JPH08512321A - H-Lower 2 Antagonist-alginate-antacid combination - Google Patents
H-Lower 2 Antagonist-alginate-antacid combinationInfo
- Publication number
- JPH08512321A JPH08512321A JP7504108A JP50410894A JPH08512321A JP H08512321 A JPH08512321 A JP H08512321A JP 7504108 A JP7504108 A JP 7504108A JP 50410894 A JP50410894 A JP 50410894A JP H08512321 A JPH08512321 A JP H08512321A
- Authority
- JP
- Japan
- Prior art keywords
- alginate
- antacid
- effective
- amount
- famotidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940069428 antacid Drugs 0.000 title claims abstract description 42
- 239000003159 antacid agent Substances 0.000 title claims abstract description 42
- 235000010443 alginic acid Nutrition 0.000 claims abstract description 57
- 229920000615 alginic acid Polymers 0.000 claims abstract description 57
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229940072056 alginate Drugs 0.000 claims abstract description 35
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 33
- 230000001458 anti-acid effect Effects 0.000 claims abstract description 23
- 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 201000006549 dyspepsia Diseases 0.000 claims abstract description 14
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000002496 gastric effect Effects 0.000 claims abstract description 12
- 208000014174 Oesophageal disease Diseases 0.000 claims abstract description 11
- 208000028299 esophageal disease Diseases 0.000 claims abstract description 11
- 208000024798 heartburn Diseases 0.000 claims abstract description 8
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 6
- 239000003485 histamine H2 receptor antagonist Substances 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 206010020601 Hyperchlorhydria Diseases 0.000 claims abstract description 5
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- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 claims description 39
- 229960001596 famotidine Drugs 0.000 claims description 38
- 239000005557 antagonist Substances 0.000 claims description 18
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims description 12
- 229940083037 simethicone Drugs 0.000 claims description 12
- 239000000783 alginic acid Substances 0.000 claims description 11
- 229960001126 alginic acid Drugs 0.000 claims description 11
- 150000004781 alginic acids Chemical class 0.000 claims description 11
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- 150000003839 salts Chemical class 0.000 claims description 10
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 8
- 206010000059 abdominal discomfort Diseases 0.000 claims description 8
- 235000010413 sodium alginate Nutrition 0.000 claims description 8
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- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 7
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- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
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- 229960001380 cimetidine Drugs 0.000 description 4
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- 229930195725 Mannitol Natural products 0.000 description 2
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- IJAAJNPGRSCJKT-UHFFFAOYSA-N tetraaluminum;trisilicate Chemical compound [Al+3].[Al+3].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-].[O-][Si]([O-])([O-])[O-].[O-][Si]([O-])([O-])[O-] IJAAJNPGRSCJKT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003357 wound healing promoting agent Substances 0.000 description 1
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/10—Carbonates; Bicarbonates
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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Abstract
(57)【要約】 本発明は、消化不良、胃酸過多、胸焼け、および他の胃腸障害を、人間を含む哺乳動物にて組成物の投与により処置および軽減する際に使用するための医薬組成物に関し、これら組成物は：（ｉ）胃腸もしくは食道障害の軽減に有効な量の式（Ｉ）の化合物およびその医薬上許容しうる塩、水和物、立体異性体もしくは多形体から選択されるＨ2拮抗剤と、（ii）胃腸もしくは食道障害の軽減に有効な量の少なくとも１種のアルギネートと、（iii）胃痛の軽減に有効な量の制酸剤（この制酸剤は緩衝作用を与えると共に二酸化炭素を発生してアルギネートを通気する）とからなっている。 (57) Summary The present invention provides a pharmaceutical composition for use in treating and reducing indigestion, hyperacidity, heartburn, and other gastrointestinal disorders in mammals, including humans, by administration of the composition. With respect to these compositions: An H 2 antagonist, (ii) an amount of at least one alginate effective in reducing gastrointestinal or esophageal disorders, and (iii) an amount of antacid effective in reducing gastric pain. It gives off carbon dioxide and aerates alginate).
Description
【発明の詳細な説明】 Ｈ2拮抗剤−アルギネート−制酸剤の組合せ物発明の背景 Ｈ2拮抗剤は胃、十二指腸もしくは食道の壁部における潰瘍を処置および防止 すべく一般に処方される。さらに、Ｈ2拮抗剤は非潰瘍性症状を処置するにも使 用される。これら組織を包囲する粘膜が損傷すると、胃酸が下部組織に浸蝕して これを破壊するよう作用しうる。潰瘍を処置する一般的に知られたＨ2拮抗剤は 、シメチジン、ラニチジン、ニザチジン、ロキサチジンおよびファモチジンを包 含する。 アルギネートと或る種のＨ2拮抗剤との組合せ物が開示されている。たとえば 米国特許第５，００７，７９０号は（シメチジン）／ポリマー（アルギン酸ナト リウム）を含有する固相薬物を開示している；ＧＢ ２２２２７７２号はＨ2拮 抗剤ラニチジンおよびアルギン酸を開示している。ＧＢ ２２０７８６５号は、 Ｈ2拮抗剤（ファモチジン）とたとえばアルギネートのようなキャリヤとからな る外傷治癒剤を開示しており、ここでは組成物を胃酸抑制剤としてではなく外傷 を処置するため使用する。ＥＰ−２９０，２２９−Ｂ号はＨ2拮抗剤（シメチジ ン）＋制酸剤および／またはアルギネートを開示している（米国特許第４，９９ ６，２２２号をも参照）。或る種のＨ2拮抗剤により胃食道逆流を処置すべく添 加されるアルギネートはＨ2拮抗剤の酸化を促進して生不活性としうることが知 られ、この反応を防止するには追加成分を添加せねばならない。制酸剤とアルギ ネートとの組合せ物が胃食道逆流の徴候軽減を与えるべく使用されている［Ｍａ ｒｔｉｎｄａｌｅ′ｓ Ｅｘｔｒａ Ｐｈａｒｍａｃｏｐｏｅｉａ、第１４３２ 頁参照）。Ｈ2拮抗剤と制酸剤との組合せ物も開示されている（ＦＲ ２６４８ ７１０号、ＧＢ ２２１９９４０号、ＥＰ−２９４９３３−Ａ号、ＥＰ−２８６ ７８１−Ａ号、ＳＵ １，３６２，４７７−Ａ号、Ｕ．Ｓ．４，８２４，６６４ 号、ＥＰ ２３３８５３号およびＷＯ ９２０９２８６ Ａ１号参照）。しかし ながら、胃食道逆流（ＧＥＲ）を防止するアルギネートもしくはアルギン酸と制 酸剤との利点を、消化不良、胃酸過多（ｓｏｕｒ ｓｔｏｍａｃｈ）、胸焼けま たはＧＥＲを含む他の胃腸障害に伴う不快感を処置および防止するファモチジン もしくはその塩、水和物、立体異性体もしくは多形体から選択されるＨ2拮抗剤 と組合せた薬物組合せ物に対する要請がある。ファモチジ ンが活性の低い代謝物へ酸化するのを防止すべく、本発明のファモチジン／アル ギネート／制酸剤の組合せ物にさらに酸化防止剤を添加することもできる。胃腸 不快感のあらゆる徴候を、入手しうる最も強力なＨ2拮抗剤とアルギネートおよ び制酸剤（たとえば炭酸塩または水酸化マグネシウムもしくはアルミニウム）と の組合せ物により効果的に処置しうる利点を有し、同時にそれぞれ胃および食道 における過度の胃酸分泌もしくは発生に伴う徴候を軽減および防止するような組 合せ物を用いる必要がある。 したがって本発明は、ファモチジンおよびその塩、水和物または薬理学上活性 な立体異性体もしくは多形体と、アルギネートおよび制酸剤との組合せ物を用い る胃腸障害の効果的かつ相乗的処置を提供する。本発明の組合せ物は夜間におけ る胃食道逆流を処置するのに特に有用である。何故なら、ファモチジンまたは生 理活性型のファモチジンは長持続作用（９時間）を示して胸焼けおよび他の胃腸 不快感の防止に役立つ一方、アルギネートはラフチング（ｒａｆｔｉｎｇ）作用 を排除するのに役立つと共に、制酸剤は胃における急速な緩衝性治癒をもたらす からである。本発明に用いうる他のＨ2拮抗剤は、シメチジン、 ラニチジン、ニザチジンおよびロキサチジンを包含する。発明の詳細な説明 本発明は、胸焼けの予防および処置を含む軽度の胃および食道障害の処置に使 用するための医薬組成物に関する。この組成物は： （ｉ）胃腸もしくは食道障害の軽減に有効な量の式： の化合物およびその医薬上許容しうる塩、水和物、立体異性体もしくは多形体か ら選択されるＨ2拮抗剤と、 （ii）胃腸もしくは食道障害の軽減に有効な量の少なくとも１種のアルギネー トと、 （iii）胃腸不快感の軽減に有効な量の制酸剤（この制酸剤は緩衝作用を与え ると共に二酸化炭素を発生してアルギネートに通気する）と、必要に応じ （iv）鼓脹防止量のシメチコンと からなっている。 さらに本発明は、以下の症状の処置を必要とする人間を含む哺乳動物における 消化不良、胃酸過多、胸焼け、飲食過多、胃食道逆流および他の胃腸障害の予防 および処置方法に向けられ、この方法は前記哺乳動物に対し： （ｉ）胃腸もしくは食道障害の軽減に有効な量の式： の化合物およびその医薬上許容しうる塩、水和物、立体異性体もしくは多形体か ら選択されるＨ2拮抗剤と、 （ii）胃腸もしくは食道障害の軽減に有効な量の少なくとも１種のアルギネー トと、 （iii）胃腸不快感の軽減に有効な量の制酸剤（この制酸剤は緩衝作用を与え ると共に二酸化炭素を発生してアルギネートに通気する）と、必要に応じ （iv）鼓脹防止量のシメチコンと を投与することからなっている。 「哺乳動物」もしくは「哺乳類生物」という用語は限定はし ないがヒト、イヌ、ネコ、ウマおよびウシを包含する。 「処置」という用語は、生物に影響を及ぼす徴候もしくは病気の減少、緩和お よび軽減を含む、医薬投与に伴う治療効果のあるあらゆる範囲の作用を包含する 。 ファモチジンは、現在市販されているのでバルク又は他の適量を購入すること ができ、かつ錠剤処方に適するアルギン酸または本発明の組合せ物の液体処方物 に適するアルギン酸ナトリウムから選択されるアルギネートと、炭酸カルシウム および他の炭酸塩、並びに水酸化アルミニウムおよびマグネシウムを包含する公 知である制酸剤と共に、慣用の製剤操作で処方される。さらに、シメチコン（す なわち公知の鼓脹防止剤）を上記組合せ物に添加して、胃腸障害および胃腸不快 感の最大かつ広範囲の軽減を与えることができる。処方医薬品としてのファモチ ジンはＰＥＰＣＩＤ（登録商標）として米国で販売されている。 本発明の医薬組成物は、消化不良、胃酸過多、飲食過多および胸焼けを包含す る各種の軽度の胃腸障害の処置に有用である。 特にファモチジン、すなわち式： の化合物またはその医薬上許容しうる塩、水和物、立体異性体もしくは多形体か ら選択されるＨ2拮抗剤と組合せた、アルギネートおよび制酸剤は、たとえば消 化不良、胃酸過多もしくは胸焼けのような各種の胃腸障害の予防および処置に有 用である。アルギン酸もしくはアルギン酸ナトリウムまたは他の医薬上許容しう るアルギン酸塩もしくは水和物および制酸剤と組合せた、ファモチジンの現在公 知の生理活性型および／またはその塩もしくは水和物の利用は、有利には軽度の 胃腸障害を処置すべく用いられる。シメチコンまははたとえばα−ガラクトシダ ーゼ（ＡＤＧ）のような他の鼓脹防止剤をこの好適組合せ物に添加して、鼓脹防 止軽減を与えることができる。特に本発明の組合せ物は、胃酸分泌に伴う徴候を 処置すると同時に、胃食道逆流および鼓脹の徴候を処置するのに用いられる。し たがって、この処置を必要とする動物、患者もしくは生物は、本発明による医薬 組成物の利点を享受する。 Ｈ2拮抗剤は潰瘍および他の胃腸障害の処置につき周知されており、本発明に よればアルギネートおよび制酸剤、並びに必要に応じ鼓脹防止剤と組合せて使用 することができる。潰瘍治療につき使用されるＨ2拮抗剤は４種の主たる構造に 分類される：すなわちイミダゾール誘導体；置換フラン；アミノアルキルフェノ キシ誘導体およびグアニジノチアゾール化合物。ファモチジン（Ｎ′−（アミノ スルホニル）−３−［［［２−［（ジアミノメチレン）アミノ］−４−チアゾリ ル］メチル］チオ］プロパンイミダミド）、すなわち最後の種類の化合物はヒス タミンＨ2リセプタの競合抑制剤であり、その主たる薬理活性は胃酸分泌の抑制 である。ファモチジンは酸濃度および胃酸分泌量の両者を抑制する。ファモチジ ンは充分許容され、副作用が少なく、したがってアルギネートおよび制酸剤と組 合せて本発明で有利に使用することができる。さらにファモチジンは最も強力か つ選択性のＨ2拮抗剤である。 ファモチジンもしくはその医薬上有効な塩、水和物、立体異性体もしくは多形 体と、制酸剤およびアルギネート並びに必要に応じシメチコンとの組合せ物は、 胃、食道もしくは十二指腸に対する過剰の胃酸生成からの不快感および障害を同 時的かつ 選択的に軽減および予防するための組合せ物を与える。さらに、アルギネートお よび制酸剤と組合せたファモチジンはアルコールと相互作用しないので、アルコ ールを含有する食事もしくは飲料の摂取前または摂取中に投与でき、胃腸不快感 の急速処置を必要とする患者はアルコールを消費する食事中をも含む適する時に 、薬物組合せ物を摂取することができる。アルギネートおよび制酸剤とファモチ ジンとの組合せは胃食道逆流の軽減を与えると共に、胃酸分泌に伴う胃腸障害を 長時間軽減し治癒する。本発明の組合せ物で投与される制酸剤は緩衝作用を与え ると同時に、二酸化炭素を発生してアルギネートから生成されるアルギネートラ フト（ｒａｆｔ）に通気する。このラフトは通気の結果密度が小さくなり、胃内 容物を浮遊させる。 ファモチジンの治療上活性な立体異性体もしくは多形体も用いることができ、 これは多形体の他の立体異性型を実質的に含まず、ここで「実質的に含まない」 という表現は、１種の異なる立体異性体もしくは多形体が少なくとも９０％を占 めることを意味すると了解すべきである。 極めて有力なＨ2拮抗剤であるファモチジンとアルギネートおよび制酸剤との 組合せ物は、あらゆる医薬供給形態物もしく は組合せ処方物においてその寸法および重量を減少させ、したがって患者の趣向 性もしくは受容性を改善する。この組合せ物の錠剤もしくはカプセルは、処置を 必要とする患者により一層容易に嚥下することができる。 ファモチジンまたはその医薬上許容しうる塩、水和物、立体異性体もしくは多 形体は、有利には本発明にてアルギン酸もしくはアルギン酸ナトリウムおよび炭 酸カルシウムと組合せて使用される。勿論、たとえば水酸化アルミニウムもしく は水酸化マグネシウム塩またはその混合物もしくは組合せ物のような他の適する 公知の制酸剤も本発明の処方に使用することができる。たとえば１：１の比にお ける水酸化マグネシウムと水酸化アルミニウムとを本発明に用いることができる 。人間において本発明で使用するファモチジンの量は、２．５〜８０ｍｇ／日の 範囲とすることができる。有利には２．５〜４０ｍｇ／日の量を、２００〜５０ ０ｍｇ／日のアルギネートおよび２５０〜７５０ｍｇ／日の炭酸カルシウムと組 合せて投与する。各活性成分の量は、特定の生化学および症状の程度および処置 を必要とする患者もしくは他の生物の必要性に応じて変化しうる。当業界の医者 もしくは臨床医または獣医は、本発明による組成物を含有 した任意の処方薬の適する投与量を容易に決定することができる。本発明による 組合せ物は有利には経口投与される。ここで用いる制酸剤は市販もしくは公知の 制酸剤またはその組合せ物、たとえば水酸化アルミニウム、炭酸カルシウム、水 酸化マグネシウムまたは重炭酸ナトリウムから選択することができる。必要に応 じ、ここで用いるシメチコンも市販されており、その経口投与量は人間において １０〜１，０００ｍｇ／日の範囲とすることができる。この量は症状の程度に応 じて変化し、典型的な投与量は文献［Ｐｈｙｓｉｃｉａｎｓ Ｄｅｓｋ Ｒｅｆ ｅｒｅｎｃｅ、第１１５５〜５６頁（１９９２）］に記載されている。ＡＤＧは ２９０〜３１，０００ガラクトシダーゼ国際単位（ＧａＩＵ）、特に６７５〜２ ２５０ ＧａＩＵの量で鼓脹防止剤として用いることができる。 本発明による組成物は、処置を必要とする患者に対し錠剤、カプレット、ゲル キャップ、カプセル、エリキシル、ロゼンジ、ウェファー、起泡性組成物、チュ ーイング錠剤、シロップもしくは懸濁液として、或いは他の公知かつ有効な供給 法により投与することができる。経口投与の場合、活性成分はたとえば乳糖、蔗 糖、セルロース、燐酸二カルシウム、硫酸カルシウム、 マニトールのような医薬上許容しうる希釈剤と混合することができ、液体組成物 ではエチルアルコールと混合することができる。たとえばＰＶＰ、ゼラチン、天 然糖類、コーン甘味料、天然および合成ガム、たとえばアカシヤ、アルギン酸ナ トリウム、グアガム、寒天、ベントナイト、カルボキシメチルセルロース ナト リウム、ポリエチレングリコールおよびワックスのような許容しうる乳化剤もし くは懸濁剤も活性成分と混合することができる。必要ならば、たとえばマグネシ ウム・ステアリン酸タルク、すなわちステアリン酸マグネシウムのような滑剤、 並びにたとえば澱粉、グリコール酸ナトリウム澱粉もしくは架橋ＰＶＰのような 崩壊剤もしくは超崩壊剤も含ませることができる。たとえば燐酸二カルシウム、 安息香酸ナトリウム、酢酸ナトリウムおよび塩化ナトリウムのような電解質も使 用することができる。さらに不活性成分はトリ珪酸マグネシウムもしくはアルミ ニウム、炭酸塩を含むナトリウムもしくはカリウム塩、水酸化アルミニウムゲル 、乳糖、ソルビトール、アスパルテームもしくはナトリウムサッカライドをも包 含する。 さらに、活性成分は持続放出性組成物もしくは起泡性製剤として処方すること もできる。持続放出性処方物は、さらに異な る放出比を与える層状組成物をも包含し、したがって短時間および長時間の軽減 を可能にして一層効果的である。 以下、容易に作成しうる本発明の組成物を実施例につき説明するがこれらは決 して本発明を限定するものでない。実施例１ アルギネート／制酸剤 ／ファモチジンの錠剤 アルギン酸 ５００ｍｇ ファモチジン ４０ｍｇ ＰＶＰ １５ｍｇ アビセルＰＨ１０１ ４０ｍｇ ステアリン酸マグネシウム ４ｍｇ 炭酸カルシウム ５００ｍｇ 三珪酸マグネシウム ２５ｍｇ 重炭酸ナトリウム １７０ｍｇ 水酸化アルミニウムゲル １００ｍｇ 実施例２アルギネート／制酸剤 ／ファモチジンの錠剤 アルギン酸 ５００ｍｇ ファモチジン ２０ｍｇ ＰＶＰ １５ｍｇ アビセルＰＨ１０１ ４０ｍｇ ステアリン酸マグネシウム ４ｍｇ 炭酸カルシウム ５００ｍｇ実施例３ アルギネート／制酸剤 ／ファモチジンの錠剤 アルギン酸 ５００ｍｇ ファモチジン １５ｍｇ ＰＶＰ １５ｍｇ アビセルＰＨ１０１ ４０ｍｇ ステアリン酸マグネシウム ４ｍｇ 炭酸カルシウム ５００ｍｇ実施例４ アルギネート／制酸剤 ／ファモチジンの錠剤 アルギン酸 ５００ｍｇ ファモチジン １０ｍｇ ＰＶＰ １５ｍｇ アビセルＰＨ１０１ ４０ｍｇ ステアリン酸マグネシウム ４ｍｇ 炭酸カルシウム ５００ｍｇ実施例５ アルギネート／制酸剤 ／ファモチジンの錠剤 アルギン酸 ５００ｍｇ ファモチジン ５ｍｇ ＰＶＰ １５ｍｇ アビセルＰＨ１０１ ４０ｍｇ ステアリン酸マグネシウム ４ｍｇ 炭酸カルシウム ５００ｍｇ実施例６ アルギネート／制酸剤 ／ファモチジンの持続放出剤 アルギン酸 ６００ｍｇ ファモチジン ４０ｍｇ ＰＶＰ ３０ｍｇ アビセルＰＨ１０１ ８０ｍｇ ステアリン酸マグネシウム ８ｍｇ メトセルＥ１０ＭＣＲ ６６ｍｇ メトセルＫ１００ＭＬＶ ２００ｍｇ 炭酸カルシウム ６００ｍｇ実施例７ アルギネート／ファモチジン／ 制酸剤の持続放出剤 アルギン酸 ６００ｍｇ ファモチジン ２０ｍｇ ＰＶＰ ３０ｍｇ アビセルＰＨ１０１ ８０ｍｇ ステアリン酸マグネシウム ８ｍｇ メトセルＥ１０ＭＣＲ ６６ｍｇ メトセルＫ１００ＭＬＶ ２００ｍｇ 炭酸カルシウム ６００ｍｇ実施例８ アルギネート／制酸剤 ／ファモチジンの溶液 アルギン酸ナトリウム ５００ｍｇ ファモチジン １０ｍｇ ｇ．ｓ．シロップ ５ｍＬ 炭酸カルシウム ５００ｍｇ実施例９ アルギネート／制酸剤 ／ファモチジンの溶液 アルギン酸ナトリウム ５００ｍｇ ファモチジン ２０ｍｇ ｇ．ｓ．シロップ ５ｍＬ 炭酸カルシウム ５００ｍｇ シメチコンは、鼓脹軽減を付与するために上記処方物もしくは実施例のそれぞ れに添加することができる。処置を必要とする患者に投与されるシメチコンの量 は、鼓脹を処置する典型的に知られた投与量範囲である。たとえば投与量は液状 の本発明による組合せ物５ｍＬ当り或いはチューイング性錠剤１個当り、２０〜 ４０ｍｇのシメチコンとすることができ、ここで他の活性成分はファモチジン（ ２０〜４０ｍｇ）、水酸化マグネシウム（２００ｍｇ）、水酸化アルミニウム（ 乾燥ゲル、２００ｍｇ）を包含する。錠剤型における不活性成分はさらにデキス トレート、マニトール、ステアリン酸マグネシウム、イエロー１０、コロイド状 二酸化珪素およびブルー１もしくはレッド２７を包含する一方、液体型はさらに たとえばブチルパラベン、カルボキシメチルセルロースナトリウム、着香料、ヒ ドロキシプロピルメチルセルロース、微晶性セルロース、プロピルパラベンおよ び精製水のような不活性物質をも含むことができる。上記実施例は決して限定を 意味するものでなく、他の投与量および投与形態または投与経路を胃腸障害の一 次的（胃腸もしくは食道障害もしくは損傷をもたらす酸過多）または二次的（感 染性）徴候につき、処置される個々の患者に応じて変化するこ とができる。さらに、公知の医薬上許容しうる賦形薬もしくは薬剤を、本発明に よる活性組合せ物に不活性成分として錠剤、カプセルまたは経時放出性薬物を包 含する各種の形態で添加することもできる。DETAILED DESCRIPTION OF THE INVENTION H 2 Antagonist-Alginate-Antacid Combinations BACKGROUND OF THE INVENTION H 2 antagonists are commonly prescribed for treating and preventing ulcers in the stomach, duodenum or esophageal wall. Furthermore, H 2 antagonists are used to treat non-ulcer symptoms. When the mucosa surrounding these tissues is damaged, gastric acid can act to erode and destroy underlying tissues. Commonly known H 2 antagonists for treating ulcers include cimetidine, ranitidine, nizatidine, roxatidine and famotidine. Combinations of alginates with certain H 2 antagonists have been disclosed. For example, US Pat. No. 5,007,790 discloses solid phase drugs containing (cimetidine) / polymer (sodium alginate); GB 2222772 discloses the H 2 antagonists ranitidine and alginic acid. GB 2207865 discloses wound healing agents consisting of a H 2 antagonist (famotidine) and a carrier such as alginate, wherein the composition is used as a gastric acid suppressor and not for treating wounds. EP-290,229-B discloses H 2 antagonists (cimetidine) + antacids and / or alginates (see also US Pat. No. 4,996,222). It is known that alginate added to treat gastroesophageal reflux by certain H 2 antagonists can promote the oxidation of H 2 antagonists and render them bioinactive. Must be added. Combinations of antacids and alginates have been used to provide symptomatic relief of gastroesophageal reflux [Martindale's Extra Pharmacopoeia, page 1432]. Combinations of H 2 antagonists and antacids have also been disclosed (FR 2648 710, GB 22199940, EP-294933-A, EP-286 781-A, SU 1,362,477-A. No., US 4,824,664, EP 233853 and WO 9209286 A1). However, the benefits of alginate or alginic acid and antacids to prevent gastroesophageal reflux (GER) are treated and prevented from discomfort associated with dyspepsia, sour stomach, heartburn or other gastrointestinal disorders including GER. There is a need for a drug combination in combination with an H 2 antagonist selected from the group consisting of famotidine or its salts, hydrates, stereoisomers or polymorphs. Further antioxidants may be added to the famotidine / alginate / antacid combination of the present invention to prevent oxidation of famotidine to less active metabolites. Has the advantage that any indication of gastrointestinal discomfort can be effectively treated by the combination of the most available H 2 antagonists with alginates and antacids (eg carbonates or magnesium or aluminum hydroxide). At the same time, it is necessary to use a combination that reduces and prevents the symptoms associated with excessive gastric acid secretion or development in the stomach and esophagus, respectively. Accordingly, the present invention provides an effective and synergistic treatment of gastrointestinal disorders using a combination of famotidine and its salts, hydrates or pharmacologically active stereoisomers or polymorphs with alginates and antacids. . The combinations of the present invention are particularly useful for treating gastroesophageal reflux at night. Because famotidine or the bioactive form of famotidine has a long-lasting effect (9 hours) and helps prevent heartburn and other gastrointestinal discomfort, alginate helps eliminate the rafting effect and inhibits it. This is because the acid agent provides a rapid buffer healing in the stomach. Other H 2 antagonists that may be used in the present invention include cimetidine, ranitidine, nizatidine and roxatidine. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical compositions for use in the treatment of mild gastric and esophageal disorders, including the prevention and treatment of heartburn. The composition comprises: (i) an amount of formula effective to reduce gastrointestinal or esophageal disorders: H 2 antagonists selected from the group consisting of: and a pharmaceutically acceptable salt, hydrate, stereoisomer or polymorph thereof, and (ii) at least one alginate effective in reducing gastrointestinal or esophageal disorders. And (iii) an amount of antacid that is effective in reducing gastrointestinal discomfort (this antacid provides a buffering action and generates carbon dioxide to ventilate alginate), and (iv) prevents bloating as necessary. It consists of a quantity of simethicone. The present invention is further directed to a method for the prevention and treatment of dyspepsia, hypergastric acidity, heartburn, hyperdigestion, gastroesophageal reflux and other gastrointestinal disorders in mammals, including humans, in need of treatment for the following conditions, which method: To the mammal: (i) an amount of a formula effective to reduce gastrointestinal or esophageal disorders: H 2 antagonists selected from the group consisting of: and a pharmaceutically acceptable salt, hydrate, stereoisomer or polymorph thereof, and (ii) at least one alginate effective in reducing gastrointestinal or esophageal disorders. And (iii) an amount of antacid that is effective in reducing gastrointestinal discomfort (this antacid provides a buffering action and generates carbon dioxide to ventilate alginate), and (iv) prevents bloating as necessary. Consists of administering an amount of simethicone. The term "mammal" or "mammalian organism" includes but is not limited to humans, dogs, cats, horses and cows. The term "treatment" includes any and all areas of therapeutic effect associated with the administration of the drug, including reduction, alleviation and alleviation of signs or illnesses affecting the organism. Famotidine is an alginate selected from alginic acid suitable for tablet formulations and sodium alginate suitable for liquid formulations of combinations according to the invention, which can be purchased in bulk or other suitable amounts as it is currently marketed, and calcium carbonate. And other carbonates, and known antacids, including aluminum hydroxide and magnesium, are formulated in conventional formulation procedures. In addition, simethicone (ie, a known anti-bloating agent) can be added to the combination to provide maximum and widespread relief of gastrointestinal disorders and gastrointestinal discomfort. Famotidine as a prescription drug is sold in the United States as PEPCID®. The pharmaceutical composition of the present invention is useful for the treatment of various mild gastrointestinal disorders including dyspepsia, hyperacidity, hyperdigestion and heartburn. In particular famotidine, ie the formula: Alginates and antacids in combination with H 2 antagonists selected from the compounds of claim 1 or pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs thereof, such as indigestion, hyperacidity or heartburn. It is useful for the prevention and treatment of various various gastrointestinal disorders. The use of the currently known bioactive form of famotidine and / or its salts or hydrates in combination with alginic acid or sodium alginate or other pharmaceutically acceptable alginates or hydrates and antacids is advantageous. Used to treat mild gastrointestinal disorders. Other antibloating agents, such as simethicone or α-galactosidase (ADG), can be added to this preferred combination to provide antibloating relief. In particular, the combinations of the invention are used to treat the symptoms associated with gastric acid secretion, as well as the symptoms of gastroesophageal reflux and bloating. Thus, any animal, patient or organism in need of this treatment will benefit from the pharmaceutical composition according to the invention. H 2 antagonists are well known for the treatment of ulcers and other gastrointestinal disorders and, according to the invention, can be used in combination with alginates and antacids, and optionally anti-bloating agents. The H 2 antagonists used for ulcer treatment are classified into four main structures: imidazole derivatives; substituted furans; aminoalkylphenoxy derivatives and guanidinothiazole compounds. Famotidine (N '- (aminosulfonyl) -3 - [[[2 - [(diaminomethylene) amino] -4-thiazolyl] methyl] thio] propanoic Imi dummy de), i.e. the last classes of compounds of the histamine H 2 receptors It is a competitive inhibitor and its main pharmacological activity is inhibition of gastric acid secretion. Famotidine suppresses both acid concentration and gastric acid secretion. Famotidine is well tolerated and has few side effects and therefore can be advantageously used in the present invention in combination with alginates and antacids. Furthermore, famotidine is the most potent and selective H 2 antagonist. Famotidine or its pharmaceutically effective salts, hydrates, stereoisomers or polymorphs in combination with antacids and alginates and optionally simethicone can be used to prevent gastric, esophageal or duodenal excess gastric acid production. A combination is provided for simultaneously and selectively reducing and preventing pleasure and disorders. In addition, famotidine in combination with alginate and antacids does not interact with alcohol, so it can be administered before or during the ingestion of an alcohol-containing diet or beverage, and patients in need of rapid treatment of gastrointestinal discomfort can consume alcohol. The drug combination may be taken at any suitable time, including during the meal consumed. The combination of alginate and antacids with famotidine provides relief of gastroesophageal reflux and at the same time reduces and cures gastrointestinal disorders associated with gastric acid secretion. The antacid administered in the combination of the present invention provides a buffering action while at the same time generating carbon dioxide to vent to the alginate rafts formed from the alginate. The raft becomes less dense as a result of aeration and floats the stomach contents. Therapeutically active stereoisomers or polymorphs of famotidine can also be used, which is substantially free of other stereoisomeric forms of the polymorph, where the phrase "substantially free" refers to one It should be understood that this means that at least 90% of the different stereoisomers or polymorphs of The combination of famotidine, an extremely potent H 2 antagonist with alginates and antacids, reduces its size and weight in any pharmaceutical delivery form or combination formulation, thus improving patient preference or acceptability. To do. Tablets or capsules of this combination can be more easily swallowed by patients in need of treatment. Famotidine or its pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs are advantageously used in the present invention in combination with alginic acid or sodium alginate and calcium carbonate. Of course, other suitable known antacids such as aluminum hydroxide or magnesium hydroxide salts or mixtures or combinations thereof can also be used in the formulations of the present invention. For example, magnesium hydroxide and aluminum hydroxide in a 1: 1 ratio can be used in the present invention. The amount of famotidine used in the present invention in humans can range from 2.5 to 80 mg / day. Advantageously an amount of 2.5-40 mg / day is administered in combination with 200-500 mg / day alginate and 250-750 mg / day calcium carbonate. The amount of each active ingredient may vary depending on the particular biochemistry and extent of the condition and the need of the patient or other organism in need of treatment. A physician or clinician or veterinarian of ordinary skill in the art can readily determine an appropriate dosage for any prescription drug containing a composition according to the present invention. The combination according to the invention is advantageously administered orally. The antacid used here can be selected from commercially available or known antacids or combinations thereof, such as aluminum hydroxide, calcium carbonate, magnesium hydroxide or sodium bicarbonate. If necessary, simethicone used here is also commercially available, and its oral dose can be in the range of 10 to 1,000 mg / day in humans. This amount varies depending on the degree of symptoms, and typical doses are described in the literature [Physicians Desk Reference, pp. 1155-56 (1992)]. ADG can be used as an anti-bloating agent in an amount of 290-31,000 galactosidase international units (GaIU), especially 675-2250 GaIU. The compositions according to the invention may be used as tablets, caplets, gelcaps, capsules, elixirs, lozenges, wafers, effervescent compositions, chewing tablets, syrups or suspensions for patients in need of treatment, or other known ingredients. And can be administered by an effective delivery method. For oral administration, the active ingredient may be mixed with a pharmaceutically acceptable diluent such as lactose, sucrose, cellulose, dicalcium phosphate, calcium sulphate, mannitol or in a liquid composition with ethyl alcohol. You can Acceptable emulsifying or suspending agents are also active, such as, for example, PVP, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, guar gum, agar, bentonite, sodium carboxymethylcellulose, polyethylene glycol and waxes. It can be mixed with the ingredients. If desired, lubricants such as magnesium talc stearate, ie magnesium stearate, and disintegrants or superdisintegrants such as starch, sodium starch glycolate or cross-linked PVP can also be included. Electrolytes such as dicalcium phosphate, sodium benzoate, sodium acetate and sodium chloride can also be used. Further inert ingredients include magnesium or aluminum trisilicate, sodium or potassium salts including carbonates, aluminum hydroxide gel, lactose, sorbitol, aspartame or sodium saccharides. In addition, the active ingredient may be formulated as a sustained release composition or a foaming formulation. Sustained release formulations also include layered compositions that provide different release ratios, thus allowing for short and long time relief to be more effective. Hereinafter, the composition of the present invention which can be easily prepared will be described with reference to Examples, but these do not limit the present invention in any way. Example 1 Alginate / antacid / famotidine tablets Alginic acid 500 mg Famotidine 40 mg PVP 15 mg Avicel PH101 40 mg Magnesium stearate 4 mg Calcium carbonate 500 mg Magnesium trisilicate 25 mg Sodium bicarbonate 170 mg Aluminum hydroxide gel 100 mg Example 2 Alginate / antacid / famotidine tablets alginate 500mg famotidine 20 mg PVP 15 mg Avicel PH101 40 mg magnesium stearate 4mg calcium carbonate 500mg example 3 alginate / antacid / famotidine tablets alginate 500mg famotidine 15 mg PVP 15 mg Avicel PH101 40 mg magnesium stearate 4mg calcium carbonate 500mg example 4 Alginate / antacid / famotidine tablets Alginic acid 500 mg Famotidine 10 mg PVP 15 mg Avicel PH101 40 mg Magnesium stearate 4 mg Calcium carbonate 500 mg Example 5 Alginate / antacid / famotidine tablets Alginic acid 500 mg Famotidine 5 mg PVP 15 mg Avicel PH stealine PH calcium 500mg example carbonate 6 alginate / antacid / sustained release dosage magnesium alginate 600mg famotidine 40 mg PVP 30 mg Avicel PH101 80 mg stearic acid famotidine 8mg Methocel E10MCR 66 mg Methocel K100MLV 200 mg calcium carbonate 600mg example 7 alginate / famotidine / braking Sustained release agent of acid agent Alginic acid 600 mg Famotidine 20 mg PVP 30 mg Avicel PH101 80 mg Magnesium stearate 8 mg Methocel E10MCR 66 mg Methocel K100 MLV 200 mg Calcium carbonate 600 mg Example 8 alginate / antacid / famotidine solution sodium alginate 500 mg Famotidine 500 mg s. Syrup 5 mL Calcium carbonate 500 mg Example 9 Alginate / antacid / famotidine solution Sodium alginate 500 mg Famotidine 20 mg g. s. Syrup 5 mL Calcium Carbonate 500 mg Simethicone can be added to each of the above formulations or examples to provide bloating relief. The amount of simethicone administered to a patient in need of treatment is within the range of doses typically known for treating bloating. For example, the dosage may be 20-40 mg simethicone per 5 mL of the liquid combination according to the invention or per chewable tablet, where the other active ingredients are famotidine (20-40 mg), magnesium hydroxide ( 200 mg), aluminum hydroxide (dry gel, 200 mg). Inactive ingredients in tablet form further include dextrate, mannitol, magnesium stearate, yellow 10, colloidal silicon dioxide and blue 1 or red 27, while liquid forms further include, for example, butyl paraben, sodium carboxymethyl cellulose, flavoring agents, Inert materials such as hydroxypropylmethylcellulose, microcrystalline cellulose, propylparaben and purified water can also be included. The above examples are not meant to be limiting in any way, as other dosages and dosage forms or routes of administration may be used for primary (gastrointestinal or esophageal disorders or acid overload leading to damage) or secondary (infectious) signs. Can vary depending on the individual patient being treated. In addition, known pharmaceutically acceptable excipients or agents can be added to the active combinations according to the invention as inactive ingredients in various forms including tablets, capsules or time-released drugs.
───────────────────────────────────────────────────── フロントページの続き (81)指定国 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)，ＡＵ，ＢＢ，ＢＧ，ＢＲ，ＢＹ，ＣＡ， ＣＮ，ＣＺ，ＦＩ，ＧＥ，ＨＵ，ＪＰ，ＫＥ，ＫＧ，Ｋ Ｒ，ＫＺ，ＬＫ，ＬＴ，ＬＶ，ＭＤ，ＭＧ，ＭＮ，ＭＷ ，ＮＯ，ＮＺ，ＰＬ，ＲＯ，ＲＵ，ＳＤ，ＳＩ，ＳＫ， ＴＪ，ＴＴ，ＵＡ，ＵＳ，ＵＺ (72)発明者 シムズ，ロバート・テイ アメリカ合衆国、ペンシルバニア・18928、 ホリコング、アンダーソン・ロード・5080 (72)発明者 スリブカ，ウイリアム アメリカ合衆国、ペンシルバニア・19118、 フイラデルフイア、メドウブルツク・レイ ン・9425─────────────────────────────────────────────────── ─── Continued front page (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), AU, BB, BG, BR, BY, CA, CN, CZ, FI, GE, HU, JP, KE, KG, K R, KZ, LK, LT, LV, MD, MG, MN, MW , NO, NZ, PL, RO, RU, SD, SI, SK, TJ, TT, UA, US, UZ (72) Inventor Sims, Robert Tay 18928, Pennsylvania, United States, Holicong Anderson Road 5080 (72) Inventor Sliveka, William Pennsylvania, 19118, USA, Fira del Fuia, Meadow Burtsk Rei 9425
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8793793A | 1993-07-06 | 1993-07-06 | |
| US087,937 | 1993-07-06 | ||
| PCT/US1994/007519 WO1995001795A1 (en) | 1993-07-06 | 1994-07-05 | H2 antagonist-alginate-antacid combinations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH08512321A true JPH08512321A (en) | 1996-12-24 |
Family
ID=22208161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7504108A Pending JPH08512321A (en) | 1993-07-06 | 1994-07-05 | H-Lower 2 Antagonist-alginate-antacid combination |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0707484A4 (en) |
| JP (1) | JPH08512321A (en) |
| AU (1) | AU7218194A (en) |
| CA (1) | CA2166731A1 (en) |
| WO (1) | WO1995001795A1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9600071D0 (en) | 1996-01-08 | 1996-01-08 | Astra Ab | New oral formulation of two active ingredients I |
| CA2251854A1 (en) * | 1996-05-02 | 1997-11-06 | Carl Shellenberger (Deceased) | Method of preventing gastrointestinal upset |
| WO1998014198A1 (en) * | 1996-10-04 | 1998-04-09 | Merck & Co., Inc. | Methods and compositions for preventing and treating heartburn |
| WO1998023272A1 (en) * | 1996-11-27 | 1998-06-04 | The Procter & Gamble Company | Compositions and methods for the treatment of gastrointestinal disorders |
| AU1453600A (en) * | 1998-11-04 | 2000-05-22 | Mcneil-Ppc, Inc. | Solid oral dosage forms containing alginic acid and famotidine |
| US6930119B2 (en) * | 2002-07-17 | 2005-08-16 | Reliant Pharmaceuticals, Inc. | Liquid pharmaceutical composition |
| EP1992345A4 (en) * | 2006-03-09 | 2010-07-28 | Espinoza Abdala Leopoldo De Je | Synergic combination of h2-receptor inhibitors, inert silicone and a hydroxymagnesium aluminate complex |
| DE102006037298A1 (en) | 2006-08-08 | 2008-02-14 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Pharmaceutical composition, in particular antacid |
| DE102008019339A1 (en) * | 2008-04-16 | 2009-10-22 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Composition for medical use, in particular antacids |
| US20180140630A1 (en) * | 2016-11-23 | 2018-05-24 | M. Michael Wolfe | Combination of an h2-receptor antagonist, antacid, and alginic acid to treat episodic heartburn |
| IT201800002625A1 (en) * | 2018-02-13 | 2019-08-13 | Drugs Minerals And Generics Italia S R L In Forma Abbreviata D M G Italia S R L | Solid form composition for use in the treatment of extra-oesophageal symptoms of gastric reflux |
| IT201800007771A1 (en) * | 2018-08-02 | 2020-02-02 | Drugs Minerals And Generics Italia Srl In Forma Abbreviata Dmg Italia Srl | Combination for use in the treatment of extra-oesophageal symptoms of gastric reflux |
| IT202100029657A1 (en) * | 2021-11-24 | 2023-05-24 | Mauro Leonardis | STERILE ANTI-REFLUX SYRUP WITHOUT PRESERVATIVES |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ230701A (en) * | 1988-09-20 | 1992-01-29 | Glaxo Group Ltd | Pharmaceutical compositions comprising ranitidine, alginic acid and a carbonate or bicarbonate |
| US5229137A (en) * | 1992-05-06 | 1993-07-20 | Brigham And Women's Hospital, Inc. | Methods and pharmaceutical compositions for treating episodic heartburn |
| GB9224855D0 (en) * | 1992-11-27 | 1993-01-13 | Smithkline Beecham Plc | Pharmaceutical compositions |
| WO1995001780A1 (en) * | 1993-07-06 | 1995-01-19 | Merck & Co., Inc. | H2 antagonist-alginate combinations |
-
1994
- 1994-07-05 JP JP7504108A patent/JPH08512321A/en active Pending
- 1994-07-05 AU AU72181/94A patent/AU7218194A/en not_active Abandoned
- 1994-07-05 WO PCT/US1994/007519 patent/WO1995001795A1/en not_active Ceased
- 1994-07-05 CA CA002166731A patent/CA2166731A1/en not_active Abandoned
- 1994-07-05 EP EP94921465A patent/EP0707484A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995001795A1 (en) | 1995-01-19 |
| EP0707484A4 (en) | 1998-07-01 |
| EP0707484A1 (en) | 1996-04-24 |
| CA2166731A1 (en) | 1995-01-19 |
| AU7218194A (en) | 1995-02-06 |
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