JP4682145B2 - ソマトスタチンアナログを含む微粒子 - Google Patents
ソマトスタチンアナログを含む微粒子 Download PDFInfo
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- JP4682145B2 JP4682145B2 JP2006538808A JP2006538808A JP4682145B2 JP 4682145 B2 JP4682145 B2 JP 4682145B2 JP 2006538808 A JP2006538808 A JP 2006538808A JP 2006538808 A JP2006538808 A JP 2006538808A JP 4682145 B2 JP4682145 B2 JP 4682145B2
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Description
X1は式(a)または(b)
R2は−Z1−CH2−R1、−CH2−CO−O−CH2−R1、
のラジカルであり、そして
X2はCα側鎖に芳香族性残基を有するα−アミノ酸であるか、またはDab、Dpr、Dpm、His、(Bzl)HyPro、チエニル−Ala、シクロヘキシル−Alaおよびt−ブチル−Alaから成る群から選択されるアミノ酸単位であり、該配列の残基Lysはは天然ソマトスタチン−14の残基Lys9に対応する。〕
のアミノ酸配列を含む。
本明細書で使用するソマトスタチン類似体は、式Iの配列を含み、そして、ここでさらに1個またはそれ以上のアミノ酸単位が欠失しているおよび/または1個またはそれ以上の他のアミノ酸ラジカルで置換されているおよび/または1個またはそれ以上の官能基が1個またはそれ以上の他の官能基に置換されているおよび/または1個またはそれ以上の基が1個または複数個の他の等配電子基で置換されているものである、天然に存在するソマトスタチン−14のものに由来する直鎖または環状ペプチドを意味する。一般に本用語は、下記で定義の少なくとも1個のソマトスタチン受容体に対してnM範囲で結合親和性を有する、上記式Iの配列を含む天然ソマトスタチン−14の全ての修飾された誘導体をカバーする。
X1は、好ましくは式(a)または(b)の残基であり、R2は好ましくは
R1が置換フェニルであるとき、それは、適当には例えばオルトおよび/またはパラをハロゲン、メチル、エチル、メトキシまたはエトキシにより置換され得る。より好ましくはR1は非置換フェニルである。
Z1は好ましくはOである。
X1およびX2は上記で定義の通りであり、
Aは、Pro、
から選択され、そして
ZZaは天然または非天然α−アミノ酸単位である。〕
の化合物である。
C−2の立体配置は(R)または(S)またはその混合物であり、そして
RはNR10R11−C2−6アルキレンまたはグアニジン−C2−6アルキレンであり、そしてR10およびR11の各々は、独立してHまたはC1−4アルキルである。〕
の化合物の、遊離形、塩形または被保護形である。
典型的に、本発明の化合物は全身的に、例えば非経腸的に送達される。しかしながら、非経腸投与は、とりわけ反復投与においては非常に痛いことがある。患者への注射回数を減らすために、適当なデポー製剤を投与すべきである。
該ポリマーマトリックスは、投与部位から、1〜6ヶ月後までに活性成分の全てまたは実質的に全てを輸送するのに十分に分解性であるように設計する。
(a)ポリオール部分、例えばグルコースから放射されている直鎖である直鎖または分枝鎖ポリエステル、例えばポリエステル、例えばD−、L−またはラセミ体ポリ乳酸、ポリグリコール酸、ポリヒドロキシ酪酸、ポリカプロラクトン、ポリアルキレンオキザレート、クレブスサイクル、例えばクエン酸サイクルの酸のポリアルキレングリコールエステルなどまたはそれらの組み合わせ、
(b)他のモノマー、例えばポリ無水酸とのコポリマー、例えば1,3−ビス−(p−カルボキシフェノキシ)−プロパンのコポリマーおよび二酸、例えばセバシン酸、またはエルカ酸ダイマーとセバシン酸のコポリマーを含む、有機エーテル、無水物、アミドおよびオルトエステルのポリマーまたはコポリマー;オルト−エステルとトリオール、例えば1,2,6−ヘキサントリオールの反応、またはジケテンアセタール、例えば3,9−ジエチリデン−2,4,8,10−テトラオキサスピロ[5,5]ウンデカンとジオール、例えば1,6−ジヘキサンジオール、トリエチレングリコールまたは1,10−デカンジオールとの反応によりもたらされるポリオルトエステル;またはアミド−ジオールモノマー、例えば1,2−ジ−(ヒドロキシアセトアミド)−エタンまたは1,10−ジ−(ヒドロキシアセトアミド)デカンと得られるポリエステルアミド;または
(c)ポリビニルアルコール。
a)好ましくは約2,000から約20,000Daの分子量のポリビニルピロリドン。適当な例は、約2,500Daの平均分子量のPovidone K12 F、約8,000Daの平均分子量のPovidone K15、または約10,000Daの平均分子量のPovidone K17として一般的に既知のものを含む。
好ましくは、該ポリビニルピロリドンは、微粒子の約0.1から約50重量%、例えば約10重量%の量で存在する。
好ましくは、該CMC−Naは、微粒子の約0.1から約20重量%、例えば約5重量%の量で存在する。
好ましくは、該デキストリンは、微粒子の約0.1から約10重量%、例えば約5重量%の量で存在する。
a)例えば約2000から約8000Daの分子量を有するポロキサマー(ポリオキシエチレンポリオキシプロピレンブロックコポリマーとしても既知)。エチレン部分の重合化度は、典型的に80から約110単位である。プロピレン部分の重合化度は、典型的に20から約60単位である。本発明に従って使用するのに適したこのような化合物の例は、既知であり、例えば、Pluronic(登録商標)F68の商品名でBASF Germanyから市販されているものを含む。
本発明の化合物の包埋に使用するポリマー(複数もある)がポリエステルであるとき、該微粒子は、好ましくはさらに塩基性化合物、例えば塩基性塩または塩基、例えば塩基性炭酸亜鉛、水酸化マグネシウム、炭酸マグネシウムまたはプロタミン、例えばヒトプロタミンまたはサケプロタミン、またはポリリシンまたはジメチルアミノエチルメタクリレートのようなアミン−残基を担持する天然もしくは合成ポリマーを含む。
(i)
(ia)適当な有機溶媒または溶媒混合物にポリマー(複数もある)を溶解し、
そして所望により
−工程(ia)で得た溶液に多孔性作用剤(porosity influencing agent)を溶解/分散させるか、または
−塩基性塩を工程(ia)で得た溶液に添加するか、
−界面活性剤を工程(ia)で得た溶液に添加し;
(ib)本発明の化合物を工程(ia)で得たポリマー溶液に溶解するか、または
本発明の化合物を、工程(ia)で使用した溶媒と混和性の溶媒に溶解し、該溶液と該ポリマー溶液を混合するか、または
本発明の化合物を直接ポリマー溶液に溶解するか、または
水溶性塩の形の本発明の化合物を水性相に溶解し、該水溶液をポリマー溶液(ia)で乳化する;
ことを含む内部有機相の製造を行い;
(ii)
(iia)pHを7−7.5に調製するために緩衝液、例えば酢酸またはリン酸緩衝液、例えばNa2HPO4およびKH2PO4を製造し、そして
(iib)工程(iia)で得た溶液に安定化剤を溶解する;
ことを含む外部水性相の製造を行い;
(iii)内部有機相と外部水性相を、例えば高剪断力を作る装置で、例えばタービンまたは静的ミキサーで混合して、エマルジョンを形成し;そして
(iv)該微粒子を、溶媒蒸発または溶媒抽出により硬化し、該微粒子を、例えば水で洗浄し、該微粒子回収し、そして、例えば凍結乾燥または真空乾燥により乾燥させる
ことを含む、本発明の微粒子の製造法を提供する。
a)好ましくは、約10,000から約150,000Da、例えば約30,000Daの重量平均分子量を有するポリビニルアルコール(PVA)。簡便には、該ポリビニルアルコールは、20℃で4%水溶液でまたはDIN 53015で測定したとき、約3から約9mPa sの動的粘度の低粘性を有する。適当には、該ポリビニルアルコールは酢酸ポリビニルの加水分解により得られる。好ましくは、酢酸ポリビニルの含量は、ポリビニルアルコールの約10から約90%である。簡便には、加水分解度は約85から約89%である。典型的に残りのアセチル含量は約10から12%である。好ましい商標は、Clariant AG Switzerlandから入手可能なMowiol(登録商標)4−88、8−88および18−88を含む。
好ましくは該ポリビニルアルコールは、外部水性相の容量の約0.1から約5重量%、例えば約0.5重量%の量で存在する;
好ましくは、HECおよび/またはHPCは、外部水性相の容量の約0.01から約5重量%、例えば約0.5重量%の量で存在する;
好ましくは、該ゼラチンは、外部水性相の容量の約0.01から約5重量%、例えば約0.5重量%の量で存在する。
投与前に、該微粒子を、注射に適当な媒体に懸濁する。
好ましくは、該媒体は、さらに等張化剤b)、例えばマンニトール、塩化ナトリウム、グルコース、デキストロース、スクロース、またはグリセリンを含む。好ましくは、該等張化剤はマンニトールである。
上記の特性を有するポリビニルピロリドンを使用し得る。
a)過剰なGH分泌および/または過剰なIGF−1を含むまたはそれが関連する病因を伴う障害の予防または処置、例えば先端巨大症の処置ならびにI型またはII型糖尿病、とりわけその合併症、例えば脈管障害、糖尿病性増殖性網膜症、糖尿病性黄斑浮腫、腎症、神経障害および曙現象、およびインシュリンまたはグルカゴン放出に関係する他の代謝障害、例えば肥満、例えば病的肥満または視床下部性または高インシュリン性肥満の処置のために、
b)腸皮膚(enterocutaneous)および膵臓皮膚(pancreaticocutaneous)フィステル、過敏性腸症候群、炎症性疾患、例えばグレーブス病、炎症性腸疾患、乾癬またはリウマチ性関節炎、多発性嚢胞腎、ダンピング症候群、水様性下痢症候群、AIDS関連下痢、化学療法誘発下痢、急性または慢性膵炎および消化器ホルモン分泌腫瘍(例えばGEP腫瘍、例えばVIP産生腫瘍、グルカゴノーマ、インシュリノーマ、カルチノイドなど)、リンパ細胞悪性物、例えばリンパ腫または白血病、肝細胞癌腫ならびに消化器出血、例えば食道静脈瘤出血の処置に、
c)血管形成、炎症性眼疾患、黄斑浮腫、例えば胞状黄斑浮腫、特発性胞状黄斑浮腫、滲出性加齢黄斑変性症、脈絡膜血管新生関連障害および増殖性網膜症を含む、上記の炎症性障害の予防または処置のために、
d)例えば臓器、例えば心臓、肺、複合心臓−肺、肝臓、腎臓または膵臓移植における、移植片血管疾患(graft vessel disease)、例えば同種−または異種移植片脈管障害、例えば移植片血管アテローム性動脈硬化症を予防しまたは戦うために、または静脈移植片狭窄、例えばカテーテル法または経皮経管的血管形成術のような血管掻爬法、レーザー処置または血管内膜もしくは内皮の無傷さを損なう他の侵襲性方法が原因の、血管傷害後の再狭窄および/または血管閉塞の予防または処置に、
e)ソマトスタチン受容体発現性または蓄積性腫瘍、例えば下垂体腫瘍、例えばクッシング病または症候群、胃腸膵臓(gastro-enteropancreatic)カルチノイド、中枢神経系の、乳房の、前立腺(進行したホルモン難治性前立腺癌を含む)の、卵巣のまたは結腸の腫瘍、小細胞肺癌、悪性腸閉塞、傍神経節腫、腎臓癌、皮膚癌、神経芽腫、クロム親和細胞腫、髄様甲状腺癌腫、骨髄腫、リンパ腫、ホジキンおよび非ホジキンリンパ腫、骨腫瘍およびそれらの転移、ならびに自己免疫性または炎症性障害、例えばリウマチ性関節炎、グレーブス病または他の炎症性眼疾患の処置のために
有用である。
本発明の微粒子および組成物の特性は、標準動物試験または臨床試験で試験し得る。
本発明の微粒子および組成物は、十分耐容性である。
下記実施例は、限定することなく、本発明を説明するために提供する。
ポリ−(D,L−ラクチド−コ−グリコリド)を、表1に示す量の塩化メチレンに溶解する。該ポリマー溶液を、次いで、化合物Aパモ酸塩に添加する。得られた懸濁液をUltra-Turraxで1分処理する。
2lの水を90℃に加熱する。加熱中に、表1に記載の量のリン酸塩を、交互に添加する。90℃で、表1に記載の量のPVA18−88を添加する。得られた溶液を、次いで20℃に冷却し、水を加えて所定量とする。
ポリマー/薬剤懸濁液およびPVA/リン酸塩溶液を混合し、塩化メチレンを真空下で蒸発させ、微粒子を濾取し、水(WBU)で洗浄し、減圧下(0.1mbar)、室温で乾燥させる。
2lの水を90℃に加熱する。加熱中に、表2に記載の量のリン酸塩を、交互に添加する。90℃で、表2に記載の量のPVA18−88を添加する。得られた溶液を、次いで20℃に冷却し、水を加えて所定量とする。
ポリマー/薬剤懸濁液およびPVA/リン酸塩溶液を混合し、塩化メチレンを真空下で蒸発させ、微粒子を濾取し、水(WBU)で洗浄し、減圧下(0.1mbar)、室温で乾燥させる。
表3に記載の量のCMC−Na、マンニトールおよびPluronic F68を、約90℃の熱い約15ml脱イオン水に、磁気撹拌子で激しく撹拌しながら溶解する。得られた透明溶液を20℃に冷却し、脱イオン水で20.0mlとする。
384mgまたは576mgの実施例2aおよび2bの微粒子を、6Rバイアル中、2.0mlの組成物Dの媒体に懸濁する。該懸濁液を約30秒振盪することにより均質化する。該再構成された懸濁液は、20ゲージ針を使用して、何の問題もなく注射できる。
240mgの実施例2aおよび2bの微粒子を、1mlの媒体組成物F中に再構成し、プロペラミキサーで400rpmで1から12時間均質化し、次いで、Telstar凍結乾燥機で凍結乾燥する。
1ml純水(WBU)での微粒子凍結乾燥物の再構成は、20ゲージ針を使用して、何の問題もなく注射できる、微粒子の速く良好な濡れをもたらす。
4mgの化合物A/ウサギkgに対応する量の実施例2aおよび2bの微粒子を、1mlの媒体組成物Dに懸濁する。該懸濁液を約30秒振盪することにより均質化し、試験開始前体重約3kgのウサギの左腓腹筋に18G針を使用して注射する。
血液サンプル(約1ml)を55日間にわたり採取する。化合物Aの血漿レベルを、ELISA法を使用して測定する。投与後の化合物Aの平均濃度を表4に示す。平均AUC(0−55 d)は、実施例2aで454ng/ml dおよび実施例2bで296ng/ml dであることが判明する。
Claims (13)
- ポリマーマトリックスに包埋された、遊離形、塩形、または被保護形のシクロ[{4−(NH 2 −C 2 H 4 −NH−CO−O−)Pro}−Phg−DTrp−Lys−Tyr(4−Bzl)−Phe]〔式中、Phgは−HN−CH(C 6 H 5 )−CO−を意味し、そしてBzlはベンジルを意味する。〕を含み、該ポリマーマトリックスが直鎖ポリラクチド−コ−グリコリドおよび分枝鎖ポリラクチド−コ−グリコリドを含む、微粒子。
- シクロ[{4−(NH 2 −C 2 H 4 −NH−CO−O−)Pro}−Phg−DTrp−Lys−Tyr(4−Bzl)−Phe]がパモ酸塩形である、請求項1に記載の微粒子。
- ポリマーマトリックスが、Resomer(登録商標)RG、および50,000Daの重量平均分子量を有する星型ポリラクチド−コ−グリコリドポリマーを含む、請求項1または2に記載の微粒子。
- 直鎖ポリラクチド−コ−グリコリド対分枝鎖ポリラクチド−コ−グリコリドの比が50:50である、請求項1から3のいずれかに記載の微粒子。
- シクロ[{4−(NH 2 −C 2 H 4 −NH−CO−O−)Pro}−Phg−DTrp−Lys−Tyr(4−Bzl)−Phe]が、5ミクロン未満の粒子サイズを有する無定形粉末である、請求項1から4のいずれかに記載の微粒子。
- シクロ[{4−(NH 2 −C 2 H 4 −NH−CO−O−)Pro}−Phg−DTrp−Lys−Tyr(4−Bzl)−Phe]の粒子サイズ分布がx90<3.0ミクロンである、請求項1から5のいずれかに記載の微粒子。
- さらに界面活性剤、多孔性作用剤および/または塩基性塩を含む、請求項1から6のいずれかに記載の微粒子。
- 請求項1から7のいずれかに記載の微粒子および湿潤剤を含む水ベースの媒体を含む、医薬組成物。
- 湿潤剤がポロキサマーおよび/またはポリオキシエチレン−ソルビタン−脂肪酸エステルを含む、請求項8記載の組成物。
- 媒体が等張化剤を含む、請求項8または9に記載の組成物。
- 媒体が増粘剤を含む、請求項8から10のいずれかに記載の組成物。
- 請求項1から7のいずれかに記載の微粒子および水ベースの媒体を含む、キット。
- 請求項1から7のいずれかに記載の微粒子または請求項8から11のいずれかに記載の医薬組成物を含む、過剰のGH−および/またはIGF−1分泌を含むまたはそれが関連する病因を伴う疾患または障害の処置用医薬。
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PCT/EP2004/012870 WO2005046645A1 (en) | 2003-11-14 | 2004-11-12 | Microparticles comprising somatostatin analogues |
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MY158342A (en) * | 2003-11-14 | 2016-09-30 | Novartis Ag | Pharmaceutical composition |
BR122019027412B8 (pt) * | 2005-12-22 | 2021-07-27 | Novartis Ag | composição farmacêutica de liberação sustentada na forma de micropartículas, processo para preparação das ditas micropartículas, e kit de administração |
KR100816065B1 (ko) * | 2006-11-27 | 2008-03-24 | 동국제약 주식회사 | 초기 방출억제 특성이 우수한 서방출성 마이크로캡슐의제조방법 및 이에 의해 제조되는 마이크로캡슐 |
EP2167039B1 (en) * | 2007-05-18 | 2016-09-28 | Durect Corporation | Improved depot formulations |
PE20090387A1 (es) | 2007-05-24 | 2009-04-28 | Novartis Ag | Formulacion de pasireotida |
KR20100110848A (ko) * | 2008-01-30 | 2010-10-13 | 노파르티스 아게 | 옥트레오티드 및 3종의 선형 폴리락티드-코-글리콜리드 중합체를 포함하는 서방형 제제 |
US9629798B2 (en) * | 2008-04-03 | 2017-04-25 | Mallinckrodt Pharma Ip Trading D.A.C. | Hemostatic microspheres |
WO2010003939A1 (en) | 2008-07-08 | 2010-01-14 | Novartis Ag | Use of pasireotide for the treatment of endogenous hyperinsulinemic hypoglycemia |
US20100151033A1 (en) * | 2008-12-15 | 2010-06-17 | Novartis Ag | Octreotide depot formulation with constantly high exposure levels |
US8815971B2 (en) | 2008-12-22 | 2014-08-26 | ATRP Solutions, Inc. | Control over controlled radical polymerization processes |
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WO2010123574A1 (en) | 2009-04-23 | 2010-10-28 | Atrp Solutions Inc | Star macromolecules for personal and home care |
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WO2014121188A1 (en) | 2013-02-04 | 2014-08-07 | ATRP Solutions, Inc. | Salt-tolerant star macromolecules |
US9587064B2 (en) | 2010-12-08 | 2017-03-07 | ATRP Solutions, Inc. | Salt-tolerant star macromolecules |
WO2013131879A1 (en) | 2012-03-07 | 2013-09-12 | Novartis Ag | New application for pasireotide |
MX368683B (es) | 2012-08-30 | 2019-10-11 | Pilot Polymer Tech Inc | Agentes espesantes de mecanismo dual para fluidos de fracturación hidráulica. |
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TW201605488A (zh) * | 2013-10-15 | 2016-02-16 | 大塚製藥股份有限公司 | 用以預防及/或治療多囊腎病之藥物 |
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