JP2004518734A - A new formulation of carvedilol - Google Patents

A new formulation of carvedilol Download PDF

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JP2004518734A
JP2004518734A JP2002565411A JP2002565411A JP2004518734A JP 2004518734 A JP2004518734 A JP 2004518734A JP 2002565411 A JP2002565411 A JP 2002565411A JP 2002565411 A JP2002565411 A JP 2002565411A JP 2004518734 A JP2004518734 A JP 2004518734A
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carvedilol
acid
formulation
pharmaceutically acceptable
organic acid
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ブラシオス・アンドロニス
キンバリー・エイ・レイミー
チョン・ケイ・オー
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SmithKline Beecham Corp
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Abstract

本発明はカルベジロールを含む新規処方ならびに高血圧、鬱血性心不全および狭心症を治療するためのこれらの処方を用いる方法に関する。The present invention relates to novel formulations containing carvedilol and methods of using these formulations to treat hypertension, congestive heart failure and angina.

Description

【０００１】
（技術分野）
本発明は、カルベジロール（ｃａｒｖｅｄｉｌｏｌ）の新規処方、およびかかる処方の、高血圧、鬱血性心不全または狭心症の治療における使用に関する。
【０００２】
（技術分野）
１−（カルバゾール−４−イルオキシ−３−［［２−（ｏ−メトキシフェノキシ）エチル］アミノ］−２−プロパノールである化合物は「カルベジロール」の名称で知られており、１９８５年３月５日付け発行の米国特許第４５０３０６７号（０６７特許）の対象である。この化合物は以下：
【化１】

Figure 2004518734
の構造を有する。カルベジロールは高血圧、鬱血性心不全または狭心症の治療に有用である。
カルベジロールについて今市販されている処方は即時放出形態のものであり、一日に２回投与される。カルベジロールの即時放出性処方は、経口投与の後に迅速かつ広範囲に吸収され、その最終的な半減期は７−１０時間である。商業的にはカルベジロールの一日に一回投与される処方が望ましく、患者の投与計画を簡単にし、承諾の割合を改良することができる。
本発明によれば、カルベジロールを一日一回投与の新規な製剤に処方し得ることが見出された。
【０００３】
（発明の開示）
本発明はカルベジロールを含む処方における医薬上許容される有機酸の使用を提供する。
本発明はまた、かかる処方の、高血圧、鬱血性心不全および狭心症を治療するための使用を提供する。
【０００４】
（発明を実施するための形態）
本発明によれば、カルベジロールの組成物が噴霧乾燥した粉末形態にて、または標準的な薬材料形態にて提供される。噴霧乾燥した粉末組成物は、湿式粉砕を含む方法を用いて調製される。こうして調製された懸濁液は噴霧乾燥機を用いて噴霧乾燥されるかまたは流動床造粒機を用いて顆粒にされる。ついで、その組成物は、例えば、錠剤またはカプセルの形態に処方することができる。経口投与される処方が好ましい。
重要なことは、本発明がカルベジロールを含み、さらに医薬上許容される有機酸を含む、処方を提供することである。
【０００５】
本明細書中で用いる場合、「医薬上許容される有機酸」なる語は、それ自体が薬理学的作用を有さないものであって、許容される官能特性を有し、許容される密度を有し、極端なｐＨを有さず、好ましくは固体である、有機酸をいう。例えば、炭素数２ないし２５の、好ましくは２ないし１０のモノ一カルボン酸およびポリ−カルボン酸；単環式および多環式アリール酸、例えば、安息香酸；ならびに多価酸の一水素、二水素および金属塩が挙げられる。単一の医薬上許容される有機酸を用いてもよく、あるいは２またはそれ以上の医薬上許容される有機酸を組み合わせて用いてもよい。好ましくは、この有機酸は、１個、２個または３個のカルボキシル基を有し、所望により１またはそれ以上のヒドロキシ置換基を有していてもよく、あるいは付加的に炭素鎖にてＣＯ基を有する、Ｃ（２−１０）アルキル−またはアルケニル−カルボン酸、例えば、マロン酸、コハク酸、フマル酸、マレイン酸、アジピン酸、乳酸、レブリン酸、ソルビン酸、グルタミン酸、アスパラギン酸、オレイン酸、グルタル酸、グリセリン、アルギニンまたは果汁酸、例えば、酒石酸、リンゴ酸、アスコルビン酸またはクエン酸、最も好ましくはクエン酸である。
【０００６】
本発明の湿式粉砕方法は当業者にとって周知であり、次の文献に記載されている：
Ｊ．Ａ．ＨｅｒｂｓｔおよびＪ．Ｌ．Ｓｅｐｕｌｖｅｄａ ”Ｆｕｎｄａｍｅｎｔａｌｓ ｏｆ Ｆｉｎｅ ａｎｄ Ｕｌｔｒａｆｉｎｅ Ｇｒｉｎｄｉｎｇ ｉｎ ａ Ｓｔｉｒｒｅｄ Ｂａｌｌ Ｍｉｌｌ” Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｐｏｗｄｅｒ ａｎｄ Ｂｕｌｋ Ｓｏｌｉｄｓ Ｈａｎｄｌｉｎｇ ａｎｄ Ｐｒｏｃｅｓｓｉｎｇ， ４５２， Ｍａｙ １９７８ および
Ｌ．Ｙ．Ｓａｄｌｅｒ ＩＩＩ， Ｄ．Ａ．ＳｔａｌｅｙおよびＤ．Ｒ．Ｂｒｏｏｌｓ ”Ａｔｔｒｉｔｉｏｎ Ｍｉｌｌ Ｏｐｅｒａｔｉｏｎａｌ Ｃｈａｒａｃｔｅｒｉｓｔｉｃｓ” Ｐｏｗｄｅｒ Ｔｅｃｈｎｏｌｏｇｙ １２（１９７５）１９−２８。
【０００７】
粉砕組成物の噴霧乾燥はヤマトＧＡ−３２スプレードライヤー（Ｙａｍａｔｏ Ｓｃｉｅｎｔｉｆｉｃ Ａｍｅｒｉｃａ Ｉｎｃ．， Ｏｒａｎｇｅｂｕｒｇ， ＮＹ）などのスプレードライヤーを用いて行うのが最適である。また、粉砕組成物の顆粒化はグラット流動床造粒機などの流動床造粒機、または高剪断造粒機を用いて行うのが最適である。
ついで、こうして製造した噴霧乾燥粉末を単位用量にて経口投与に用いる。これらの経口用錠剤は、徐放性または腸溶性コーティングを有するか、さもなければ、例えば、ゲル形成ポリマーまたはマトリックス形成ワックスを配合することによるなどの、有効成分の放出を制御するように修飾した、錠剤などの一般的な放出制御処方を含む。
【０００８】
加えて、カルベジロール薬材料を有機酸と溶液または懸濁液のいずれかにて混合して薬物媒体を形成させ、その後でペレットまたは顆粒上に積層させる。ついで、薬物の積層したペレットまたは顆粒を、標準的なシールコート、腸溶性コートまたは胃液が通る徐放性コートからなるようにコーティングに付す。放出制御処方は、例えば、米国特許第４５２４０６０号（１９８５年６月１８日発行）および米国特許第４９８３４０１号（１９９１年１月８日発行）に記載されるように調製される。他の放出制御処方は第４８８０８３０号（１９８９年１１月１４日発行）および米国特許第５０６８１１２号（１９９１年１１月２６日発行）に記載されている。
カルベジロールおよび有機酸を含有する放出制御処方はまた、標準的なカプセルに圧縮されていない薬物積層のペレットを充填した形態であってもよい。ついで、このカプセルを放出を遅延させるために腸溶性コーティングに付し、その後で、カルベジロールの即時放出成分でコーティングし、２段階バーストシステムに付す。
【０００９】
経口投与用の錠剤またはカプセルは、通常、単位用量にて提供され、結合剤、充填剤および希釈剤（錠剤化または圧縮を目的とする）、滑沢剤、崩壊剤、着色剤、矯味矯臭剤および湿潤剤などの慣用的賦形剤を含有する。錠剤は当該分野にて周知の方法に従ってコーティングされる。
これらの経口的処方は、混合、充填、錠剤化などの慣用的方法により調製することができる。繰返し混合操作を用いて活性物質を多量の充填剤を利用する組成物全体に分配させることができる。かかる操作ももちろん当該分野にて周知である。
かくして、本発明はカルベジロールを含む処方における医薬上許容される有機酸の使用を提供する。該処方は経口投与に適する。該処方は単位用量にて投与される。かかる処方は一日に一回投与される。好ましい単位投与形態は２５ｍｇまたは５０ｍｇのカルベジロールを含む錠剤またはカプセルを包含する；しかし、本発明はまた６．２５ｍｇないし１００ｍｇの用量を包含する。
カルベジロールを本発明の指示に従って投与した場合、許容できない毒物学的作用は考えられない。
次に実施例を用いて本発明を説明する。これらの実施例は上記した本発明の範囲および特許請求の範囲を限定するものではない。
【００１０】
（実施例）
実施例１＆２−カルベジロール５０ｍｇの放出制御された水性フィルムコーティング錠
カルベジロール５０ｍｇの放出制御（ＣＲ）された水性フィルムコーティング（ＡＦＣ）錠剤を、カルベジロール噴霧乾燥粉末を外部賦形剤および滑沢剤と混合し、圧縮し、最後に透明な水性フィルムコーティング剤で、つづいてオイドラギット（登録商標）をベースとするコーティング剤でコーティングすることで調製した。ＣＥ錠製品はフマール酸を用いて製造し、ＣＦ錠製品はクエン酸を用いて製造する。
【００１１】
【表１】
Figure 2004518734
【００１２】
１：「カルベジロール噴霧乾燥粉末」の９６％ラベルクレイムを基礎とする。これらのレベルは噴霧乾燥工程の間に達成される％ラベルクレイムによって変化し、混合工程の間に調整される。
２：噴霧乾燥工程の間に除去される。
３：乾燥の間に除去される。
【００１３】
実施例３＆４−カルベジロール５０ｍｇの放出制御されたマトリックス錠
カルベジロールの放出制御（ＣＲ）マトリックス錠（ＣＧおよびＣＨ製品）を、各々、カルベジロール噴霧乾燥粉末またはカルベジロール薬標準材料のいずれかを含有するカルベジロール顆粒より調製する。クエン酸顆粒を別個に調製する。所望のカルベジロール顆粒およびクエン酸顆粒を外部賦形剤と、最後に滑沢剤と一緒に混合して混合物を製造し、ついでその混合物を打錠する。
【００１４】
【表２】
Figure 2004518734
【００１５】
４：「カルベジロール噴霧乾燥粉末」の９６％ラベルクレイムを基礎とする。これらのレベルは噴霧乾燥工程の間に達成される％ラベルクレイムによって変化し、混合工程の間に調整される。
５：乾燥の間に除去される。
【００１６】
実施例５−カルベジロール２５ｍｇ放出制御カプセル
カルベジロール放出制御（ＣＲ）カプセルを、カルベジロール薬標準材料、アスパラギン酸およびオパドライクリア（Ｏｐａｄｒｙ Ｃｌｅａｒ）を含有するカルベジロール薬積層ペレットから調製する。ついで、その薬積層ペレットを徐放性コーティング剤、アクアコート（Ａｑｕａｃｏａｔ）ＥＣＤ−３０でコーティングし、投与用の標準カプセル殻に充填する。
【００１７】
【表３】
Figure 2004518734
１：積層工程またはコーティング工程の間に除去される。
【００１８】
実施例６−カルベジロール２５ｍｇ放出制御カプセル
カルベジロール放出制御（ＣＲ）カプセルを、カルベジロール薬標準材料、アスパラギン酸およびオパドライクリアを含有するカルベジロール薬積層ペレットから調製する。２２．５ｍｇ重の薬積層ペレットを標準カプセル殻に充填する。そのカプセルを遅延放出部分について腸溶性コーティングに付し、ついで最初のバースト効果を得るために２．５ｍｇ重の即時放出性トップコーティングに付す。
【００１９】
【表４】
Figure 2004518734
１：薬積層工程またはコーティング工程の間に除去される。
【００２０】
処方のインビボ薬物動態学的評価
本発明の処方の生物学的利用能を健康なヒトボランティアで評価する。この実験は非盲検、単回投与、無作為化、４期間、不完全ブロック、交差実験である。被検体は、各々、無作為投与計画による４回の放出制御処方のうちの３回の単回経口用量に加えて、単回用量の即時放出処方を摂取する。この実験の投与計画を以下の表に示す：
【００２１】
【表５】
Figure 2004518734
【００２２】
血漿中カルベジロール濃度を測定するために薬物動態学的サンプリングを、各実験セッションにおける実験用薬物の投与の後の４８時間の期間にわたって行った。セッションにおける投与の間に少なくとも７日の洗浄期間を設ける。女性の被検体はフォローアップ妊娠試験での最後の実験セッションにおける投与から７−１０日で元に戻る。各被検体の関与の総合期間（スクリーニングから実験の終わりまで）は５ないし８週であろう。
主要評価項目はカルベジロールのＡＵＣである。副次的評価項目はデータパミットとしてのＣｍａｘ、ＴｍａｘおよびＴ１／２を包含する。
【００２３】
本発明は上記した具体例に限定されるものではなく、特許請求の範囲内にあるすべての修飾する権利も保存されていると解すべきである。本明細書にて引用されている種々の刊行物、特許および他の出版物は現状を構成し、仮に十分に開示されているとしても、出典を明示することにより本明細書の一部とされる。[0001]
(Technical field)
The present invention relates to novel formulations of carvedilol and the use of such formulations in the treatment of hypertension, congestive heart failure or angina.
[0002]
(Technical field)
The compound that is 1- (carbazol-4-yloxy-3-[[2- (o-methoxyphenoxy) ethyl] amino] -2-propanol is known by the name "carbedilol" and is dated March 5, 1985. It is the subject of U.S. Pat.
Embedded image
Figure 2004518734
It has the structure of Carvedilol is useful for treating hypertension, congestive heart failure or angina.
The currently marketed formulation for carvedilol is in immediate release form and is administered twice daily. The immediate release formulation of carvedilol is rapidly and widely absorbed after oral administration, with a final half-life of 7-10 hours. Commercially, a once-daily carvedilol prescription is desirable, which simplifies the dosing regimen for the patient and can improve the rate of compliance.
In accordance with the present invention, it has been found that carvedilol can be formulated into a new once-daily formulation.
[0003]
(Disclosure of the Invention)
The present invention provides for the use of a pharmaceutically acceptable organic acid in a formulation comprising carvedilol.
The present invention also provides the use of such a formulation for treating hypertension, congestive heart failure and angina.
[0004]
(Mode for Carrying Out the Invention)
According to the invention, the composition of carvedilol is provided in the form of a spray-dried powder or in the form of a standard drug substance. Spray-dried powder compositions are prepared using a method that includes wet milling. The suspension thus prepared is spray dried using a spray dryer or granulated using a fluid bed granulator. The composition can then be formulated, for example, in the form of tablets or capsules. Orally administered formulations are preferred.
Importantly, the present invention provides a formulation comprising carvedilol and further comprising a pharmaceutically acceptable organic acid.
[0005]
As used herein, the term "pharmaceutically acceptable organic acid" is one that has no pharmacological action per se, has acceptable organoleptic properties, and has an acceptable density. , An organic acid that does not have an extreme pH and is preferably solid. For example, mono- and poly-carboxylic acids having 2 to 25, preferably 2 to 10 carbon atoms; mono- and polycyclic aryl acids such as benzoic acid; And metal salts. A single pharmaceutically acceptable organic acid may be used, or two or more pharmaceutically acceptable organic acids may be used in combination. Preferably, the organic acid has one, two or three carboxyl groups and may optionally have one or more hydroxy substituents, or may additionally have CO 2 at the carbon chain. C 2-10 alkyl- or alkenyl-carboxylic acids having a group such as malonic acid, succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, glutamic acid, aspartic acid, oleic acid , Glutaric acid, glycerin, arginine or juice acids such as tartaric acid, malic acid, ascorbic acid or citric acid, most preferably citric acid.
[0006]
The wet grinding method of the present invention is well known to those skilled in the art and is described in the following documents:
J. A. Herbst and J.M. L. Sepulveda, "Fundamentals of Fine and Ultrafine Grinding in a Sirrred Ball Mill", International Powerer and Bulk Solids, and a proprietary approach to the UK. Y. Sadler III, D.S. A. Staley and D.M. R. Brooks "Attrition Mill Operational Characteristics" Powder Technology 12 (1975) 19-28.
[0007]
The spray drying of the pulverized composition is most preferably performed using a spray dryer such as a Yamato GA-32 spray dryer (Yamato Scientific America Inc., Orangeburg, NY). The granulation of the pulverized composition is optimally performed using a fluidized bed granulator such as a Glatt fluidized bed granulator or a high shear granulator.
The spray-dried powder thus produced is then used for oral administration in unit dose. These oral tablets have a sustained release or enteric coating, or are otherwise modified to control the release of the active ingredient, such as by incorporating a gel-forming polymer or matrix-forming wax. , Tablets and other common controlled release formulations.
[0008]
In addition, the carvedilol drug material is mixed with the organic acid, either in solution or suspension, to form a drug vehicle, which is then laminated onto pellets or granules. The layered pellets or granules of drug are then applied to the coating such that they consist of a standard seal coat, enteric coat or sustained release coat through which gastric fluid passes. Controlled release formulations are prepared, for example, as described in US Pat. No. 4,542,060 (issued June 18, 1985) and US Pat. No. 4,983,401 (issued January 8, 1991). Other controlled release formulations are described in US Pat. No. 4,880,830 (issued Nov. 14, 1989) and US Pat. No. 5,068,112 (issued Nov. 26, 1991).
Controlled release formulations containing carvedilol and an organic acid can also be in the form of standard capsules filled with uncompacted drug laminate pellets. The capsules are then coated with an enteric coating to delay release, followed by coating with the immediate release component of carvedilol and a two-stage burst system.
[0009]
Tablets or capsules for oral administration are usually provided in unit doses, binders, fillers and diluents (for tableting or compression), lubricants, disintegrants, coloring agents, flavoring agents And conventional excipients such as wetting agents. Tablets are coated according to methods well known in the art.
These oral formulations can be prepared by conventional methods such as mixing, filling, tableting and the like. The active substance can be distributed throughout the composition utilizing a high amount of filler using a repeated mixing operation. Such operations are, of course, well known in the art.
Thus, the present invention provides the use of a pharmaceutically acceptable organic acid in a formulation comprising carvedilol. The formulation is suitable for oral administration. The formulation is administered in a unit dose. Such a formulation is administered once a day. Preferred unit dosage forms include tablets or capsules containing 25 or 50 mg of carvedilol; however, the invention also encompasses doses of 6.25 mg to 100 mg.
No unacceptable toxicological effects are expected when carvedilol is administered according to the instructions of the present invention.
Next, the present invention will be described using examples. These examples do not limit the scope of the invention and the claims described above.
[0010]
(Example)
Example 1 & 2-Carvedilol 50 mg controlled release aqueous film coated tablet Carvedilol 50 mg controlled release (CR) aqueous film coated (AFC) tablet was prepared by mixing carvedilol spray-dried powder with external excipients and lubricant. , Compressed and finally coated with a clear aqueous film coating, followed by a coating based on Eudragit®. CE tablet products are manufactured using fumaric acid, and CF tablet products are manufactured using citric acid.
[0011]
[Table 1]
Figure 2004518734
[0012]
1: Based on 96% label claim of "Carvedilol spray dried powder". These levels will vary with the% label claim achieved during the spray drying process and will be adjusted during the mixing process.
2: Removed during the spray drying process.
3: Removed during drying.
[0013]
Examples 3 & 4-Carvedilol 50 mg Controlled Release Matrix Tablets Carvedilol Controlled Release (CR) matrix tablets (CG and CH products) were prepared from carvedilol granules containing either a carvedilol spray-dried powder or a carvedilol drug reference material, respectively. Prepare. Prepare the citric acid granules separately. The desired carvedilol granules and citric acid granules are mixed with external excipients and finally with a lubricant to produce a mixture, which is then compressed.
[0014]
[Table 2]
Figure 2004518734
[0015]
4: Based on 96% label claim of "Carvedilol spray dried powder". These levels will vary with the% label claim achieved during the spray drying process and will be adjusted during the mixing process.
5: Removed during drying.
[0016]
Example 5-Carvedilol 25 mg Controlled Release Capsules Carvedilol controlled release (CR) capsules are prepared from carvedilol drug laminated pellets containing carvedilol drug reference material, aspartic acid and Opadry Clear. The drug-laminated pellets are then coated with a sustained-release coating agent, Aquacoat ECD-30, and filled into standard capsule shells for administration.
[0017]
[Table 3]
Figure 2004518734
1: Removed during lamination or coating steps.
[0018]
Example 6-Carvedilol 25 mg Controlled Release Capsules Carvedilol controlled release (CR) capsules are prepared from carvedilol drug laminated pellets containing carvedilol drug reference material, aspartic acid and opadry clear. Fill 22.5 mg weight drug-laminated pellets into standard capsule shells. The capsules are applied with an enteric coating for the delayed release portion and then a 2.5 mg weight immediate release top coating to obtain an initial burst effect.
[0019]
[Table 4]
Figure 2004518734
1: Removed during the drug lamination or coating process.
[0020]
In Vivo Pharmacokinetic Evaluation of Formulations The bioavailability of the formulations of the invention is evaluated in healthy human volunteers. The experiment is an open label, single dose, randomized, 4 period, incomplete block, crossover experiment. Subjects each receive a single dose of the immediate release formulation in addition to three single oral doses of the four controlled release formulations according to the randomized dosing regimen. The regimen for this experiment is shown in the following table:
[0021]
[Table 5]
Figure 2004518734
[0022]
Pharmacokinetic sampling to determine plasma carvedilol concentrations was performed over a 48 hour period following administration of the experimental drug in each experimental session. There is a washout period of at least 7 days between doses in the session. Female subjects return 7-10 days after dosing in the last experimental session in the follow-up pregnancy test. The overall period of involvement (from screening to the end of the experiment) for each subject will be 5 to 8 weeks.
The primary endpoint is the AUC for carvedilol. Secondary evaluation items include Cmax, Tmax and T1 / 2 as data summits.
[0023]
It is to be understood that the invention is not limited to the embodiments described above, but that all rights of modification within the scope of the appended claims are preserved. The various publications, patents, and other publications cited herein are incorporated by reference and, if fully disclosed, are incorporated herein by reference. You.

Claims (7)

カルベジロールと、医薬上許容される有機酸とを含む、マトリックス処方。A matrix formulation comprising carvedilol and a pharmaceutically acceptable organic acid. 医薬上許容される有機酸がクエン酸であるところの、請求項１記載の処方。The formulation of claim 1, wherein the pharmaceutically acceptable organic acid is citric acid. カルベジロールと、医薬上許容される有機酸とを含む、腸溶性処方。An enteric formulation comprising carvedilol and a pharmaceutically acceptable organic acid. 医薬上許容される有機酸がクエン酸であるところの、請求項３記載の処方。4. The formulation of claim 3, wherein the pharmaceutically acceptable organic acid is citric acid. カルベジロールと、医薬上許容される有機酸とを含む、薬物積層処方。A drug layered formulation comprising carvedilol and a pharmaceutically acceptable organic acid. 医薬上許容される有機酸がアスパラギン酸であるところの、請求項５記載の処方。The formulation of claim 5, wherein the pharmaceutically acceptable organic acid is aspartic acid. 高血圧、鬱血性心不全または狭心症の治療方法であって、その治療を必要とする対象に、有効量の請求項１ないし６のいずれか１つに記載の処方を投与することを含む、方法。A method of treating hypertension, congestive heart failure or angina, comprising administering to a subject in need thereof an effective amount of a prescription according to any one of claims 1 to 6. .
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013505970A (en) * 2009-09-29 2013-02-21 ティーエスエイチ バイオファーム コーポレーション リミテッド Sustained release carvedilol formulation

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1067910B1 (en) 1998-04-03 2004-05-26 Egalet A/S Controlled release composition
IN191028B (en) * 2001-05-17 2003-09-13 Sun Pharmaceutical Ind Ltd
WO2003024429A1 (en) * 2001-09-21 2003-03-27 Egalet A/S Polymer release system
US20040253310A1 (en) 2001-09-21 2004-12-16 Gina Fischer Morphine polymer release system
US20050019399A1 (en) * 2001-09-21 2005-01-27 Gina Fischer Controlled release solid dispersions
AU2003275953A1 (en) 2002-11-08 2004-06-07 Egalet A/S Controlled release carvedilol compositions
EP1610767B1 (en) 2003-03-26 2011-01-19 Egalet A/S Morphine controlled release system
EP2186510B1 (en) 2003-03-26 2013-07-10 Egalet Ltd. Matrix compositions for controlled delivery of drug substances
ES2662903T3 (en) * 2003-11-25 2018-04-10 Smithkline Beecham (Cork) Limited Carvedilol-free base, salts, anhydrous or solvate forms thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or administration procedures
US20050169994A1 (en) * 2003-11-25 2005-08-04 Burke Matthew D. Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods
WO2006091941A2 (en) * 2005-02-25 2006-08-31 The Regents Of The University Of Michigan Compositions and methods for treating and preventing cardiomyopathy and heart disease
HU227490B1 (en) * 2005-08-26 2011-07-28 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Sustained release pharmaceutical preparation containing carvedilol
AU2007281531B2 (en) 2006-08-01 2013-07-04 Phrixus Pharmaceuticals, Incorporated Use of poloxamer for the prevention and/or treatment of heart failure
HU227881B1 (en) * 2007-02-23 2012-05-29 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Sustained release pharmaceutical preparation containing carvedilol
WO2008114276A1 (en) * 2007-03-16 2008-09-25 Lupin Limited Novel oral controlled release composition of carvedilol
EP2150260A2 (en) 2007-04-05 2010-02-10 Phrixus Pharmaceuticals, Inc. Compositions and methods for the treatment of heart failure
AU2008258596B2 (en) 2007-06-04 2013-02-14 Egalet Ltd Controlled release pharmaceutical compositions for prolonged effect
FR2936709B1 (en) * 2008-10-02 2012-05-11 Ethypharm Sa ALCOHOL-RESISTANT TABLETS.
EP2393484A1 (en) 2009-02-06 2011-12-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
CA2766179A1 (en) 2009-06-24 2010-12-29 Egalet Ltd. Controlled release formulations
EP2877161A1 (en) 2012-07-06 2015-06-03 Egalet Ltd. Abuse deterrent pharmaceutical compositions for controlled release

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19637082A1 (en) * 1996-09-12 1998-03-19 Boehringer Mannheim Gmbh Rapidly disintegrating pellets
US6056968A (en) * 1997-03-11 2000-05-02 Darwin Discovery Limited Pharmaceutical drug dosage forms providing different release rates
DE19816036A1 (en) * 1998-04-09 1999-10-14 Roche Diagnostics Gmbh Production of pharmaceutical preparations with high disintegration rate containing difficultly soluble active ingredient, e.g. carvedilol
KR100336090B1 (en) * 1998-06-27 2002-05-27 윤승원 Solid dispersed preparation of poorly water-soluble drug containing oil, fatty acid or mixture thereof
DE19833119A1 (en) * 1998-07-23 2000-01-27 Roche Diagnostics Gmbh Storage-stable injectable solution of vasodilator and beta blocker Carvedilol contains buffer, organic solvent, antioxidant and complexing agent
PE20001302A1 (en) * 1998-11-27 2000-11-30 Hoffmann La Roche PREPARATIONS OF A PHARMACEUTICAL COMBINATION CONTAINING CARVEDILOL AND HYDROCHLOROTHIAZIDE
AU1657001A (en) * 1999-11-15 2001-05-30 Smithkline Beecham Corporation Carvedilol methanesulfonate
CA2402336C (en) * 2000-04-03 2008-03-11 F. Hoffmann-La Roche Ag Concentrated solutions of carvedilol

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013505970A (en) * 2009-09-29 2013-02-21 ティーエスエイチ バイオファーム コーポレーション リミテッド Sustained release carvedilol formulation

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