JP6560166B2 - 薬物徐放性担体及びその製造方法 - Google Patents
薬物徐放性担体及びその製造方法 Download PDFInfo
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- JP6560166B2 JP6560166B2 JP2016138977A JP2016138977A JP6560166B2 JP 6560166 B2 JP6560166 B2 JP 6560166B2 JP 2016138977 A JP2016138977 A JP 2016138977A JP 2016138977 A JP2016138977 A JP 2016138977A JP 6560166 B2 JP6560166 B2 JP 6560166B2
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- polysaccharide
- hyaluronic acid
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Description
(1)固相を用いないために生体物質の吸着とそれに伴う構造破壊・変性などが回避でき、かつ親水性高分子の共存により安定化され常温での操作が可能である。
(2)二相間の界面張力の差がわずかであるために、二相を混和すると比較的安定な徴細液滴の懸濁状態が得られ、分配平衡の達成が迅速かつ容易である。
(3)目的物質に親水基を導入すれば、分離の特異性が向上しうる。
(4)分配係数が系の全体積、二相の体積比、分離対象の濃度に鈍感なため、試験管規模の実験結果に基づきスケールアップを容易に行える。
蛋白質医薬品の徐放製剤への応用を目指した水性二相分配現象が現在研究されてはいるが、PEGをグラフトした高分子のDDS担体としての有用性はまだ明らかにはされていない。さらにその作製法は未確立でありまた、PEG相へ分配したタンパク質の分配条件制御、放出制御、などはいまだ検討されていない。本発明は、高分子にPEGの繰り返し単位構造を有する片末端アミノ化PEG(PEG-NH2)をグラフトさせた化合物の新しい製法を提供する。またその化合物を用いて蛋白質薬物の徐放のためのDDSへ応用することを目的とする。
ここにPEGカルボキシ基含有高分子(多糖類)グラフトとは、カルボキシ基含有高分子(多糖類)を主鎖としてPEGがグラフト化したものをいう。好適には、PEGにアミノ基を導入し、高分子(多糖類)にカルボキシ基を導入する、あるいは、カルボキシ基含有高分子(多糖類)を用いて無水環境下において塩基あるいは酸触媒によるエステル化により、高分子(多糖類)のカルボキシ基とPEG末端水酸基とを縮合させてできる化合物をいう。PEGカルボキシ基含有高分子グラフトの構造は、1H−NMRのスペクトルにより確認することができる。
PEGカルボキシ基含有多糖類グラフトにおけるPEGとカルボキシ基含有多糖類との重量比は特に制限はないが、PEG:カルボキシ基含有多糖類=1:20〜1:0.1(重量比)が望ましい。カルボキシ基含有多糖類にグラフトするPEGの量が少なすぎるとPEGのタンパク質性医薬や低分子薬物に対する親和性の効果を発現しにくい。またカルボキシ基含有多糖類にグラフトするPEGの量が多すぎるようなグラフト物は製造が困難である。
PEGカルボキシ基含有多糖類グラフトの分子量は、本発明においては特に制約はなく、目的に応じて適切な範囲のものを選択することができるが、医薬品のDDS用担体の場合、分子量200以上20,000万以下が望ましく、かつ分子量の異なるPEGのブレンド物であってもよい。
蛋白質性医薬としては、例えば、インスリン、エクセンジン−4、カルシトニン、副腎皮質刺激ホルモン、副甲状腺ホルモン(PTH)、hPTH(1→34)、セクレチン、オキシトシン、アンギオテンシン、β−エンドルフィン、グルカゴン、バソプレッシン、ソマトスタチン、ガストリン、黄体形成ホルモン放出ホルモン、エンケファリン、ニューロテンシン、心房性ナトリウム利尿ペプチド、成長ホルモン、成長ホルモン放出ホルモン、ブラジキニン、サブスタンスP、ダイノルフィン、甲状腺刺激ホルモン、プロラクチン、インターフェロン、インターロイキン、G−CSF、グルタチオンパーオキシダーゼ、スーパーオキシドディスムターゼ、デスモプレシン、ソマトメジン、エンドセリン、及びこれらの塩等が挙げられる。抗原蛋白質ないしはウイルス断片としては、インフルエンザ抗原、破傷風抗原、ジフテリア抗原、HBs表面抗原、HBe抗原等が挙げられる
1.蛋白質性医薬、低分子薬物に対しすぐれた保持性を有し、それゆえ薬物の徐放性担体として有効である。
2.PEGがグラフトすることによりHAの生体内分解性が抑制され担体としての作用を長期持続できる。
500mlフラスコに水100mlを入れ、ヒアルロン酸(FCH-SU, 分子量 8〜11万,(株)キッコーマンバイオケミファ)0.1gを加えて室温で撹拌して溶解させた。末端にアミノ基を持つメトキシポリエチレングリコール(SUNBRIGHT(MEPA-50H))0.1gを添加して攪拌し一様な溶液とした。さらに室温下でDMTMMを0.1g添加して縮合反応を開始し5時間反応させた。反応終了後、低分子生成物を24時間の透析により除き精製した。その後凍結乾燥してPEG-graft-HA-1の粉末を得た。
実施例1により作製し乾燥させたPEG-graft-HA-1を、重水を用いて1重量%になるよう溶解させて試験溶液とした。核磁気共鳴(NMR)装置はJEOL-LA300FTNMR SYSTEM(日本電子(株))を用いた。データ解析はJEOL NMR DataProcessing Software ALICE2を用いた。
得られたNMRチャートを図1に示す(1H-NMR(400 MHz, D2O)。図1において、: δ (ppm) = 1.97のピークはヒアルロン酸の NHCO-CH 3 におけるHAのメチル末端由来である。δ (ppm) =3.5-3.7のピークは -CH 2CH 2O- におけるメチレン基由来である。本NMRチャートからヒアルロン酸に PEGがグラフトされていることが分かる。両ピークの面積からのPEGのヒアルロン酸へのグラフト率(重量比換算のグラフト率)は41%と算出された。
上記グラフト率は、HAのメチル基とPEGのエチレン基における水素原子との数の比をNMR測定結果から算出したものである。すなわち、グラフト率は、グラフト化されたPEGとHAとの重量比を百分率で示した値である。
1H-NMRのケミカルシフト(TMS基準)において、PEGのエチレン基のケミカルシフトはδ (ppm) =約3.5-3.7に位置する。カルボキシ基含有高分子(多糖類)に固有のケミカルシフトにおけるピーク面積と、PEGのエチレン基のケミカルシフトにおけるピーク面積とを算出し、その比率を計算することによって、カルボキシ基含有高分子(多糖類)へのPEGのグラフト率を求めることができる。
多角光散乱検出器付きサイズ排除クロマトグラフ(SEC-MALS)によるグラフト反応物の単一性確認及び分子量測定を行った。実施例1により作製し乾燥させたPEG-graft-HAの0.1 WT%水溶液を試料とした。測定条件は以下のようであった。
カラム: Shodex PROTEIN GF-710HQ(7.6mmI.D. x 300mm)+Shodex Asahipak GS-510 HQ (7.5mmI.D. x 300mm)
注入量:150μL
溶離液: 0.1M Phosphate buffer(pH7.0)
流量: 1.0mL/min
検出: MALS(Multi angle laser light scattering), 90度
カラム温度: 26℃
得られたクロマトグラムを図2に示す。ピークは単一ピークであり、PEG-graft-HAのみが検出されている。未反応のPEG及びヒアルロン酸は検出されなかった。分子量は44.3万と算定された。
HAとしてFCH-SU の代わりにFCH-80LE(分子量 60〜100万、(株)キッコーマンバイオケミファ)を用いた以外は全て実施例1と同様にして合成されたPEG-graft-HA-2(49.7mg)とHA-80LE(28.9 mg)とをPBS 0.7 mlに溶解し、HA濃度4wt%の溶液を調製した。溶液は白濁していた。
FITC-Insulin(インスリンにFITCラベルして蛍光測定を容易化したもの、自家製) 0.87mgを上記溶液に溶解させ、黄芭透明の溶液を得た。 透析チューブ(分画分子量3,000の透析膜、スペクトラムラボ社製)に溶液をうつし、ビーカー(500 ml)に満たした試験液(500 ml )に浸し、透析チューブを動かないよう固定した。試験液にはPBSを用いた。 PBSはあらかじめ1日以上静置し室温とした。ビーカー内には攪拌子を入れマグネティックスターラーを用いて145 rpm で回転させた。実験系の上部はラップで覆い、試験液が蒸発し液量が変化しないようにした。10時間毎にビーカーの中心付近から試験液1 mLを素早く披き取った。抜き取り直後に1 mLのPBSを静かに加え、試験液の液量は常に一定に保った。採取した試験液は、励起波長495 nm、測定波長510〜600 nm、温度25 ℃で蛍光を測定した。 520 nmでの蛍光強度によりFITC-Insulinの量を求め放出率を算出した。結果を実施例2として表1に示す。
同様なFITC-Insulinの放出実験をPEG-graft-HA-2の代わりにHAを用いて行った。結果を比較例1として表1に示した。
インスリンの放出率(%)
実施例2で合成したPEG-graft-HA-2を2WT%になるよう0.15mole%PBSに溶解させた。HAも同様に2WT%になるよう0.15mole%PBSに溶解させた。ヒアルロニダーゼ(ヒアルロニダーゼ”アマノ“、和光純薬)をそれぞれの溶液中に30units/mgHA になるように添加し、ヒアルロン酸の分子量低下を測定することによりヒアルロン酸の分解を測定した。
PEG-graft-HA-2を用いてマイクロニードルを作製し、社内ボランティアの額のしわ部に適用し、抗しわ効果の持続性を検証試験した。効果を肉眼で観察しやすいよう医療用マイクロニードル(針長さ800μm)を用いた。マイクロニードルの成型は鋳型法により行い、長径1.0cm、短径0.6cmの楕円形マイクロニードルパッチを作製し、額のしわ部位に貼付し経時変化を観察し、図3の結果を得た。
試薬類はいずれも和光純薬(株)より購入、試薬特級を使用した。
THFの100g、PEG400の50g中にヒアルロン酸(FCH-SU, 分子量 8〜11万,(株)キッコーマンバイオケミファ)の6.0gを懸濁させ、濃硫酸1mlを加えて50℃で攪拌しつつ10時間反応させた。10時間後に取り出し精製し乾燥した(PEG-HA−5という)。
PEG400の70g中にヒアルロン酸(FCH-SU)の6.0gを懸濁させ、過塩素酸1mlを加えて50℃で攪拌しつつ10時間反応させた。20時間後に取り出し精製し乾燥した(PEG-HA−6という)。
PEG-HA−5、PEG-HA−6のPEGグラフト率は赤外スペクトルにより定量した。PEGの2870cm−1ピークとヒアルロン酸の1025cm−1ピークに着目し、PEGとヒアルロン酸の種々のブレンド物の赤外スペクトルを測定し(2870cm−1の強度/1025cm−1 )と両高分子の組成比からなる検量線を作成した。ついで、PEG-HA−5、PEG-HA−6の赤外スペクトルを測定し検量線からグラフト率を算出した。赤外分光計は、高速FT-IRイメージングシステム(型式:Spectrum100FT-IR/Spotlight400,(株)パーキンエルマージャパン製)を用いた。算出されたPEGグラフト率はPEG-HA−5においては 0.27、PEG-HA−6においては 0.29であった。
PEG-HA−5、PEG-HA−6、Q社製耐酵素性付与ヒアルロン酸、及び参照のためのHA(FCH-SU9)を用いて酵素分解抑制試験を行った。各試料を2WT%になるよう0.15mole%PBSに溶解させた。ヒアルロニダーゼ(ヒアルロニダーゼ”アマノ“、和光純薬)をそれぞれの溶液中に2units/mgHA になるように添加し、0、8、16、24、32時間後の分子量低下から分解率を算出しプロットしたのが図4である。ヒアルロン酸の分子量低下を測定することによりヒアルロン酸の分解を測定した。
Claims (14)
- 非水溶媒又は無溶媒下及び酸共存下でPEGとカルボキシ基含有多糖類とを縮合反応する工程を含む、PEGと多糖類のカルボキシ基とがエステル結合によりグラフトしているPEGカルボキシ基含有多糖類グラフトの製造方法。
- カルボキシ基含有多糖類がヒアルロン酸であることを特徴とする請求項1に記載の製造方法。
- PEGカルボキシ基含有多糖類グラフトから構成されるDDS用担体であって、多糖類のカルボキシ基とPEGとがエステル結合によりグラフトしていることを特徴とするDDS用担体。
- カルボキシ基含有多糖類がヒアルロン酸であることを特徴とする請求項3に記載のDDS用担体。
- 請求項3又は4に記載のDDS用担体を含有する注射剤。
- 請求項3又は4に記載のDDS用担体を含有する内服剤。
- 請求項3又は4に記載のDDS用担体を含有する埋め込み製剤。
- 請求項3又は4に記載のDDS用担体を含有する経皮吸収製剤。
- 請求項3又は4に記載のDDS用担体を含有する化粧品。
- 請求項3又は4に記載のDDS用担体を含有するマイクロニードル製剤。
- インスリンと、PEGと多糖類のカルボキシ基とがエステル結合によりグラフトしているPEGカルボキシ基含有多糖類グラフトから構成される徐放性インスリン。
- カルボキシ基含有多糖類がヒアルロン酸であることを特徴とする請求項11に記載の徐放性インスリン。
- エクセンジン−4と、PEGと多糖類のカルボキシ基とがエステル結合によりグラフトしているPEGカルボキシ基含有多糖類グラフトから構成される徐放性エクセンジン−4。
- カルボキシ基含有多糖類がヒアルロン酸であることを特徴とする請求項13に記載の徐放性エクセンジン−4。
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US4851521A (en) * | 1985-07-08 | 1989-07-25 | Fidia, S.P.A. | Esters of hyaluronic acid |
US5202431A (en) * | 1985-07-08 | 1993-04-13 | Fidia, S.P.A. | Partial esters of hyaluronic acid |
US8313765B2 (en) * | 2003-12-04 | 2012-11-20 | Industrial Technology Research Institute | Biodegradable hyaluronic acid derivative, biodegradable polymeric micelle composition and pharmaceutical or bioactive composition |
US8293890B2 (en) * | 2004-04-30 | 2012-10-23 | Advanced Cardiovascular Systems, Inc. | Hyaluronic acid based copolymers |
US7910134B2 (en) * | 2007-10-29 | 2011-03-22 | Ayman Boutros | Alloplastic injectable dermal filler and methods of use thereof |
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US20120186571A1 (en) * | 2009-10-16 | 2012-07-26 | Linda Yi-Ping Zhu | Aqueous Cutting Fluid for Use with a Diamond Wiresaw |
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US20190358331A1 (en) | 2019-11-28 |
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AU2016293784B2 (en) | 2021-11-11 |
EP3323429A4 (en) | 2019-02-27 |
AU2016293784A1 (en) | 2018-01-25 |
NZ739748A (en) | 2022-04-29 |
WO2017010518A1 (ja) | 2017-01-19 |
CA2992258A1 (en) | 2017-01-19 |
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