JP6045347B2 - ラサギリンの持続放出性製剤およびその使用 - Google Patents
ラサギリンの持続放出性製剤およびその使用 Download PDFInfo
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- JP6045347B2 JP6045347B2 JP2012551732A JP2012551732A JP6045347B2 JP 6045347 B2 JP6045347 B2 JP 6045347B2 JP 2012551732 A JP2012551732 A JP 2012551732A JP 2012551732 A JP2012551732 A JP 2012551732A JP 6045347 B2 JP6045347 B2 JP 6045347B2
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- rasagiline
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- 230000008685 targeting Effects 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Description
(i)不活性なペレットコアと、
(ii)前記ペレットコアをコーティングしている薬物層であって、プロパルギルアミン部分、アミノインダン部分もしくはプロパルギルアミン部分とアミノインダン部分の両方を含む活性薬剤またはその薬学的に許容される塩を含み、任意に結合剤および/またはフィルム形成ポリマーと適切に混合され、かつ任意に滑剤とさらに混合されている薬物層と、
(iii)任意に、前記薬物層をコーティングしている隔離/保護サブコーティング層と、
(iv)もし存在すれば前記サブコーティング層を、または前記薬物層をコーティングしている持続放出性コーティング層と
を含む、持続放出性ペレットを提供する。
(i)前記活性薬剤を、任意に結合剤および/または滑剤と適切に混合し、適当な溶媒に溶解させて、均一な懸濁液を調製する段階と、
(ii)(i)で得られた懸濁液の被覆を不活性なノンパレルシードのような不活性なペレットに塗布する段階と、
(iii)任意に、(ii)で得られた活性薬剤を充填したペレットを、隔離/保護サブコーティング層でコーティングする段階と、
(iv)(ii)または(iii)で得られたペレットを前記活性薬剤の持続放出を可能にする持続放出性コーティング層でコーティングすることにより前記持続放出性製剤を得る段階と、
(v)任意に、(iv)で得られたコーティング済みのペレットを適当な添加剤と混合する段階と
を含む調製方法に関する。
さらなる特定の実施形態では、本発明の医薬組成物に含まれる活性薬剤は、セレギリン、デスメチルセレギリン、パルギリンまたはクロルギリンである。
(i)不活性なペレットコアと、
(ii)上記ペレットコアをコーティングしている薬物層であって、プロパルギルアミン部分、アミノインダン部分もしくはプロパルギルアミン部分とアミノインダン部分の両方を含み、任意に結合剤および/またはフィルム形成ポリマーと適切に混合され、さらに任意に滑剤と混合されている活性薬剤またはその薬学的に許容される塩を含む薬物層と、
(iii)任意に、前記薬物層をコーティングしている隔離/保護サブコーティング層と、
(iv)もし存在すれば前記サブコーティング層を、または前記薬物層をコーティングしている持続放出性コーティング層と
を含む、持続放出性(ER)ペレットを提供する。
本発明のERペレットは浸透圧/等張化剤のような不活性成分をさらに含み得る。このような薬剤は、パルス状の薬物送達が必要な場合に崩壊時間を制御するために一般的に使用される。ERペレットの調製で使用し得る適当な浸透圧/等張化添加剤の例としては、塩化ナトリウムおよびマンニトールが非限定的に挙げられる。浸透圧/等張化剤は、ERペレットに含まれる場合、ペレットの総重量の20%以下、好ましくは約0.5%〜約10%の量で存在していてよい。
(i)任意に結合剤および/または滑剤と適切に混合した前記活性薬剤を適切な溶媒系に溶解させて、均一な懸濁液に調製する段階と、
(ii)不活性ノンパレルシードのような不活性なペレットに、(i)で得られた懸濁液の被覆を塗布する段階と、
(iii)(ii)で得られた活性薬剤充填ペレットを、任意に隔離/保護サブコーティング層でコーティングする段階と、
(iv)(ii)または(iii)で得られたペレットを、持続放出性コーティング層、すなわち、前記活性薬剤の持続放出を可能にするポリマー層でコーティングして前記持続放出性製剤を得る段階と、
(v)(iv)で得られたコーティングペレットを、任意に適当な添加剤と混合する段階と
を含む方法に関する。
パーキンソン病モデル
パーキンソン病(PD)の実験モデルは、この疾患の考え得る病理学的機序に関する洞察を得るために必要であり、さらに、薬理学的またはその他の新たな治療戦略の開発および試験に不可欠である。
ヒト脳の剖検研究および動物モデルの生化学的データの重要な主要部は、ドーパミン作動性神経変性を惹起する可能性のある、黒質での進行中の酸化ストレスの過程を示している。酸化ストレスが一次事象であるか二次事象であるかは不明であるが、抗酸化神経保護薬を開発する目的で、神経毒MPTP(N−メチル−4−フェニル−1,2,3,6−テトラヒドロピリジン)により誘発される酸化ストレスを動物モデルに用いて、神経変性の過程が調べられてきた。
PDのモデル化は、カテコールアミン神経毒である6−ヒドロキシドーパミン(6−OHDA)により進歩した。この分子は、ドーパミン作動性およびノルアドレナリン作動性の両方のニューロンの細胞体および線維内に輸送されて、神経終末の変性を引き起こし、また特に細胞体領域に投与した場合、細胞体にも影響を及ぼし得る。6−OHDAの神経毒性は、ミトコンドリアの呼吸酵素(呼吸鎖複合体IおよびIV)に対するその強力な阻害作用に基づくものである。これらの酵素のブロックによる代謝欠陥により、ニューロンは正常な生理的機能を発揮することができなくなり、その結果死に至る。PDでは、変性の対象となるのは主としてドーパミン作動性黒質線条体経路であるため、黒質線条体束の主要な遠心性投射に毒素を片側注射により直接注射してドーパミン作動性系の6−OHDA損傷を生じさせた動物モデルが開発されてきた。
500μlのホモジナイゼーション緩衝液(0.1M過塩素酸、0.02%EDTAおよび1%ETOH)中の線条体組織試料を、OMNI International社製のOMNI Tipホモジナイジングキットを用いて(中速、5秒のインターバルで3×10秒)氷中でホモジナイズした。ホモジネートを5分間、超音波処理し、次いで4℃で15分間、15,000rpmで遠心分離した。上清を新たなチューブに移し、HPLCによりドーパミン含有量を解析した。
この実験にはそれぞれ約7〜9匹のマウスからなる10個の群が含まれ、それぞれ表1のように処置した。具体的には、マウスにMPTPを腹腔内(IP)投与してパーキンソン病(PD)モデルを誘発し、一定用量のプラミペキソール(初期段階のPDの治療に適応される非エルゴリン系ドーパミンアゴニスト)と種々の用量のラサギリンとを含有する配合剤で処置した。MPTPを最初の5日間(0〜4日目)、毎日注射し、配合剤を、IPまたは徐放を模擬するALZETポンプ(ALZET微小浸透圧ポンプ、1002モデル、速度0.25μl/時、DURECT社、Cupertino、USA)を用いて、0〜11日目に投与した。群5〜7には、最初の5日間(0〜4日目)は毎日、MPTP投与の30分前に配合剤を投与し、残りの日(5〜11日目)は、各投与日のほぼ同じ時間に薬物を投与した。ALZETポンプを最初のMPTP投与の15〜17時間前に腹腔内に埋め込んだ(群8〜10)。投与期間中にポンプにより投与した薬物の総量は、IP注射群に投与した総量と同じであった。対照は、生理食塩水を注射した未処置マウスおよび生理食塩水を注射したMPTP投与マウスであった。
すべての実験で体重20±1gのC57B1/6雄性マウスを使用した(1群当たり10匹のマウス)。MPTPを1日当たり40mg/kgの用量で5日間、IP注射により投与した。対照は、生理食塩水を注射した未処置マウスおよび生理食塩水を注射したMPTP投与マウスであった。アミノインダンを、毎日のIP注射により、または腹腔内に埋め込まれたALZETポンプを用いた徐放により12日間投与した。実験終了時にマウスから採取した左右の線条体中のドーパミンおよびその代謝産物(ジヒドロキシフェニル酢酸およびホモバニリン酸)を測定して処置効果を評価した。線条体組織試料を実験の章に記載されている通りにHPLC用に調製した。
6−OHDAによる内側前脳束(MFB)の片側損傷は、片側での黒質線条体経路のドーパミン作動性ニューロン破壊を生じ、ラットの非対称な運動行動を引き起こす。損傷を受けたラットにドーパミン系に作用する薬物を与えると、ラットは活発な回旋行動を示す。より具体的には、DA放出薬剤であるD−アンフェタミンの投与により、損傷を受けていない黒質線条体投射に好発するドーパミンの不均衡が生じ、これにより時計回りの回旋が生じる。処置効果により、より多くのDAが利用可能になり、時計回りの回旋が増えると予想される。薬物誘発性の回旋は、回旋ボウルとラットの胴体に取り付ける回り継手とからなる自動ロタメータを用いて測定される。
サブコーティングを有さない表2に示される組成のメシル酸ラサギリン持続放出(ER)ペレットを調製した。具体的には、薬物層の調製では、ポビドンUSP(PVP K29/32)を蒸留水と96%エタノールの混合物に溶解させ、次いで、形成された溶液にメシル酸ラサギリンを溶解させた。超微末タルクを分散させて形成された溶液に加え均一な懸濁液を形成し、次いで、流動床コーティング機を用いて600〜710μm(直径)の糖球状顆粒にコーティングした。アセトンと96%エタノールの混合物中にEthocel 45cps(エチルセルロース;放出制御ポリマー)を溶解させて機能性のコーティング懸濁液を調製し、次いでポリエチレングリコール(PEG)4000を蒸留水中に溶解させ、これを形成された溶液に加えた。得られた懸濁液を、流動床コーティング機を用いて薬物充填ペレットにコーティングした。
サブコーティングを有する表4に示される組成のメシル酸ラサギリンERペレットを調製した。具体的には、薬物層の調製では、ポビドン(PVP K25)を蒸留水と96%エタノールの混合物に溶解させ、次いで、形成された溶液にメシル酸ラサギリンを溶解させた。形成された溶液に超微末タルクを分散させて加え、均一な懸濁液を形成し、次いでこれを600〜710μmの糖球状顆粒に流動床コーティング機を用いてコーティングした。PVP K25を蒸留水と96%エタノールの混合物に溶解させてサブコーティング溶液を調製し、次いで、得られた溶液を薬物充填ペレットに流動床コーティング機を用いてコーティングした。アセトンと96%エタノールの混合物中にEthocel 45cpsを溶解させて機能性のコーティング懸濁液を調製し、次いでPEG3000を蒸留水中に溶解させ、これを形成された溶液に加えた。得られた懸濁液を、流動床コーティング機を用いて薬物充填ペレットにコーティングした。形成された溶液に超微末タルクを分散させて加え、均一な懸濁液を形成し、次いで、これをサブコーティングされたペレットに流動床コーティング機を用いてコーティングした。Tumbler Bin Blenderを用いて、ラサギリンERペレットとAerosil200の乾燥混合物を調製した。
サブコーティングを有する表6に示される組成物のメシル酸ラサギリンERペレットを、実施例7〜8に記載されている通りに調製した。ただし、乾燥混合物の調製には、Aerosil200の代わりにコロイド状二酸化ケイ素を使用した。調製したこれらのERコーティングペレットの溶出プロファイルを、実施例4〜8で用いた条件下で評価し、これを表7および図8に示す。
サブコーティングを有するまたは有さない、表8〜12に示される組成のさらなるメシル酸ラサギリンERペレットを、実施例4〜9に記載されている手順に従って調製することができる。本実施例に含まれる各表で言及されている脚注は、表16の下に記載されている。
2浸透圧剤の代わりに、またはそれに加えて追加のpH依存性ポリマーを含ませて、パルス状放出性製剤を作製し得る。
3別の結合剤としては、例えば、ヒドロキシプロピルメチルセルロース(HPMC)、ポビドン(PVP)、微結晶性セルロースおよび前記結合剤の組合せが挙げられる。
4別の滑剤としては、例えば、コロイド状二酸化ケイ素、モノステアリン酸グリセリル、ステアリン酸マグネシウムおよび前記滑剤の組合せが挙げられる。
5別のフィルム形成ポリマーとしては、例えば、HPMC、PVP、微結晶性セルロース、ポリエチレングリコール(PEG)および前記フィルム形成ポリマーの組合せが挙げられる。
6別のpH非依存性ポリマーとしては、例えば、Surelease(登録商標)、Eudragit(登録商標)RL、Eudragit(登録商標)RS、Eudragit(登録商標)NEおよび前記ポリマーの組合せが挙げられる。
7別の細孔形成剤としては、例えば、HPMC、PVP、PEGおよび前記細孔形成剤の組合せが挙げられる。
8別の可塑剤としては、例えば、セバシン酸ジブチル/フタル酸ジブチル、トリアセチン、クエン酸トリエチルおよび前記可塑剤の組合せが挙げられる。
9別のpH依存性腸溶性コーティングポリマーとしては、例えば、Eudragit(登録商標)S、Kollicoat(登録商標)、ヒドロキシプロピルメチルセルロースフタラート(HPMCP)および前記薬剤の組合せが挙げられる。
10別の錠剤賦形剤としては、例えば、ラクトース、マンニトール/Parteck(登録商標)、ソルビトール、デンプンおよび前記錠剤賦形剤の組合せが挙げられる。
11別の崩壊剤としては、例えば、ナトリウムCMC/カルシウムCMC、クロスポビドン、低置換度クロスカルメロースナトリウムヒドロキシプロピルセルロース、炭酸水素ナトリウム、デンプン、デンプングリコール酸ナトリウムおよび前記崩壊剤の組合せが挙げられる。
12別の滑沢剤としては、例えば、グリセリルベヘナート、ステアリン酸、タルク、ステアリン酸亜鉛、ステアリン酸カルシウムおよび前記滑沢剤の組合せが挙げられる。
薬物は胃腸管の各種部分から異なって吸収される。経口投与用の24時間型徐放性製剤を設計するためには、薬物が全時間にわたって、すなわち、胃腸管のすべての部分から吸収される必要である。薬物の大部分は十二指腸からよく吸収されるが、多くの薬物は結腸からはあまり吸収されないということが知られている。薬物は体内から排泄されるまでに、かなりの長時間にわたって結腸内に留まるため、放出プロファイルを効率的に設計するためには、結腸からの薬物吸収を評価することが重要である。
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Claims (11)
- 薬学的に許容される担体と、R(+)−N−プロパルギル−1−アミノインダン(ラサギリン)、S(−)−N−プロパルギル−1−アミノインダンから選択される活性薬剤またはその薬学的に許容される塩とを含む医薬組成物であって、前記活性薬剤の持続放出のために製剤化された経口投与のための医薬組成物であり、前記医薬組成物は、薬学的に許容される担体と持続放出性(ER)ペレットを含み、前記持続放出性(ER)ペレットは、
(i)不活性なペレットコアと、
(ii)前記ペレットコアをコーティングしている薬物層であって、結合剤および/またはフィルム形成ポリマーとしてのポリビニルピロリドン(PVP)および滑剤としての超微末タルクと混合した前記活性薬剤含む薬物層と、
(iii)任意に、前記薬物層をコーティングしている隔離/保護サブコーティング層であって、前記隔離/保護サブコーティング層はフィルム形成ポリマーとしてPVPを含み、
(iv)存在すれば前記サブコーティング層を、または前記薬物層をコーティングしているERコーティング層であって、前記ERコーティング層は、pH非依存性ポリマーとしてエチルセルロース、細孔形成剤としてポリエチレングリコール(PEG)、および任意に滑剤として超微末タルクとを含み、
前記薬物層中の前記フィルム形成ポリマー/結合剤の量が前記薬物層の総重量の90%以下、または前記ペレットの総重量の0.5%〜20%であり、前記薬物層中の前記滑剤の量が前記薬物層の総重量の30%以下、または前記ペレットの総重量の0.1%〜10%であり、前記サブコーティング層中の前記フィルム形成ポリマーの量が前記サブコーティング層の総重量の100%以下、または前記ペレットの総重量の0.5%〜20%であり、前記pH非依存性ポリマーの量が前記ERコーティング層の総重量の50%〜90%、または前記ペレットの総重量の10%〜30%であり、前記細孔形成剤の量が前記ERコーティング層の総重量の1%〜20%、または前記ペレットの総重量の0.1%〜10%であり、かつ存在すれば前記ERコーティング層中の前記滑剤の量が前記ERコーティング層の総重量の0.1%〜20%、または前記ペレットの総重量の0.1%〜10%である、
前記医薬組成物。 - 前記薬学的に許容される塩が、R(+)−N−プロパルギル−1−アミノインダンまたはS(−)−N−プロパルギル−1−アミノインダンのメシル酸塩、エシル酸塩、トシル酸塩、硫酸塩、スルホン酸塩、リン酸塩、カルボン酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、安息香酸塩、酢酸塩、塩酸塩または臭化水素酸塩から選択される、請求項1に記載の医薬組成物。
- 錠剤、カプセルまたは小袋の形態である、請求項1に記載の医薬組成物。
- 前記医薬組成物における前記活性薬剤の1日用量が0.2〜2.0mgの範囲である、請求項1〜3いずれか1項に記載の医薬組成物。
- 前記医薬組成物における前記活性薬剤の1日用量が0.2〜1.0mgの範囲である、請求項4に記載の医薬組成物。
- 前記医薬組成物における前記活性薬剤の1日用量が0.5〜1.0mgの範囲である、請求項5に記載の医薬組成物。
- USP装置1(バスケット)37℃、7.4以下のpH値、50〜150rpmにおいて、以下の溶出プロファイル:
- 前記活性薬剤が、R(+)−N−プロパルギル−1−アミノインダンまたはその薬学的に許容される塩である、請求項7に記載の医薬組成物。
- 神経変性疾患または神経系の損傷の治療のための、請求項1〜8のいずれか1項に記載の医薬組成物。
- 前記神経変性疾患がパーキンソン病またはアルツハイマー病であり、かつ前記神経系の損傷が急性脳損傷である、請求項9に記載の医薬組成物。
- 前記神経変性疾患がパーキンソン病である、請求項10に記載の医薬組成物。
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