JP5586123B2 - テトラサイクリンの1日1回製剤 - Google Patents
テトラサイクリンの1日1回製剤 Download PDFInfo
- Publication number
- JP5586123B2 JP5586123B2 JP2006509767A JP2006509767A JP5586123B2 JP 5586123 B2 JP5586123 B2 JP 5586123B2 JP 2006509767 A JP2006509767 A JP 2006509767A JP 2006509767 A JP2006509767 A JP 2006509767A JP 5586123 B2 JP5586123 B2 JP 5586123B2
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- JP
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- Prior art keywords
- doxycycline
- pellets
- composition
- tetracycline
- drug
- 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.)
- Expired - Lifetime
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Description
本発明はテトラサイクリンの1日1回組成物(once−daily compositions)に関し、これは急性または慢性疾患、例えば炎症性コンポーネントを備えるものの治療に使用し得る。より詳細には、本発明は、炎症のようなものに関わるコラーゲン破壊酵素または分子が要因である疾患または状態の治療のためのドキシサイクリンの薬学的組成物に向けられ、そして、これは1日1回製剤である。該組成物は、特に歯周病、酒さ(rosacea)、ドライアイ、アクネ(acne)及び慢性関節リウマチのような一般的な疾患状態の処置に有用である。
通常、ドキシサイクリン及び関連するテトラサイクリンは、様々な細菌感染症を治療するための広域スペクトル抗生物質として使用される。テトラサイクリンはアミノアシル−tRNAのリボゾームへの結合を阻止することにより、グラム陽性及びグラム陰性細菌のタンパク合成を阻害する。これらの作用は殺菌(殺菌性)よりむしろ静菌(細菌の増殖阻止)である。抗生物質効果を達成するために一般的に使用されるドキシサイクリンの用量は、100mg及び50mgである。
本発明は、その最も広い意味において、定常状態で、疾患または状態の処置において有益な効果を有することには十分有効であるが、抗菌効果を発揮するほど高くない有効成分のin vivoレベルの徐放性プロフィールを提供するために設計されたテトラサイクリンの薬学的組成物に向けられている。このような薬学的組成物は、1日1回摂取され得る剤形で処方される。
次の記載は主としてドキシサイクリンに向けられるが、本発明は他のテトラサイクリン類、特にドキシサイクリンと類似のin vivo吸収プロフィールを有する他のテトラサイクリン類、より具体的にはドキシサイクリンと同様の消化管内での吸収域を有するテトラサイクリン類に適用できるということが予想される。様々な種類のテトラサイクリン類及び様々な疾患状態に対する有益な効果は、例えばWO02/083106及び米国特許第6,638,922号に開示され、これらのそれぞれは、これら全体を本明細書において参考として援用する。
ドキシサイクリンのこのような組成物は、液状懸濁液または溶液の形態で、あるいは、錠剤、ペレット(本明細書ではビード(bead)とビードレット(beadlet)を区別なく使用する)、粒子(particle)、カプセルまたはゲルのような固形物の形態であり得る。本発明において好ましくは、錠剤またはカプセル中のビードレットである。
このような即効型剤形を処方するための当業者に公知の多くの方法がある。例えば、即効型錠剤は、ドキシサイクリンと、微結晶性セルロース、例えばAVICEL(登録商標)(FMC Corp.)またはEMCOCEL(登録商標)(Mendell Inc.);リン酸ジカルシウム、例えばEMCOMPRESS(登録商標)(Mendell Inc.);硫酸カルシウム、例えばCOMPACTROL(登録商標)(Mendell Inc.);及びスターチ、例えばSTARCH 1500のようなバルキング剤(bulking agent)を混合することにより調製され得る。さらに、微結晶性セルロース、スターチ、クロスポビドン、例えばPOLYPLASDONE XL(登録商標)(International Specialty Products);ソディウムスターチグリコレート、例えばEXPLOTAB(登録商標)(Mendell Inc.);及びクロスカルメロースナトリウム(croscarmellose sodium)、例えばAC−DI−SOL(登録商標)(FMC Corp.)のような崩壊剤を添加し得る。本明細書で使用する抗粘着剤(Antiadherant)及びグリダント(glidant)はタルク、コーンスターチ、二酸化珪素、ラウリル硫酸ナトリウム、コロイド状二酸化珪素(silica dioxide)及びメタリックステアラート(metallic stearate)を挙げることができる。
本発明の他の実施形態は、1単位用量において、ドキシサイクリンの実質的な即効投与を有する組成物に、あらかじめ決められた時間少なくとも一つのさらなる投与が続く。組成物の第1の即効型用量は散剤、顆粒剤、ビードレットまたは錠剤の形態であり得、第2の遅延放出部分は被覆された顆粒、被覆されたビードレット、被覆された錠剤、または被覆されていないマトリックス錠剤であり得る。即効部分またはコンポーネントと遅延放出部分またはコンポーネントの割合は、in vitroでの薬剤放出プロフィール及びin vivoでの血中濃度プロフィールを調整するために利用され得る。このような薬剤放出プロフィールを提供することにより、組成物はその日の2回目の投与の必要性を排除する。さらに、ドキシサイクリンの全投与量は、その抗生物質特性由来の望ましくない副作用を回避するために、50mg未満であるが、抗−コラゲナーゼ及び/または抗−炎症効果を達成するために25mgより多い。
好ましい実施形態として、ドキシサイクリンのIR/DR組成物は、ビードレットを含有するカプセルの形態である。現在、単一形態の複合単位剤形において、2つの異なるタイプの単位を有することが好ましい。第1ユニットは即効剤形であり、好ましくはペレット形態にある。このコンポーネントはまた、望ましいまたは必要ならば、粉末であり得る。いずれの場合でも、剤形はラウリル硫酸ナトリウム、ソディウムモノグリセラート、ソルビタンモノオレエート、ポリオキシエチレンソルビタンモノオレエート、グリセリルモノステアレート、グリセリルモノオレエート、グリセリルモノブチレート、界面活性ポリマーのプルロニック(Pluronic)系列のいずれか一つ、あるいは、界面活性特性を有する任意の他の適した物質または上記の任意の組み合わせのような界面活性剤を有し得る。好ましくは、界面活性剤はソディウムモノグリセラートとラウリル硫酸ナトリウムの組み合わせである。このコンポーネントのこれらの物質の濃度は約0.05〜約10.0%(W/W)の範囲であり得る。
実施例1:ドキシサイクリンモノハイドレートを含有する層状IRペレットの調製
ドキシサイクリンモノハイドレートのディスパージョンは次のように調製した:5.725キログラムの脱イオン水を0.113キログラムのヒドロキシプロピルメチルセルロース及び1.5キログラムのドキシサイクリンモノハイドレートに添加し、続いて撹拌パドルを使用して30分間ゆっくり混合した。薬物ディスパージョンはGPCG−15流動床プロセッサーの9”Wurster Columnにおいてシュガーシード(sugar seeds)(30/35メッシュ)上にスプレーした。全ディスパージョンが適用されるまで、ペレットはカラムにおいて5分間乾燥させた。薬剤を詰めたペレットは、Wurster Columnから出し、そして、20メッシュのふるいを通過させた。保護コート(例えば、OPADRY(登録商標)ベージュ)もまた、色彩及び物理的な保護を提供するためにIRビーズ上に適用し得る。図1は、ドキシサイクリンモノハイドレート即効型ビーズに関する典型的な溶解プロフィールを示す。
0.127キログラムのクエン酸トリエチルを3.538キログラムのEUDRAGIT(登録商標)L30D55(固形含有量:1.061キログラム)に添加し、そして少なくとも30分間撹拌することにより、EUDRAGIT(登録商標)L30D55コーティングディスパージョンを調製した。タルク0.315キログラムを2.939キログラムの脱イオン水に分散させた。可塑化EUDRAGIT(登録商標)L30D55をタルクディスパージョンと合わせ、60メッシュのふるいを通してふるいにかけた。生じた混合ディスパージョンを、GPCG−15流動床プロセッサーの9”Wurster Columnにおいて実施例1に従い調製した薬剤を詰めたペレット(3.5キログラム)にスプレーした。保護コート(例えば、OPADRY(登録商標)ベージュ)を、色彩及び物理的な保護を提供するためにDRビーズ上に適用し得る。図2はドキシサイクリンモノハイドレートの遅延放出ビーズに関する典型的な溶解プロフィールを示す。
薬剤を詰めたペレット及び腸溶性被覆ペレットのそれぞれを適当なサイズのカプセルシェルに充填することにより、カプセルを調製し得る。薬剤を詰めたペレットと腸溶性被覆ペレットの割合は、100:0〜70:30であり得る。例えば、75:25の割合において、薬剤を詰めたペレットの充填重量は、薬剤を詰めたペレットの実際の有効性に基づいて、30mgのドキシサイクリンを送達するように算出し得;腸溶性被覆ペレットの充填重量は、腸溶性被覆ペレットの実際の有効性に基づいて、10mgのドキシサイクリンを送達するように算出し得る。Romoco CD5またはMG−2ペレット充填機は、ペレットを望ましいカプセルシェルに正確に充填するために使用し得る。図3は、即効ビーズ75%及び遅延放出ビーズ25%の複合カプセルに関する典型的な溶解プロフィールを示す。
ドキシサイクリンモノハイドレート0.5625キログラムを、V型ブレンダー中で15分間、3.15キログラムの微結晶セルロースと混合し、粉末ブレンドをステアリン酸マグネシウム(0.0375キログラム)で、さらに5分間、滑らかにした。造粒流体としてイソプロピルアルコールを使用して、ドキシサイクリンモノハイドレート(0.2キログラム)をEUDRAGIT(登録商標)L100粉末(1.280キログラム)及び微結晶セルロース粉末(0.5キログラム)と共に粒状にした。湿った粒を流動床ドライヤー内で乾燥させ、そして、乾燥した粒を、V型ブレンダー中で5分間、ステアリン酸マグネシウム(0.020キログラム)とブレンドした。ドキシサイクリン粉末ブレンド及び粒を遅延錠剤プレス(belayed tablet press)に置き、粉末ブレンド及び粒状層のそれぞれが200mg及び100mgである目的の重量を備えた遅延錠剤(belayed tablet)に圧縮した。
ドキシサイクリンモノハイドレート1.0キログラムを、V型ブレンダー中で5分間、2.225キログラムの微結晶セルロース(AVICEL(登録商標)PH102)と混合した。そして、残りの微結晶セルロース(1.75キログラムのAVICEL(登録商標)PH202)を、V型ブレンダー中の粉末ブレンドに添加し、さらに30分間混合した。そして、該粉末ブレンドをステアリン酸マグネシウム(0.025キログラム)で、5分間、滑らかにした。滑らかになった粉末混合物は200mgの目的の重量を備えた錠剤に圧縮した。該錠剤はさらに重合保護層で被覆し得る。
様々な治療(例えば、40mgの1日1回のIR処方、70:30及び80:20の割合の40mgの1日1回のIR及びDR組み合わせ、及び、1日2回の20mgドキシサイクリン治療)に関する定常状態のシミュレートされた血中レベル−時間プロフィールをin silicoモデリングにより決定し、そして図4に示す。独特の投与量(すなわち、<50mg、好ましくは40mg)及び組成物(IRビーズまたはIR/DR組み合わせ)を使用すると、歯周病及び皮膚病のような状態を処置するために、最小約0.1μg/ml、好ましくは約0.3μg/ml及び最大約1.0μg/ml、さらに好ましくは約0.8μg/mlのドキシサイクリンの定常状態の血中レベルが達成され得る。
薬剤を詰めたIRペレット及び腸溶性被覆DRペレットを75:25の割合で含有するサイズ0カプセルは、次のように調製する。IR及びDRペレットは、実施例1及び2に記載するように調製した。ペレットを製造するために使用されるドキシサイクリンのアッセイ値から、41.26mgのカプセルの有効性は40mgのドキシサイクリンの実際の濃度と一致しているということを決定した。IRペレットの有効性は、ペレットのグラムあたり194mgドキシサイクリンであり(mg/g)、DRペレットに関しては133mg/gであった。従って、各カプセルにおいて、IRビーズの充填質量は159.5mgであり、そしてDRビーズは77.6mgである(40mgカプセルのIR:DRで75:25に一致している)ことを算出した。
薬物動力学的な(PK)研究を、1日1回経口投与される徐放性ドキシサイクリンカプセルを摂取する第1群(実施例7を参照)(75/25 IR/DR 40mg)と1日2回、12時間間隔で、経口投与されるPeriostat(登録商標)錠剤(20mg)を摂取する第2群を比較するために、ヒト被験者で、実施した。
それぞれの投薬終了時に、高ピークの血漿濃度(>1000ng/ml)と低血漿濃度(<100ng/ml)の頻度がより少ない点で、より一貫したin vivo性能を提供することが分かる。
Claims (5)
- 層状ペレットの形態で即効型コンポーネント及び遅延放出型コンポーネントを含むドキシサイクリンの経口薬学的組成物であって、前記組成物は50mgと25mgの間のドキシサイクリンを含み;前記即効型コンポーネント中のドキシサイクリンの量と前記遅延放出型コンポーネント中のドキシサイクリンの量の割合が80:20〜70:30であり、及び1日1回の投与で、最小0.1μg/ml及び最大1.0μg/mlのドキシサイクリンの定常状態の血中レベルを与える組成物。
- 1日1回の用量が、0.3μg/ml〜0.8μg/mlの間のドキシサイクリンの定常状態の血中レベルを与える、請求項1の組成物。
- 40mgのドキシサイクリンが存在する請求項1の組成物。
- 即効型コンポーネント中のドキシサイクリンの量と遅延放出型コンポーネント中のドキシサイクリンの量の割合が75:25である請求項1の組成物。
- 遅延放出型コンポーネント(DR)部分がペレットのコアを構成し、そして、即効型コンポーネント(IR)部分がコアを取り囲む請求項1の組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2803922C (en) | 2003-04-07 | 2015-09-15 | Supernus Pharmaceuticals, Inc. | Once daily formulations of tetracyclines |
AU2004261143B2 (en) * | 2003-07-25 | 2009-11-05 | Allergan Pharmaceuticals International Limited | A doxycycline metal complex in a solid dosage form |
KR20060126555A (ko) * | 2004-01-20 | 2006-12-07 | 스티펠 래버러토리즈, 인코포레이티드 | 피부학적 연질 겔 조성물 |
AU2006206359B2 (en) * | 2005-01-21 | 2011-03-31 | Allergan Pharmaceuticals International Limited | A tetracycline metal complex in a solid dosage form |
US20080241235A1 (en) * | 2007-04-02 | 2008-10-02 | Medicis Pharmaceutical Corporation | Minocycline oral dosage forms for the treatment of acne |
US20080242642A1 (en) | 2007-04-02 | 2008-10-02 | Medicis Pharmaceutical Corporation | Minocycline oral dosage forms for the treatment of acne |
US7541347B2 (en) * | 2007-04-02 | 2009-06-02 | Medicis Pharmaceutical Coropration | Minocycline oral dosage forms for the treatment of acne |
US8252776B2 (en) * | 2007-04-02 | 2012-08-28 | Medicis Pharmaceutical Corporation | Minocycline oral dosage forms for the treatment of acne |
US7919483B2 (en) * | 2005-06-24 | 2011-04-05 | Medicis Pharmaceutical Corporation | Method for the treatment of acne |
US8722650B1 (en) | 2005-06-24 | 2014-05-13 | Medicis Pharmaceutical Corporation | Extended-release minocycline dosage forms |
WO2008061226A2 (en) | 2006-11-17 | 2008-05-22 | Supernus Pharmaceuticals Inc. | Sustained-release formulations of topiramate |
CN101668511A (zh) * | 2007-02-28 | 2010-03-10 | 阿西克斯医疗公司 | 正常化睑板腺分泌的方法和化合物 |
GB2463181B (en) | 2007-05-14 | 2013-03-27 | Univ New York State Res Found | Induction of a physiological dispersion response in bacterial cells in a biofilm |
WO2010017310A1 (en) | 2008-08-06 | 2010-02-11 | Medicis Pharmaceutical Corporation | Method for the treatment of acne and certain dosage forms thereof |
KR20140011302A (ko) * | 2010-10-21 | 2014-01-28 | 갈데르마 소시에떼아노님 | 지속-방출 정제 및 그의 제조 방법 |
US9119793B1 (en) | 2011-06-28 | 2015-09-01 | Medicis Pharmaceutical Corporation | Gastroretentive dosage forms for doxycycline |
US9561241B1 (en) | 2011-06-28 | 2017-02-07 | Medicis Pharmaceutical Corporation | Gastroretentive dosage forms for minocycline |
CN104271121A (zh) * | 2012-04-19 | 2015-01-07 | 高德美国际公司 | 治疗痤疮的方法 |
US8652516B1 (en) * | 2013-03-15 | 2014-02-18 | Cerovene, Inc. | Doxycycline formulations, and methods of treating rosacea |
US10842802B2 (en) * | 2013-03-15 | 2020-11-24 | Medicis Pharmaceutical Corporation | Controlled release pharmaceutical dosage forms |
US9561242B2 (en) | 2014-07-09 | 2017-02-07 | Sun Pharmaceutical Industries Limited | Doxycycline composition |
US9566287B2 (en) | 2014-07-09 | 2017-02-14 | Sun Pharmaceutical Industries Limited | Pharmaceutical composition of doxycycline with reduced food effect |
US9463196B2 (en) | 2014-07-09 | 2016-10-11 | Sun Pharmaceutical Industries Limited | Pharmaceutical composition of doxycycline with reduced food effect |
US9132092B1 (en) | 2014-07-09 | 2015-09-15 | Ranbaxy Laboratories Limited | Pharmaceutical composition of doxycycline |
US20160143924A1 (en) * | 2014-11-20 | 2016-05-26 | Sun Pharmaceutical Industries Limited | Low dose pharmaceutical composition of doxycycline |
US9511031B2 (en) * | 2014-10-08 | 2016-12-06 | Mayne Pharma International Pty. Ltd. | Controlled release doxycycline |
US20170182070A1 (en) * | 2014-10-08 | 2017-06-29 | Mayne Pharma International Pty Ltd. | Controlled Release Doxycycline |
US9295652B1 (en) * | 2014-10-08 | 2016-03-29 | Mayne Pharma International Pty. Ltd. | Controlled release doxycycline |
CA2968316A1 (en) | 2014-11-19 | 2016-05-26 | Nestle Skin Health Sa | Modified release doxycycline composition |
PL3873432T3 (pl) * | 2018-10-29 | 2023-02-27 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Kompleksy tetracyklinowe o przedłużonym działaniu |
WO2022269475A1 (en) * | 2021-06-21 | 2022-12-29 | Nicoventures Trading Limited | Oral product tablet and method of manufacture |
Family Cites Families (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4293539A (en) * | 1979-09-12 | 1981-10-06 | Eli Lilly And Company | Controlled release formulations and method of treatment |
WO1983000628A1 (en) | 1981-08-27 | 1983-03-03 | Bernstein, Joel, E. | A method of treating acne vulgaris and composition containing carbamide peroxide |
US4935412A (en) * | 1983-12-29 | 1990-06-19 | The Research Foundation Of State University Of New York | Non-antibacterial tetracycline compositions possessing anti-collagenolytic properties and methods of preparing and using same |
US4925833A (en) * | 1983-12-29 | 1990-05-15 | The Research Foundation Of State University Of New York | Use of tetracycline to enhance bone protein synthesis and/or treatment of osteoporosis |
US4666897A (en) | 1983-12-29 | 1987-05-19 | Research Foundation Of State University | Inhibition of mammalian collagenolytic enzymes by tetracyclines |
US4704383A (en) * | 1983-12-29 | 1987-11-03 | The Research Foundation Of State University Of New York | Non-antibacterial tetracycline compositions possessing anti-collagenolytic properties and methods of preparing and using same |
USRE34656E (en) * | 1983-12-29 | 1994-07-05 | The Research Foundation Of State University Of New York | Use of tetracycline to enhance bone protein synthesis and/or treatment of bone deficiency |
US5238686A (en) * | 1986-03-27 | 1993-08-24 | Kinaform Technology, Inc. | Sustained-release pharmaceutical preparation |
US4837030A (en) * | 1987-10-06 | 1989-06-06 | American Cyanamid Company | Novel controlled release formulations of tetracycline compounds |
US5277916A (en) * | 1988-02-01 | 1994-01-11 | F. H. Faulding & Co., Ltd. | Tetracycline dosage form |
AU618590B2 (en) | 1988-04-11 | 1992-01-02 | Allergan, Inc. | Tetralin esters of phenols or benzoic acids having retinoid like activity |
US5122519A (en) | 1989-06-27 | 1992-06-16 | American Cyanamid Company | Stable, cosmetically acceptable topical gel formulation and method of treatment for acne |
EP0418596A3 (en) * | 1989-09-21 | 1991-10-23 | American Cyanamid Company | Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form |
IL95423A (en) * | 1989-09-21 | 1994-11-11 | American Cyanamid Co | Pulse system for delivery of minocycline once daily |
US5308839A (en) * | 1989-12-04 | 1994-05-03 | The Research Foundation Of State University Of New York | Composition comprising non-steroidal anti-inflammatory agent tenidap and effectively non-antibacterial tetracycline |
JP3016587B2 (ja) * | 1989-12-04 | 2000-03-06 | ザ・リサーチ・ファンデーション・オブ・ステート・ユニバーシティ・オブ・ニューヨーク | 非ステロイド抗炎症剤及びテトラサイクリンの配合 |
US5045538A (en) | 1990-06-28 | 1991-09-03 | The Research Foundation Of State University Of New York | Inhibition of wasting and protein degradation of mammalian muscle by tetracyclines |
US5188836A (en) * | 1990-07-27 | 1993-02-23 | Warner-Lambert Company | Sustained release formulations |
US5223248A (en) * | 1991-02-11 | 1993-06-29 | The Research Foundation Of State University Of New York | Non-antibacterial tetracycline compositions possessing antiplaque properties |
US5770588A (en) * | 1991-02-11 | 1998-06-23 | The Research Foundation Of State University Of New York | Non-antibacterial tetracycline compositions of the prevention and treatment of root caries |
US5260292A (en) * | 1991-03-05 | 1993-11-09 | Marvin S. Towsend | Topical treatment of acne with aminopenicillins |
US5286497A (en) * | 1991-05-20 | 1994-02-15 | Carderm Capital L.P. | Diltiazem formulation |
US5167964A (en) * | 1992-02-14 | 1992-12-01 | Warner-Lambert Company | Semi-enteric drug delivery systems and methods for preparing same |
US5262173A (en) * | 1992-03-02 | 1993-11-16 | American Cyanamid Company | Pulsatile once-a-day delivery systems for minocycline |
US5258371A (en) * | 1992-05-29 | 1993-11-02 | Kuraray Co., Ltd. | Method to reduce connective tissue destruction |
EP0653935B1 (en) * | 1992-08-05 | 2002-05-08 | F.H. FAULDING & CO. LIMITED | Pelletised pharmaceutical composition |
DK0599397T3 (da) * | 1992-11-17 | 1996-09-16 | Univ New York State Res Found | Tetracycliner, herunder non-mikrobielle, kemisk-modificerede tetracycliner, inhiberer overdreven collagentværbinding ved diabetes |
US5523297A (en) * | 1993-03-02 | 1996-06-04 | The Research Foundation Of State University Of New York | Inhibition of excessive phospholipase A2 activity and/or production by non-antimicrobial tetracyclines |
US6043231A (en) * | 1993-03-02 | 2000-03-28 | The Research Foundation Of State Univ. Of New York | Inhibition of excessive phospholipase A2 activity and/or production by non-antimicrobial tetracyclines |
US5449688A (en) * | 1993-03-30 | 1995-09-12 | The United States Of America As Represented By The Department Of Health And Human Services | Method of treating chronic inflammatory diseases |
US5517049A (en) * | 1994-09-30 | 1996-05-14 | Vlsi Technology, Inc. | CMOS output buffer with enhanced ESD resistance |
US5505949A (en) * | 1994-10-13 | 1996-04-09 | Benitez; Juan E. | Topical treatment for acne |
WO1996016648A1 (en) | 1994-11-29 | 1996-06-06 | New York Society For The Ruptured And Crippled Maintaining The Hospital For Special Surgery | Method for regulating metalloproteinase activity |
US5674539A (en) * | 1994-12-09 | 1997-10-07 | Tomas; Robert E. | Method of treating skin and composition |
US5834449A (en) * | 1996-06-13 | 1998-11-10 | The Research Foundation Of State University Of New York | Treatment of aortic and vascular aneurysms with tetracycline compounds |
US5827840A (en) * | 1996-08-01 | 1998-10-27 | The Research Foundation Of State University Of New York | Promotion of wound healing by chemically-modified tetracyclines |
US5827503A (en) * | 1996-08-08 | 1998-10-27 | Collagenex Pharmaceuticals, Inc. | Method and composition for treating periodontitis |
US5789395A (en) * | 1996-08-30 | 1998-08-04 | The Research Foundation Of State University Of New York | Method of using tetracycline compounds for inhibition of endogenous nitric oxide production |
US5837696A (en) * | 1997-01-15 | 1998-11-17 | The Research Foundation Of State University Of New York | Method of inhibiting cancer growth |
US5792446A (en) * | 1997-02-18 | 1998-08-11 | Collagenex Pharmaceuticals, Inc. | Delivery system for administering dentin-hypersensitivity-ameliorating compositions |
US5773430A (en) * | 1997-03-13 | 1998-06-30 | Research Foundation Of State University Of New York | Serine proteinase inhibitory activity by hydrophobic tetracycline |
US5753711A (en) * | 1997-03-18 | 1998-05-19 | Collagenex Pharmaceuticals, Inc. | Method for treatment of H. pylori |
US5929055A (en) * | 1997-06-23 | 1999-07-27 | The Research Foundation Of State University Of New York | Therapeutic method for management of diabetes mellitus |
CA2212196A1 (en) * | 1997-08-01 | 1999-02-01 | Is2 Research Inc. | Medical diagnostic apparatus and method |
FR2772615B1 (fr) * | 1997-12-23 | 2002-06-14 | Lipha | Comprime multicouche pour la liberation instantanee puis prolongee de substances actives |
US5908838A (en) * | 1998-02-19 | 1999-06-01 | Medics Pharmaceutical Corporation | Method for the treatment of acne |
US6015803A (en) * | 1998-05-04 | 2000-01-18 | Wirostko; Emil | Antibiotic treatment of age-related macular degeneration |
WO1999058131A1 (en) * | 1998-05-08 | 1999-11-18 | University Of Miami | Use of tetracyclines for treating meibomian gland disease |
US6143506A (en) * | 1998-08-13 | 2000-11-07 | The Research Foundation Of State Of Ny | Diagnostic method for detection of periodontitis or peri-implantitis |
US6015804A (en) * | 1998-09-11 | 2000-01-18 | The Research Foundation Of State University Of New York | Method of using tetracycline compounds to enhance interleukin-10 production |
US5977091A (en) * | 1998-09-21 | 1999-11-02 | The Research Foundation Of State University Of New York | Method of preventing acute lung injury |
KR20010073190A (ko) | 1998-09-28 | 2001-07-31 | 제임스 알. 데니히 | 백내장 형성 억제제 |
US5998390A (en) * | 1998-09-28 | 1999-12-07 | The Research Foundation Of State University Of New York | Combination of bisphosphonate and tetracycline |
US20010055613A1 (en) | 1998-10-21 | 2001-12-27 | Beth A. Burnside | Oral pulsed dose drug delivery system |
WO2000025752A1 (en) | 1998-11-02 | 2000-05-11 | Church, Marla, J. | Multiparticulate modified release composition |
US6506740B1 (en) * | 1998-11-18 | 2003-01-14 | Robert A. Ashley | 4-dedimethylaminotetracycline derivatives |
US6217904B1 (en) * | 1999-04-06 | 2001-04-17 | Pharmaquest Ltd. | Pharmaceutical dosage form for pulsatile delivery of d-threo-methylphenidate and a second CNS stimulant |
US6179849B1 (en) * | 1999-06-10 | 2001-01-30 | Vascular Innovations, Inc. | Sutureless closure for connecting a bypass graft to a target vessel |
US6673843B2 (en) * | 1999-06-30 | 2004-01-06 | Emory University | Curcumin and curcuminoid inhibition of angiogenesis |
US6133310A (en) * | 1999-08-26 | 2000-10-17 | Parks; L. Dean | Method of treatment of rosacea |
US6485746B1 (en) * | 2000-08-25 | 2002-11-26 | Neurocrine Biosciences, Inc. | Controlled-release sedative-hypnotic compositions and methods related thereto |
US6953593B2 (en) * | 2000-02-01 | 2005-10-11 | Lipoprotein Technologies, Inc. | Sustained-release microencapsulated delivery system |
US6638532B2 (en) * | 2000-02-24 | 2003-10-28 | Advancis Pharmaceutical Corp. | Tetracycline—doxycycline antibiotic composition |
US6730320B2 (en) * | 2000-02-24 | 2004-05-04 | Advancis Pharmaceutical Corp. | Tetracycline antibiotic product, use and formulation thereof |
JP2003523372A (ja) * | 2000-02-24 | 2003-08-05 | アドバンシス ファーマシューティカル コーポレイション | 抗生物質及び抗真菌剤組成物 |
US6664287B2 (en) * | 2000-03-15 | 2003-12-16 | Bethesda Pharmaceuticals, Inc. | Antioxidants |
US6500457B1 (en) * | 2000-08-14 | 2002-12-31 | Peirce Management, Llc | Oral pharmaceutical dosage forms for pulsatile delivery of an antiarrhythmic agent |
US6344215B1 (en) * | 2000-10-27 | 2002-02-05 | Eurand America, Inc. | Methylphenidate modified release formulations |
US6610274B1 (en) * | 2000-12-22 | 2003-08-26 | Wallace J. Gardner | Anti-inflammatory composition comprising tetracycline |
EP1383483A4 (en) * | 2001-04-05 | 2006-08-09 | Collagenex Pharm Inc | CONTROLLED RELEASE OF TETRACYCLIN COMPOUNDS AND TETRACYCLINE DERIVATIVES |
ATE330615T1 (de) | 2001-04-05 | 2006-07-15 | Collagenex Pharm Inc | Doxycyclin zur behandlung von akne |
US7211267B2 (en) | 2001-04-05 | 2007-05-01 | Collagenex Pharmaceuticals, Inc. | Methods of treating acne |
EP2332548A1 (en) * | 2001-07-13 | 2011-06-15 | Paratek Pharmaceuticals, Inc. | Tetracyclines for the treatment of stroke |
US20030082120A1 (en) * | 2001-10-26 | 2003-05-01 | Milstein Harold J. | Method for reducing systemic effects of aging, effects of aging on the skin, and incidence of skin damage from sun exposure using antibiotics of the tetracycline family |
US6663888B2 (en) * | 2001-12-14 | 2003-12-16 | Eurand Pharmaceuticals Ltd. | Pulsatile release histamine H2 antagonist dosage form |
US20040014731A1 (en) * | 2002-03-29 | 2004-01-22 | Golub Lorne M. | Use of non-antibacterial tetracycline analogs and formulations thereof for the treatment of bacterial exotoxins |
KR20050005444A (ko) * | 2002-04-16 | 2005-01-13 | 콜라제넥스 파마슈티칼스, 인크 | 안구 주사 및 적창의 동시 치료 방법 |
US8192749B2 (en) * | 2003-04-16 | 2012-06-05 | Galderma Laboratories Inc. | Methods of simultaneously treating ocular rosacea and acne rosacea |
AU2003256496A1 (en) * | 2002-07-12 | 2004-02-02 | The Research Foundation Of State University Of New York | Method for reducing c-rective protein levels with non-antibacterial tetracycline formulations |
US6913768B2 (en) * | 2002-09-24 | 2005-07-05 | Shire Laboratories, Inc. | Sustained release delivery of amphetamine salts |
ES2645930T3 (es) * | 2003-01-03 | 2017-12-11 | Supernus Pharmaceuticals, Inc. | Utilización de una mezcla de dos o más materiales entéricos para regular la liberación de fármacos a través de una membrana o matriz para terapias sistémicas |
CA2803922C (en) | 2003-04-07 | 2015-09-15 | Supernus Pharmaceuticals, Inc. | Once daily formulations of tetracyclines |
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