as follows: 10 parts by weight cisapride, 2 parts by weight polyvinylpyrrolidone and doxate sodium 0.8 1 part by weight of ethanol and 40 parts by weight of acetone To dry. The granules obtained are passed through a 0.1-0.3 mm sieve. c) Preparation of the final mixture 1152 parts by weight of effervescent granules, 50 parts by weight of maltodextrin, 100 parts by weight of lactose, 184 parts by weight of mannitol, 40 parts by weight of flavor, 50.2 parts by weight of antifoam granules (50 parts by weight of mannitol and 0.2 parts by weight of simethicone). Parts) and the drug granules prepared in b) are added, mixed for 15 minutes until evenly distributed, and the mixture is compressed to give tablets of 1.6 g. The acid binding capacity of this tablet is only 2 meq. No cisapride effervescent tablet having such a low acid binding capacity has been known so far. Example 6: Beta-Carotene Effervescent Tablets Special care should be taken in the coating of acids, especially in the case of substances that are sensitive to acids and oxidation. The surface and contact area of β-carotene must be kept alkaline. Therefore, at least a portion of the effervescent granules is covered with calcium carbonate to ensure an alkaline surface. However, this results in somewhat longer dissolution times. In this case, since it takes time from the dissolution of the tablet to the suspension of β-carotene, the longer dissolution time is preferable. Large amounts of sorbitol, such as those mentioned at the beginning of US A-5 223 264, are never preferred for beta-carotene effervescent tablets intended to be dissolved or suspended in water. a) Preparation of effervescent granules 1315 parts by weight of citric acid, 7 parts by weight of sodium saccharin and 45 parts by weight of sodium cyclamate are heated to 50 ° C. in a vacuum tank. 16.8 parts by weight of a solution prepared from 3.6 parts by weight of calcium carbonate, 19 parts by weight of citric acid, 12 parts by weight of sorbitol and 45 parts by weight of water are added with stirring and distributed on the citric acid by mixing. Then 400 parts by weight of calcium carbonate and 190 parts by weight of citric acid are added and the mixture is heated to 60 ° C. with stirring. A second granulation is then carried out with 44 parts by weight of the above solution, after mixing with bistributing, 403 parts by weight of sodium hydrogen carbonate are added and, before drying, 52 parts by weight of sodium carbonate are added. The mixture is then dried under a vacuum of 15 mbar with gentle stirring. b) Preparation of the final mixture 130 parts by weight of sorbitol, 540 parts by weight of mannitol, 50 parts by weight of flavor, equivalent to 2 to 15 parts by weight of 100% β-carotene, β-carotene in water-suspendable capsules, required 50 to 250 parts by weight of solid tocopheryl acetate that can be suspended in vitamin C and / or water (corresponding to 10 to 75 parts by weight of 100% tocopheryl acetate), and other vitamins if necessary. , 2415 parts by weight of boiling granules prepared in a) are mixed. The product has a tablet weight of 3.3 g and its dissolution time is 60-90 seconds. Example 7: Ranitidine effervescent tablets a) Preparation of effervescent granules 840 parts by weight of crystalline citric acid, 210 parts by weight of citric acid powder, 45 parts by weight of sodium cyclamate and 4 parts by weight of sodium saccharin in a vacuum mixing tank at 60 ° C. Heat with. Then a solution consisting of 6 parts by weight of water, 1 part by weight of sodium citrate and 3 parts by weight of sorbitol is aspirated and dispensed by mixing. Then, 500 parts by weight of sodium hydrogen carbonate is added and reacted. Further, 370 parts by weight of monosodium citrate is added and this is also reacted. Finally, 100 parts by weight of sodium carbonate are added and then the granules are dried under vacuum to 15 mbar with slow stirring. b) Preparation of final mixture To the effervescent granules thus prepared, 167 parts by weight of ranitidine hydrochloride, 125 parts by weight of mannitol, 100.4 parts by weight of granulated antifoam (composition of 100 parts by weight of mannitol and 0.4 parts by weight of simethicone) and Add flavor. The mixture is mixed for even distribution for 15 minutes and compressed into 2.5 g tablets. The tablet has a dissolution time of 60-80 seconds and an acid binding capacity of about 2 meq, and (expressed in wt%) ranitidine hydrochloride 6.8, citric acid 42.0, monosodium citrate 14.8, sodium bicarbonate 20.0, sodium carbonate. It contains 4.0, sweetener 2.0, mannitol 5.0, sorbitol 0.1, granulated defoamer 4.0 (including dimethylpolysiloxane 0.016) and flavor 1.2. Example 8: 545 parts by weight of crystalline citric acid and 133 parts by weight of citric acid or tartaric acid powder are mixed while heating to 60 ° C. Then, as a first coating, a solution of 6 parts by weight of water and 4 parts by weight of sorbitol is distributed on the surface of the mixture while stirring. Then 222 parts by weight of sodium hydrogen carbonate are reacted on the surface of citric acid, and finally 80 parts by weight of sodium hydrogen carbonate are added. The product is dried with slow stirring. Pass the resulting granules through a 1.5 mm sieve, and 167 parts by weight of ranitidine hydrochloride, 100 parts by weight of antifoam granules (including 0.4 parts by weight of simethicone and 100 parts by weight of lactose), 54 parts by weight of sweetener and flavor. Mix at 40 rpm for 10 minutes to obtain a uniform distribution with 40 parts by weight of material. The mixture is compressed to make tablets weighing 1.43 g. The tablets have a dissolution time of 65-70 seconds, a hardness of 8 and an acid binding capacity of about 1.5 meq. Ranitidine effervescent tablets with such low acid binding capacity have never been published. Example 9: 38.2% citric acid is heated to 60 ° C. with 0.26% sodium saccharin, to which is added 2/3 of a solution of 0.6% water, 0.18% sorbitol and 0.12% sodium citrate to the final mixture, Mix at 5 rpm for 10 minutes and dispense. Next, 16.2% sodium hydrogen carbonate and 2.9% aspartame are added and deposited on the surface of citric acid by reaction on the coating of neutrals. A second wetting is then carried out with 1/3 of the solution. Then add 12.9% monosodium citrate and finally 5.2% sodium carbonate, respectively. The effervescent granules obtained are dried under a vacuum of 15 mbar at a temperature of at least 50 ° C. with slow mixing. The base effervescent granule product, which was passed through a 1.5 mm sieve, was mixed with ranitidine hydrochloride 11.0%, mannitol 6.5%, defoamer granules 6.5% and flavor 0.2%, and the mixture was compressed. Make a tablet weighing 1.55 g. The tablets have a dissolution time of 50 seconds, a hardness of 7.3 and an acid binding capacity of less than 2 meq. Example 10: Excipient Crystal Granules Coated Only With Neutral Material For example, cisapride is not as highly reactive with acid as ranitidine, so again cisapride is not sensitive to acid by the method described below. It is also possible to protect, in which case it is still effective as the drug is embedded in the granules. a) Preparation of acid crystals coated with a neutral substance 593 parts by weight of crystalline citric acid and 70 parts by weight of citric acid powder are heated to 60 ° C., and a solution of 4 parts by weight of sorbitol in 4 parts by weight of water is added thereto. , Mix and distribute on the surface of citric acid. The citric acid thus coated is finally vacuum dried at 50-60 ° C. In the case of both effervescent formulations of the form described here and effervescent granules of the form comprising a second alkali or alkaline earth metal carbonate coating, sodium bicarbonate is added to add cisapride in the drug granules. It is possible to protect from the action of citric acid. b) Preparation of drug granules 160 parts by weight of mannitol, 10 parts by weight of cisapride, 5 parts by weight of Aerosil and 10 parts by weight of sodium hydrogen carbonate are mixed and heated to 60 ° C. Add half of the solution consisting of 27 parts by weight of methyl ethyl ketone (or 45 parts by weight of acetone), 2 parts by weight of alcohol, 2 parts by weight of poly (vinylpyrrolidone) K30, 1 part by weight of propylene glycol and 0.8 parts by weight of doxate sodium, and mix evenly. Disperse for 5 minutes to wet. The mixture is dried at 0.8 bar, the other half of the solution is aspirated, stirred for 5-10 minutes, redistributed and finally dried. The active substance granules obtained are passed through a 0.3 mm sieve. It has an improved protective action against the action of acids due to the sodium hydrogen carbonate already contained in this state. The granules can be mixed with the neutral-coated acid crystals, the remaining carbonates and bicarbonates, and other tablet ingredients, and the mixture compressed into tablets. c) Preparation of the final mixture The citric acid dry-coated according to a), the drug granules prepared according to b), 50 parts by weight of sweetener, 80 parts by weight of sodium carbonate, 430 parts by weight of sodium hydrogen carbonate, 50 parts by weight of maltodextrin, 100 parts of lactose. Parts by weight, 150 parts by weight of mannitol, 50 parts by weight of antifoam granules and 20 parts by weight of flavourant, and compressed to give tablets of about 1.6 g. The hardness 7 tablets dissolve in 60 to 70 seconds. Example 11: Cisapride effervescent tablets a) Preparation of effervescent granules Citric acid consisting of 300 parts by weight of granules, 80 parts by weight of fine granules and 40 parts by weight of powder, together with 5 parts by weight of sodium saccharin, 0.4 parts by weight of sorbitol, 0.15 parts of sodium hydrogen carbonate. A solution consisting of 1 part by weight, 0.45 parts by weight citric acid and 1.2 parts by weight water is uniformly wetted at 60 ° C with 2.2 parts by weight. Next, 12 parts by weight of malic acid is sucked and uniformly adhered to the sorbitol layer formed on the citric acid crystals. Finally, 205 parts by weight of sodium hydrogen carbonate and 1.2 parts by weight of aspartame are sucked and uniformly distributed again. Finally the material is coated with 46 parts by weight of sodium carbonate, vacuum dried and passed through a 1.2 mm sieve. b) Preparation of active ingredient granules 12 parts by weight of polyvinylpyrrolidone are dissolved in 12 parts by weight of ethanol. Then, 6 parts by weight of propylene glycol and 6 parts by weight of sodium doxate are added, and the obtained mixture is diluted with 165 parts by weight of ethyl methyl ketone. Half of this solution Distribute over a mixture of 61 parts by weight of supplement and heat to 60 ° C. Partially dry under vacuum, then wet with the other half of the solution, dry completely and pass through a 0.3 mm sieve. The final mixture is prepared according to Example 5.

───────────────────────────────────────────────────── フロントページの続き (31)優先権主張番号９４２０３１１２．１ (32)優先日 1994年10月26日 (33)優先権主張国オランダ（ＮＬ） (81)指定国ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＤＥ，ＤＫ，ＥＳ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，ＩＴ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ，ＣＦ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＭＬ，ＭＲ，ＮＥ，ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＫＥ，ＭＷ，ＳＤ，ＳＺ，ＵＧ)，ＡＭ，ＡＴ，ＡＵ，ＢＢ，ＢＧ，ＢＲ，ＢＹ，ＣＡ，ＣＨ，ＣＮ，ＣＺ，ＤＥ，ＤＫ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，ＧＥ，ＨＵ，ＪＰ，ＫＥ，ＫＧ，ＫＰ，ＫＲ，ＫＺ，ＬＫ，ＬＲ，ＬＴ，ＬＵ，ＬＶ，ＭＤ，ＭＧ，ＭＮ，ＭＷ，ＭＸ，ＮＬ，ＮＯ，ＮＺ，ＰＬ，ＰＴ，ＲＯ，ＲＵ，ＳＤ，ＳＥ，ＳＧ，ＳＩ，ＳＫ，ＴＪ，ＴＴ，ＵＡ，ＵＳ，ＵＺ，ＶＮ (72)発明者ゲルゲリイ、シュテファンオーストリア国エー−1053 ウィーン、ガルテンガッセ８────────────────────────────────────────────────── ─── Continuation of front page (31) Priority claim number 94203112.1 (32) Priority Date October 26, 1994 (33) Netherlands claiming priority (NL) (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, M C, NL, PT, SE), OA (BF, BJ, CF, CG , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, MW, SD, SZ, UG), AM, AT, AU, BB, BG, BR, BY, CA, C H, CN, CZ, DE, DK, EE, ES, FI, GB , GE, HU, JP, KE, KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN, M W, MX, NL, NO, NZ, PL, PT, RO, RU , SD, SE, SG, SI, SK, TJ, TT, UA, US, UZ, VN (72) Inventor Gergerii, Stephan Austria A-1053 Vienna, Gartengasse 8

Claims

[Claims] 1. Effervescent particles obtainable from at least one edible edible solid organic acid carrier crystals, the crystals being substantially coated with at least one layer comprising at least one neutral substance soluble in water and / or alcohol. The neutral substance is effective in lowering the melting point on the surface of the acid crystal, and the coating contains an alkali metal carbonate, an alkali metal hydrogen carbonate, an alkaline earth metal. At least one selected from the group consisting of carbonates, hydrogen carbonates of alkaline earth metals, alkali metal salts of at least one edible solid organic acid, alkaline earth metal salts of at least one edible solid organic acid Suitable for the preparation of an aqueous solution or suspension of one or several pharmaceutically active substances for oral administration, characterized by the addition of one substance, which may be compressed into tablets. it can Particulate expandable products. 2. The neutral material is selected from the group consisting of water-soluble polymers, higher alcohols, carbohydrates and hydrocolloids, and the neutral material is present in about 0.05 to about 1.0% by weight, preferably about 0.07 to about 0.8% by weight. The granular product or tablet according to claim 1, characterized in that 3. A moisture binder is attached to the effervescent tablet, which moisture binder is preferably selected from the group consisting of anhydrous sodium carbonate and sodium sulphate, preferably about 4 to about 10 wt.% Of the total mixture. % The granular product or tablet according to claim 1 or 2, characterized in that it is added. 4. At least one layer of coating is added onto the effervescent tablet, the coating being selected from the group consisting of alkali metal salts and / or alkaline earth metal salts of at least one edible solid organic acid as a buffer. Any of the preceding claims 1 to 3, characterized in that it comprises one substance and optionally one additional neutral substance, wherein preferably at least one layer of the coating contains an antifoaming agent. A granular product or tablet according to any one of the above. 5. The granular product or the granular product compressed into a tablet form contains at least one antifoaming agent in the granular product itself, according to any one of claims 1 to 5. Granular product or tablet according to one section. 6. The antifoaming agent is selected from the group consisting of dimethicone and simethicone and is present in an amount of about 0.005 to about 0.5% by weight of the total mixture and about 0.05 to about 2.0% by weight of the pharmaceutically active substance. The granular product or tablet according to claim 4 or 5, characterized in that 7. Granular product or tablet according to any one of claims 1 to 6 characterized in that it has an acid binding capacity of less than 5 meq, preferably less than 3 meq, measured according to USP XXII. . 8. A total weight of less than or equal to 2.5 g, preferably less than or equal to 2.0 g, and a dissolution time in water at room temperature of less than 180 seconds, preferably less than 120 seconds. Granules or tablets. 9. Comprising a hydrophobic pharmaceutically active substance, said hydrophobic substance being present in a granule separate from said effervescent ingredient, in which said hydrophobic substance is a suspending agent-preferably Preferably, at least one substance selected from the group consisting of mannitol and sorbitol is coated on or adhered to at least one substance selected from the group consisting of mannitol and sorbitol. Granular product or tablet according to one section. Ten. The granules further comprise a binder-preferably polyvinylpyrrolidone (PVP) -a small amount of a surfactant-preferably selected from the group consisting of sodium dioctyl sulfosuccinate and sodium lauryl sulphate-and alkali metals and / or alkaline earth metals. The granular product or tablet according to claim 9, which comprises at least one component selected from the group consisting of the carbonate and / or hydrogen carbonate of 11. Based on the total mixture, from about 2 to about 30% by weight cimetidine, from about 30 to about 60% by weight of an edible solid organic acid, from about 12 to about 12 alkali metal or alkaline earth metal carbonates or bicarbonates. About 40% by weight (about 2 to about 10% by weight of which is sodium carbonate as a water-binding agent), about 1 to about 4% by weight of a sweetener, and about 0.01 to about 30% by weight of a neutral substance (of which about 0.01 to About 0.05% by weight is a coating neutral material), preferably about 3 to about 20% by weight sorbitol, about 2 to about 10% by weight mannitol, about 0.005 to about 0.5% by weight antifoam, and about 0.1 to about 10% flavor. Granular product or tablet according to any one of the preceding claims 1 to 10, characterized in that it contains about 3% by weight. 12． Granules or tablets according to any one of the preceding claims 1 to 10, characterized in that the total mixture contains the following ingredients: cisapride about 0.4 to about 4.5% by weight, suspension About 0.4 to about 4.5% by weight, binder, preferably polyvinylpyrrolidone (PVP) about 0.1 to about 1% by weight, surfactant, preferably sodium dioctylsulfosuccinate about 0.03 to about 0.35% by weight, edible solid organic An acid, preferably about 30 to about 55% by weight citric acid, about 12 to about 40% by weight of at least one alkali metal or alkaline earth metal carbonate or bicarbonate, of which about 2 to about 10% by weight. Sodium carbonate as a water-binding agent), a sweetener about 0.3 to about 2.5% by weight, preferably about 0.02 to about 55% by weight of a neutral substance selected from the group consisting of maltodextrin, lactose and mannitol (of which about 0.02 to about 0.1% by weight is a neutral substance for coating) Properly antifoam about 0.005 to about 0.05 wt% selected from the group consisting of dimethicone and simethicone and about 0.2 to about 5 wt% flavorant. 13. Granular product or tablet according to any one of the preceding claims 1 to 10, characterized in that it contains the following ingredients for the whole mixture: -β-carotene (100%) about 0.1 To about 0.5% by weight, tocopheryl acetate (100%) about 0 to about 2% by weight, edible solid organic acid about 35 to about 55% by weight, preferably ascorbic acid about 0 to about 10% by weight, About 35 to about 55% by weight citric acid, and about 0 to about 5% by weight malic acid, about 11 to about 38% by weight of at least one alkali metal or alkaline earth metal carbonate or hydrogen carbonate, preferably carbonic acid. About 5 to about 15% by weight of sodium, and about 5 to about 20% by weight of sodium hydrogencarbonate, about 1 to about 4% by weight of a sweetener, about 0.1 to about 35.0% by weight of a neutral substance (of which about 0.1 to about 0.5%). % By weight of the coating neutral material), preferably about 1 to about 10% by weight of sorbitol and about 5 to about 25% by weight of mannitol, and About 0.3 to about 3% by weight fee. 14. Granular product or tablet according to any one of the preceding claims 1 to 10, characterized in that it contains the following components in relation to the total mixture: Ranitidine hydrochloride about 3 to about 14% by weight ( (75-300 mg per dose), about 30 to about 50 wt% citric acid, about 0 to about 20 wt% monosodium citrate, about 10 to about 30 wt% sodium hydrogen carbonate, about 2 to about 10 wt% sodium carbonate. , Sweetening agent about 1 to about 3% by weight, initial coating neutral material about 0.05 to about 0.2% by weight, additional neutral material about 0 to about 15% by weight, defoamer granules about 0 to about 8%. % By weight and about 0.1 to about 4% by weight of flavor. 15. Consisting of at least one pharmaceutically active substance and at least one edible solid organic acid, at least one alkali metal carbonate or hydrogen carbonate as gas generating component and at least one acid alkali metal salt A carrier crystal containing an effervescent system and comprising at least one acid is provided with at least two layers, the first layer being at least one other edible solid organic acid or an alkali of this other acid. The second layer comprises at least one alkali metal salt of at least one acid as described above, and the first layer further comprises a water-soluble polymer, a higher alcohol, a carbohydrate and a hydrocolloid. An effervescent tablet containing one kind of neutral substance selected from the group consisting of: 16． A foaming system having a total weight of less than 2 g, preferably less than 1.6 g and an acid binding capacity of less than 5 meq, preferably less than 3 meq, and cisapride as pharmaceutically active substance. Granular product or tablet. 17． Equipped with an effervescent system and cimetidine as pharmaceutically active substance, the total weight of which is less than 2.5 g, preferably less than 2.0 g and whose acid binding capacity is less than 5 m eq, preferably less than 3 meq. A granular product or tablet. 18. Equipped with ranitidine as an effervescent system and a pharmaceutically active substance, the total weight of which is less than 2.6 g, preferably less than 2.0 g and whose acid binding capacity is less than 3 m eq, preferably less than 2 meq. Granular product or tablet. 19. By wetting at least one edible edible solid organic acid with an aqueous solution of a neutral substance and mixing with powdered alkali metal and / or alkaline earth metal carbonates and / or hydrogen carbonates before it is completely dried. The evenly distributed deposition on the moist surface layer, followed by drying the effervescent granules prepared in this way, which are treated with a pharmaceutically active substance-preferably an acid-sensitive substance, especially H2-blocking The drug, a substance selected from the group consisting of cimetidine, ranitidine, cisapride and β-carotene, and a pharmaceutically acceptable auxiliary agent, and if necessary, compressed into a tablet. A method for preparing a granular product or tablet according to any one of claims 1-18. 20. Solutions of buffer substances, preferably alkali metal carbonates, alkali metal hydrogen carbonates, alkaline earth metal carbonates, alkaline earth metal hydrogen carbonates, at least one edible solid organic acid alkali metal Wetting the effervescent granules with a solution of at least one substance selected from the group consisting of a salt, at least one edible alkaline earth metal salt of an edible solid organic acid, and forming at least one layer of the effervescent granules on the granules. 20. The method according to claim 19, characterized in that an additional coating is provided. twenty one. 21. The method according to claim 19 or 20, characterized in that the solution further comprises a neutral substance selected from the group consisting of water-soluble polymers, higher alcohols, carbohydrates and hydrocolloids. twenty two. In addition to the drug, an antifoaming agent dissolved in a suitable solvent is applied to the surface of the particles of the neutral substance, and the granulated product prepared by drying the solvent is mixed with the effervescent granules. 22. A method according to any one of claims 19 to 21. twenty three. 23. Drying of the effervescent granules, preferably by wetting it with ethanol in which an antifoaming agent is dissolved, and evaporating the ethanol to remove residual water content. the method of. twenty four. Prior to mixing the pharmaceutically active substance with the effervescent system, the active substance, together with a binder and / or a surfactant, is applied as a solution to the granules of the suspension and evenly distributed and then dried. The method according to any one of claims 19 to 23, characterized in that twenty five. Prior to mixing the pharmaceutically active substance with the effervescent system, the active substance is mixed with at least one neutral substance, at least one suspending agent, and alkali metal carbonates, alkali metal hydrogen carbonates. From alkaline earth metal carbonates, alkaline earth metal hydrogen carbonates, at least one edible solid organic acid alkali metal salt, at least one edible solid organic acid alkaline earth metal salt Mixing with at least one substance selected from the group consisting of, then applying a solution of at least one binder and / or surfactant at least once to the granules of said mixture, distributing and drying. 25. A method according to any one of claims 19 to 24, characterized in that 26. In order to passivate at least one surface of the components to a state of strong inertness to the reaction, a defined amount of polar solvent is added to the heated mixture during the treatment under vacuum, during the reaction. The pressure difference generated due to the generation of carbon dioxide due to the addition of the solvent of up to 1000 mbar was measured, the volume and mass of the released carbon dioxide was confirmed from this pressure difference, and after rapid drying of the mixture , Repeating the heat treatment as necessary to obtain a surface passivation indicated by a clear slowing of the reaction and a reduction of gas evolution, and selected from the group consisting of water-soluble polymers, higher alcohols, carbohydrates and hydrocolloids. A neutral organic substance dissolved in the polar solvent, and a powder of an edible solid organic acid and a carbonate and / or bicarbonate of an alkali metal and / or an alkaline earth metal. Method for producing effervescent granules under vacuum from the particulate mixture. 27. Preparing an expandable particulate material containing at least one edible solid organic acid and at least one carbonate of an alkali metal or alkaline earth metal that reacts with the organic acid in an aqueous solution to generate carbon dioxide A method comprising the steps of preparing the effervescent granules; the step of pre-reacting a portion of the organic acid and the carbonate in a solution of water and / or alcohol to produce a pre-reaction product. -Adding the pre-reaction product to the additional portion of the organic acid in the form of crystals and mixing well to form a first coating by reaction with the organic acid and the resulting liberation of water of crystallization. Forming at least one additional coating comprising the carbonate on the organic acid crystals to which the first coating adheres; drying the final coating to complete the reaction. , Then water and / or Soluble polymer to alcohol, higher alcohol, a method of adjusting the effervescent granules, characterized in that a neutral substance selected from the group consisting of carbohydrates and hydrocolloids comprising the step, adding to the pre-reaction product.