JP2694923B2 - Water-soluble polymerized pharmaceutical preparation - Google Patents
Water-soluble polymerized pharmaceutical preparationInfo
- Publication number
- JP2694923B2 JP2694923B2 JP7211596A JP21159695A JP2694923B2 JP 2694923 B2 JP2694923 B2 JP 2694923B2 JP 7211596 A JP7211596 A JP 7211596A JP 21159695 A JP21159695 A JP 21159695A JP 2694923 B2 JP2694923 B2 JP 2694923B2
- Authority
- JP
- Japan
- Prior art keywords
- drug
- water
- segment
- block copolymer
- adriamycin
- 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
Links
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、親水性セグメント
と、側鎖に薬物を結合せしめた疎水性の薬理機能セグメ
ントとを有する水溶性ブロック共重合体からなる水溶性
高分子化医薬に関するものである。TECHNICAL FIELD The present invention relates to a water-soluble polymerized drug comprising a water-soluble block copolymer having a hydrophilic segment and a hydrophobic pharmacologically functional segment having a drug bound to its side chain. is there.
【０００２】[0002]
【従来の技術】低分子薬物を高分子に結合させることに
より、薬物の体内分布を望ましいものとし、薬物の体内
半減期を増大させる試みは過去に幾つかなされてきた。
しかし、それらの試みで用いられた高分子は単一成分か
らなるホモポリマーか、２つの成分を交互か順不同に重
合させたものであった。従来の上記のようなポリマーの
場合においては、薬効を上昇させるために薬物の担持量
を多くすると薬物の疎水性により、水溶性が低下する欠
点があった。2. Description of the Related Art Several attempts have been made in the past to bind a low molecular weight drug to a polymer to make the distribution of the drug in the body desirable and to increase the half-life of the drug in the body.
However, the polymers used in those attempts were homopolymers consisting of a single component or two components polymerized in alternating or random order. In the case of the conventional polymers as described above, when the amount of the drug carried is increased in order to increase the drug effect, there is a drawback that the water solubility is lowered due to the hydrophobicity of the drug.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、薬物の担持
量を多くしても水溶性が低下しない水溶性の高分子化医
薬を提供することを目的とする。SUMMARY OF THE INVENTION It is an object of the present invention to provide a water-soluble polymerized drug which does not decrease in water solubility even if the amount of the drug carried is increased.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、従来の高
分子化医薬の持つ欠点を解消しうる高分子化医薬の開発
を試み、鋭意研究を行った結果、今回、親水性の第１の
セグメントと第２のセグメントから成るブロックコポリ
マーのうち第２のセグメントに薬物を選択的に導入する
ことで、この第２のセグメント成分を疎水性化すること
により、第２のセグメントを内核に、第１のセグメント
を外側とするミセルを形成させることで薬物の導入に伴
う水溶性の低下、沈澱の生成を防ぐことに成功したもの
であり、本発明者らが開発した高分子化医薬はミセルを
形成することで良好な水溶性を有すると共に、水溶液中
での薬品としての安定性も、元の薬物よりも増大させる
ことができるものである。[Means for Solving the Problems] The inventors of the present invention tried to develop a polymerized drug capable of eliminating the disadvantages of the conventional polymerized drugs, and conducted extensive research. By selectively introducing a drug into the second segment of the block copolymer consisting of the first segment and the second segment to make the second segment component hydrophobic, the second segment becomes the inner core. The present inventors have succeeded in preventing the decrease in water solubility and the formation of a precipitate due to the introduction of a drug by forming a micelle having the first segment on the outer side. The polymerized drug developed by the present inventors is By forming micelles, it has good water solubility, and the stability as a drug in an aqueous solution can be increased more than that of the original drug.
【０００５】すなわち、本発明は、親水性セグメント
と、側鎖に薬物を結合せしめた疎水性の薬理機能セグメ
ントとを有するブロック共重合体からなる水溶性高分子
化医薬である。ここで上記水溶性高分子化医薬は、薬理
機能セグメントを内核に、親水性セグメントを外核とす
るミセルを形成するものである。また、薬物としては抗
ガン剤、例えばアドリアマイシンが挙げられる。That is, the present invention is a water-soluble polymerized drug comprising a block copolymer having a hydrophilic segment and a hydrophobic pharmacologically functional segment having a drug bound to its side chain. Here, the water-soluble polymerized drug forms micelles having a pharmacologically functional segment as an inner core and a hydrophilic segment as an outer core. In addition, examples of the drug include anticancer agents such as adriamycin.
【０００６】さらに、本発明は、親水性セグメントと、
薬物と結合可能な側鎖を有し、該薬物を結合した場合に
おいて疎水性となる第２のセグメントからなる薬物担持
用担体である。さらに、本発明は、下記式Ｉ：Further, the present invention comprises a hydrophilic segment,
The drug-carrying carrier comprises a second segment having a side chain capable of binding to a drug and being hydrophobic when the drug is bound. Further, the present invention provides the following formula I:
【０００７】[0007]
【化３】 (式中、ｎは５〜400、ｍは１〜300、ｘは０〜300の整数
を表す。)Embedded image (In the formula, n represents 5 to 400, m represents 1 to 300, and x represents an integer of 0 to 300.)
【０００８】で示されるブロック共重合体である。さら
に、本発明は、下記式II：It is a block copolymer represented by: Further, the present invention provides the following formula II:
【０００９】[0009]
【化４】 （式中、ｎは５〜400 、ｍは１〜300 の整数を表す。）Embedded image (In the formula, n represents an integer of 5 to 400 and m represents an integer of 1 to 300.)
【００１０】で示されるブロック共重合体をアルカリ加
水分解することを特徴とする下記式Ｉ：A block copolymer represented by the formula:
【００１１】[0011]
【化５】 （式中、ｎは５〜400 、ｍは１〜300 、ｘは０〜300 の
整数を表す。）Embedded image (In the formula, n represents an integer of 5 to 400, m represents 1 to 300, and x represents an integer of 0 to 300.)
【００１２】で示されるブロック共重合体の製造方法で
ある。以下、本発明を詳細に説明する。本発明における
親水性の第１のセグメントとしては、例えばポリエチレ
ングリコール、ポリサッカライド、ポリアクリルアミ
ド、ポリメタクリルアミド、ポリビニルピロリドン、ポ
リビニルアルコール、ポリメタクリル酸エステル、ポリ
アクリル酸エステル、ポリアミノ酸等あるいはこれらの
誘導体由来のセグメントが挙げられる。また、薬物と結
合して疎水化する第２のセグメントとしては、側鎖にポ
リアスパラギン酸、ポリグルタミン酸、ポリリシン、ポ
リアクリル酸、ポリメタクリル酸、ポリリンゴ酸、ポリ
乳酸, ポリアルキレンオキシド、長鎖アルコール等ある
いはこれらの誘導体由来のセグメントが挙げられる。A method for producing a block copolymer represented by: Hereinafter, the present invention will be described in detail. Examples of the hydrophilic first segment in the present invention include polyethylene glycol, polysaccharides, polyacrylamide, polymethacrylamide, polyvinylpyrrolidone, polyvinyl alcohol, polymethacrylic acid ester, polyacrylic acid ester, polyamino acid and the like or derivatives thereof. The segment of origin is mentioned. The second segment, which binds to the drug and becomes hydrophobic, has polyaspartic acid, polyglutamic acid, polylysine, polyacrylic acid, polymethacrylic acid, polymalic acid, polylactic acid, polyalkylene oxide, long-chain alcohol in the side chain. Etc. or segments derived from these derivatives.
【００１３】更に、第２のセグメントに結合させる薬物
としては、例えばアドリアマイシン、ダウノマイシン、
メソトレキセート、マイトマイシンＣ等の抗ガン剤、中
枢神経系用薬、末梢神経系用薬、アレルギー用薬、循環
器官用薬、呼吸器官用薬、消化器官用薬、ホルモン剤、
代謝性医薬品、抗生物質、化学療法剤等の薬物が挙げら
れる。Further, as the drug to be bound to the second segment, for example, adriamycin, daunomycin,
Anticancer agents such as methotrexate and mitomycin C, central nervous system agents, peripheral nervous system agents, allergic agents, circulatory organ agents, respiratory organ agents, digestive organ agents, hormone agents,
Examples include drugs such as metabolic drugs, antibiotics, and chemotherapeutic agents.
【００１４】以下に、ポリエチレングリコール誘導体由
来のセグメントとポリアスパラギン酸由来のセグメント
からなるブロックコポリマーで、抗ガン剤のアドリアマ
イシンをポリアスパラギン酸セグメントに結合させた場
合を例にとり、本発明を更に詳述する。The present invention will be described in more detail below by taking a case where an anticancer drug adriamycin is bound to a polyaspartic acid segment in a block copolymer composed of a segment derived from a polyethylene glycol derivative and a segment derived from polyaspartic acid. To do.
【００１５】第１図はポリエチレングリコールとポリア
スパラギン酸の２成分からなるブロックコポリマーで、
抗ガン剤のアドリアマイシンをポリアスパラギン酸の側
鎖カルボキシル基に体内で加水分解可能なアミド結合で
結合させた場合における、本発明の高分子化医薬の構造
概略図である。FIG. 1 shows a block copolymer consisting of two components, polyethylene glycol and polyaspartic acid.
FIG. 2 is a schematic structural diagram of the polymerized drug of the present invention in which an anticancer agent adriamycin is bound to a side chain carboxyl group of polyaspartic acid by an amide bond which can be hydrolyzed in the body.
【００１６】この高分子化医薬の合成は、以下の反応式
に示すごとくβ−ベンジル Ｌ−アスパルテートＮ−カ
ルボン酸無水物（ＢＬＡ−ＮＣＡ）を、片末端メトキシ
基等のアルコキシ基、片末端１級アミノ基のポリエチレ
ングリコール(分子量250〜1800) を開始剤として重合さ
せ、ポリエチレングリコール−ポリ (β−ベンジルＬ−
アスパルテート) ブロックコポリマー (ＰＥＧ−ＰＢＬ
Ａ）を得、次いでこのＰＥＧ−ＰＢＬＡをアルカリ加水
分解して本発明の薬物担持用担体であるポリエチレング
リコール−ポリアスパラギン酸ブロックコポリマー〔Ｐ
ＥＧ−Ｐ (Asp)〕を得る。このＰＥＧ−Ｐ(Asp) のアス
パラギン酸残基の80％がアルカリ加水分解の際にβ−ア
ミド化している。このＰＥＧ−Ｐ(Asp) に抗ガン剤のア
ドリアマイシンと水溶性カルボジイミド (ＥＤＣ) を加
えることによりアドリアマイシンの１級アミノ基とポリ
アスパラギン酸セグメントの側鎖カルボキシル基との間
にアミド結合を形成させて、高分子化医薬ＰＥＧ−Ｐ
〔Asp(ＡＤＲ) 〕を得ることにより行う。The synthesis of this polymerized drug was carried out by using β-benzyl L-aspartate N-carboxylic acid anhydride (BLA-NCA) as shown in the following reaction formula, with an alkoxy group such as a methoxy group at one end, and one end. Polyethylene glycol-poly (β-benzyl L-) was polymerized by using polyethylene glycol of primary amino group (molecular weight 250-1800) as an initiator.
Aspartate) Block Copolymer (PEG-PBL
A) is obtained, and then this PEG-PBLA is hydrolyzed with alkali to form a polyethylene glycol-polyaspartic acid block copolymer [P
EG-P (Asp)] is obtained. 80% of this aspartic acid residue of PEG-P (Asp) is β-amidated during alkaline hydrolysis. The anticancer drug adriamycin and water-soluble carbodiimide (EDC) were added to this PEG-P (Asp) to form an amide bond between the primary amino group of adriamycin and the side chain carboxyl group of the polyaspartic acid segment. , High molecular weight medicine PEG-P
This is performed by obtaining [Asp (ADR)].
【００１７】[0017]
【化６】 Embedded image
【００１８】上記において得られたＰＥＧ−Ｐ（Asp)及
びＰＥＧ−Ｐ〔Asp(ＡＤＲ）〕のいずれも化学物質とし
て新規なものである。ポリアスパラギン酸 (ＰAsp)部分
の分子量は 116から35,000まで可変であり、また、アド
リアマイシンの置換率(アスパラギン酸残基に対して)は
ＰAsp の分子量が1900の場合12〜33mol％、また、10,00
0の場合３〜37mol％のものを得ている。Both PEG-P (Asp) and PEG-P [Asp (ADR)] obtained above are novel chemical substances. The molecular weight of the polyaspartic acid (PAsp) portion can be varied from 116 to 35,000, and the substitution rate of adriamycin (based on the aspartic acid residue) is 12 to 33 mol% when the molecular weight of PAsp is 1900, and 10, 00
In the case of 0, 3 to 37 mol% is obtained.
【００１９】合成した高分子医薬はいずれの場合も高い
アドリアマイシン置換率にもかからわず良好な水溶性を
有しており、凍結乾燥したり濃縮したり (アドリアマイ
シン換算 20mg/ml) してもその水溶性は保たれている。In each case, the synthesized high-molecular-weight drugs have good water solubility regardless of the high adriamycin substitution rate, and even if they are freeze-dried or concentrated (adriamycin conversion 20 mg / ml). Its water solubility is retained.
【００２０】そして、この高分子化医薬は元のアドリア
マイシン (ＡＤＲ) に比べて医薬としての高い安定性を
有している。またこの高分子化医薬は水溶液中でミセル
を形成する。そのミセルの大きさは約30nmから 200nmの
直径である。また、そのミセルを壊すには界面活性剤Ｓ
ＤＳの添加という極端にきびしい条件が必要であること
が明らかとなり、本高分子ミセルの水中での安定性が示
された。また、超音波照射、あるいは凍結乾燥によって
もミセル形成能に変化はみられなかった。合成した高分
子化医薬の抗ガン活性は表１（実施例３参照）に示すよ
うに元のアドリアマイシンよりも高いものであった。し
かもその高い抗ガン活性は元のアドリアマイシンよりも
少ない副作用の範囲で達成された。This polymerized drug has higher stability as a drug than the original adriamycin (ADR). Further, this polymerized drug forms micelles in an aqueous solution. The size of the micelle is about 30 nm to 200 nm in diameter. In order to destroy the micelle, surfactant S
It became clear that extremely severe conditions such as the addition of DS were necessary, and the stability of this polymer micelle in water was shown. In addition, the micelle forming ability was not changed by ultrasonic irradiation or freeze-drying. The anticancer activity of the synthesized polymerized drug was higher than that of the original adriamycin as shown in Table 1 (see Example 3). Moreover, its high anti-cancer activity was achieved in a range of fewer side effects than the original adriamycin.
【００２１】[0021]
〔実施例１〕β−ベンジル Ｌ−アルパルテート Ｎ−
カルボン酸無水物 (ＢＬＡ−ＮＣＡ、7.21ｇ) をＮ,
Ｎ’−ジメチルホルムアミド (ＤＭＦ) 12mlに溶かし、
クロロホルム60mlを加える。片末端メトキシ基片末端ア
ミノ基のポリエチレングリコール (分子量4300) 6.00ｇ
をクロロホルム60mlに溶かしてその溶液をＢＬＡ−ＮＣ
Ａ溶液に加える。70時間後に反応混合液を２Lのジエチ
ルエーテルに滴下して沈澱したポリマーをろ過で回収し
て、ジエチルエーテルで洗浄した後に真空で乾燥してポ
リエチレングリコール−ポリ (β−ベンジル Ｌ−アス
パルテート) ブロックコポリマー (ＰＥＧ−ＰＢＬＡ)
を得る。収量 10.09ｇ (84％)。[Example 1] β-benzyl L-alpartate N-
Carboxylic anhydride (BLA-NCA, 7.21 g) was added to N,
Dissolve in 12 ml of N'-dimethylformamide (DMF),
Add 60 ml of chloroform. One end methoxy group One end amino group polyethylene glycol (molecular weight 4300) 6.00 g
Is dissolved in 60 ml of chloroform and the solution is BLA-NC
Add to solution A. After 70 hours, the reaction mixture was added dropwise to 2 L of diethyl ether, and the precipitated polymer was collected by filtration, washed with diethyl ether, and dried in vacuum to remove polyethylene glycol-poly (β-benzyl L-aspartate) block. Copolymer (PEG-PBLA)
Get. Yield 10.09 g (84%).
【００２２】ＰＥＧ−ＰＢＬＡ 10.03ｇを１00mlクロロ
ホルムに溶かす。水：メタノール：１−プロパノール＝
１：１：２ (体積割合) に水酸化ナトリウムを0.43Ｎ溶
かしたアルカリ混合液をＰＥＧ−ＰＢＬＡ溶液に加え
る。そのアルカリの等量はＰＢＬＡ部分のベンジルエス
テルの1.５倍になるようにした。０℃、10分かくはん
後、２Lのジエチルエーテルに滴下する。沈澱したポリ
マーをろ別して、20mlの蒸留水に溶かしてSpectrapor７
透析膜 (分子量分画＝1000) を用いて水中で39時間透析
する。膜内の溶液を凍結乾燥してポリエチレングリコー
ル−ポリアスパラギン酸ブロックコポリマー〔ＰＥＧ−
Ｐ（Asp)〕を得る。収量3.94ｇ (49％) 。このブロック
コポリマー鎖１本当り、17個のアスパラギン酸残基があ
ることがプロトンＮＭＲの測定によりわかった。PEG-PBLA 10.03 g is dissolved in 100 ml chloroform. Water: methanol: 1-propanol =
An alkali mixed solution prepared by dissolving 0.43 N of sodium hydroxide in a ratio of 1: 1: 2 (volume ratio) is added to the PEG-PBLA solution. The equivalent amount of the alkali was set to be 1.5 times that of the benzyl ester of the PBLA portion. After stirring at 0 ° C for 10 minutes, the mixture was added dropwise to 2 L of diethyl ether. The precipitated polymer was filtered off and dissolved in 20 ml of distilled water to prepare Spectrapor 7
Dialyze for 39 hours in water using a dialysis membrane (molecular weight fraction = 1000). The solution in the membrane was freeze-dried to obtain a polyethylene glycol-polyaspartic acid block copolymer [PEG-
P (Asp)]. Yield 3.94 g (49%). It was found by proton NMR measurement that there were 17 aspartic acid residues in each block copolymer chain.
【００２３】この〔ＰＥＧ−Ｐ（Asp)〕230.3mg を１ml
の蒸留水に溶かしておく。アドリアマイシン塩酸塩349.
2 mgを 260mlのＤＭＦに溶かし、1.３倍等量のトリエチ
ルアミンを加える。アドリアマイシン溶液に〔ＰＥＧ−
Ｐ（Asp)〕水溶液を加え、さらに水溶性カルボジイミド
(ＥＤＣ) を 886ml加えて、０℃で４時間かくはんす
る。その後、水溶性カルボジイミド 886mlをもう一度加
えて室温下19時間かくはんする。反応混合液をSpectrap
or７透析膜 (分子量分画＝1000) を用いて0.１Ｍ酢酸ナ
トリウム緩衝液(pＨ4.5)中で３時間透析する。透析後、
AmiconYM30の膜で限外濾過して未反応のアドリアマイシ
ンやその他の低分子物を除く。得られたブロックコポリ
マーＰＥＧ−Ｐ〔Asp(ＡＤＲ) 〕中のアドリアマイシン
含率は、アスパラギン酸残基に対して 31mol％であっ
た。(485nmの吸収より) 同様の手順で、ポリエチレング
リコールの分子量が4000から6000、ブロックコポリマー
１本鎖当りアスパラギン酸残基が17から92まで、アドリ
アマイシン含率が９mol％から37mol％のものが合成で
き、それらはすべて良好な水溶性を示した。230.3 mg of this [PEG-P (Asp)] is added to 1 ml.
Dissolve in distilled water. Adriamycin hydrochloride 349.
Dissolve 2 mg in 260 ml DMF and add 1.3 times equivalent amount of triethylamine. Add [PEG-
P (Asp)] aqueous solution was added, and the water-soluble carbodiimide was added.
Add (886 ml) (EDC) and stir at 0 ° C. for 4 hours. Then, 886 ml of water-soluble carbodiimide is added again and the mixture is stirred at room temperature for 19 hours. Spectrap the reaction mixture
Dialyze for 3 hours in 0.1 M sodium acetate buffer (pH 4.5) using an or7 dialysis membrane (molecular weight fraction = 1000). After dialysis,
The unreacted adriamycin and other low molecular weight substances are removed by ultrafiltration with an Amicon YM30 membrane. The content of adriamycin in the obtained block copolymer PEG-P [Asp (ADR)] was 31 mol% with respect to the aspartic acid residue. (From absorption at 485 nm) Polyethylene glycol having a molecular weight of 4000 to 6000, an aspartic acid residue of 17 to 92 per block copolymer single chain, and an adriamycin content of 9 mol% to 37 mol% can be synthesized by the same procedure. , They all showed good water solubility.
【００２４】〔実施例２〕ＰＥＧ−Ｐ〔Asp(ＡＤＲ) 〕
(ＰＥＧの分子量4300、ブロックコポリマー１本鎖当り
17個のアスパラギン酸残基、アドリアマイシン 31mol％
のもの) のリン酸等張液(pＨ7.4)中でのミセル径はレー
ザー光散乱により重量平均57nm、数平均49nmと測定され
た (図５参照) 。また、図３に示すようにゲルろ過ＨＰ
ＬＣでは、界面活性剤であるドデシル硫酸ナトリウム
(ＳＤＳ) の添加により元のピークの大部分が低分子量
側に移動することより、ＳＤＳによる高分子量ミセルの
破壊が観察された。また、図４に示すように、アドリア
マイシンに基づく蛍光がミセル形成による局部的な高濃
度のために消光し、その消光がＳＤＳ添加によってミセ
ルが壊れることで解消していることがわかる。その他の
割合のものも30nmから80nmの直径を有するミセルであっ
た。Example 2 PEG-P [Asp (ADR)]
(PEG molecular weight 4300, per block copolymer single chain)
17 aspartic acid residues, adriamycin 31mol%
The average micelle diameter in the isotonic solution of phosphoric acid (pH 7.4) was measured by laser light scattering to have a weight average of 57 nm and a number average of 49 nm (see FIG. 5). In addition, as shown in FIG. 3, gel filtration HP
In LC, surfactant sodium dodecyl sulfate
Destruction of high molecular weight micelles by SDS was observed because most of the original peaks moved to the lower molecular weight side by the addition of (SDS). Further, as shown in FIG. 4, it can be seen that the fluorescence based on adriamycin is quenched due to the locally high concentration due to the formation of micelles, and the quenching is eliminated by the destruction of the micelles by the addition of SDS. Other proportions were also micelles with diameters of 30 nm to 80 nm.
【００２５】図２は pＨ7.4 のリン酸緩衝液中 (37℃)
でアドリアマイシン特有の485nm の吸収強度を経時的に
追跡したものである。アドリアマイシンが１00時間以内
にその吸収を半減するのに対し、合成された高分子化医
薬では 168時間経過後も約90％の吸収が保持され、極め
て安定であることがわかる。Figure 2 shows the pH 7.4 in phosphate buffer (37 ° C)
Fig. 4 shows the absorption intensity at 485 nm, which is peculiar to adriamycin, traced over time. Adriamycin halves its absorption within 100 hours, whereas the synthesized polymerized drug retains about 90% absorption even after 168 hours and is extremely stable.
【００２６】〔実施例３〕ＣＤＦ１メスのマウスにＰ38
8 マウス白血病細胞を106 個腹腔内に投与し、24時間後
に生理食塩水に溶かしたＰＥＧ−Ｐ〔Asp(ＡＤＲ) 〕
(ＰＥＧの分子量4300、ブロックコポリマー１本鎖当り1
7個のアスパラギン酸残基、アドリアマイシン31 mol％
のもの) 腹腔内に投与した。コントロール (１日後に生
理食塩水を投与) に対する生存日数の比 (Ｔ／Ｃ) と体
重変化を測定した。１群は６匹で行った。結果を表１に
示す。アドリアマイシン (ＡＤＲ) ではＴ／Ｃは最大 3
81％であるのに対し高分子化医薬ではＡＤＲ換算 200mg
/kg にて49０％以上という大きな値を得た。さらに副作
用の度合を示す体重減少においてもＡＤＲでＴ／Ｃが 3
81％得られた投与量において12.5％の減少を示したのに
対し、高分子化医薬では最大7.４％しか減少していな
い。このことより、合成した高分子化医薬はＡＤＲに比
較して少ない副作用で大きな抗ガン活性があることがわ
かった。[Example 3] P38 was applied to CDF1 female mice.
8 mouse leukemia cells were administered to 10 6 intraperitoneal, PEG-P dissolved in physiological saline after 24 hours [Asp (ADR)]
(PEG molecular weight 4300, 1 per block copolymer single chain)
7 aspartic acid residues, adriamycin 31 mol%
It was administered intraperitoneally. The ratio of survival days (T / C) to the control (saline was administered 1 day later) and body weight change were measured. One group consisted of 6 animals. Table 1 shows the results. Up to 3 T / C for Adriamycin (ADR)
81%, whereas high-molecular-weight drugs have ADR equivalent of 200 mg
A large value of 490% or more was obtained at / kg. In addition, T / C was 3 in ADR even in weight loss showing the degree of side effects.
81% showed a 12.5% decrease in the obtained dose, whereas the polymerized drug showed a maximum decrease of 7.4%. From this, it was found that the synthesized high molecular weight drug has a large anticancer activity with fewer side effects than ADR.
【００２７】[0027]
【表１】 表１ マウスＰ388白血病に対する抗ガン活性 ──────────────────────────────────── サンプル 投与量 中間生存 T/C(%) 体重変化 (mg/kg) 日数1) (5日目) ──────────────────────────────────── ADR 7.5 15.3 191 + 4.4 ADR 15 30.5 381 -12.5 ADR 30 6.5 81 -17.1 PEG-P(Asp(ADR)) 80 18.0 225 + 6.1 PEG-P(Asp(ADR)) 120 32.5 382 - 5.5 PEG-P(Asp(ADR)) 200 >42.0 >490 - 7.4 ──────────────────────────────────── 1)無処置：8.０〜8.６日[Table 1] Table 1 Anticancer activity against mouse P388 leukemia ──────────────────────────────────── Sample Dose Intermediate survival T / C (%) Change in body weight (mg / kg) Days 1) (Day 5) ────────────────────────── ─────────── ADR 7.5 15.3 191 + 4.4 ADR 15 30.5 381 -12.5 ADR 30 6.5 81 -17.1 PEG-P (Asp (ADR)) 80 18.0 225 + 6.1 PEG-P (Asp (ADR )) 120 32.5 382-5.5 PEG-P (Asp (ADR)) 200>42.0> 490-7.4 ──────────────────────────── ───────── 1) No treatment: 8.0-8.6 days
【００２８】[0028]
【発明の効果】本発明の高分子化医薬は薬物の担持量を
増やしても良好な水溶性を保持するとともに医薬として
高い安定性を有しており、しかも副作用も軽減され、し
たがって、本発明により極めて有用な医薬を提供するこ
とができた。INDUSTRIAL APPLICABILITY The polymerized drug of the present invention retains good water solubility even when the amount of the drug carried is increased, has high stability as a drug, and has reduced side effects. It was possible to provide an extremely useful medicine.
【図１】本発明の高分子化医薬製剤ＰＥＧ−Ｐ〔Asp(Ａ
ＤＲ) 〕の構造概略図である。FIG. 1 shows the polymerized pharmaceutical preparation PEG-P [Asp (A
DR)].
【図２】アドリアマイシン (ＡＤＲ) 及び本発明の高分
子化医薬製剤ＰＥＧ−Ｐ〔Asp(ＡＤＲ)〕の485 nmの吸
収強度の経時変化を示す図である。FIG. 2 is a diagram showing the time-dependent changes in absorption intensity at 485 nm of adriamycin (ADR) and the polymerized pharmaceutical preparation PEG-P [Asp (ADR)] of the present invention.
【図３】本発明の高分子化医薬製剤ＰＥＧ−Ｐ〔Asp(Ａ
ＤＲ)〕、及び該製剤に界面活性剤ＳＤＳを加えた場合
のゲルろ過ＨＰＬＣによる分析結果を示す図である。FIG. 3 shows a polymerized pharmaceutical preparation PEG-P [Asp (A
DR)], and the results of analysis by gel filtration HPLC when a surfactant SDS is added to the preparation.
【図４】本発明の高分子化医薬製剤ＰＥＧ−Ｐ〔Asp(Ａ
ＤＲ) 〕、及び該製剤に界面活性剤ＳＤＳを加えた場合
の蛍光分析結果を示す図である。FIG. 4 shows the polymerized pharmaceutical preparation PEG-P [Asp (A
DR)], and a fluorescence analysis result when a surfactant SDS is added to the preparation.
【図５】本発明の高分子化医薬製剤ＰＥＧ−Ｐ〔Asp(Ａ
ＤＲ) 〕のミセル径の分布状態をレーザー光散乱により
測定した結果を示す図である。FIG. 5: PEG-P [Asp (A
DR)] of micelle diameter distribution state is measured by laser light scattering.
フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０８Ｇ 69/40 ＮＳＰ Ｃ０８Ｇ 69/40 ＮＳＰ 69/48 ＮＲＨ 69/48 ＮＲＨ (72)発明者 井上 祥平 東京都豊島区千早町４−12 キャニオン マンション千早町206 (72)発明者 横山 昌幸 東京都品川区東大井５−26−25Continuation of front page (51) Int.Cl. 6 Identification number Internal reference number FI Technical display location C08G 69/40 NSP C08G 69/40 NSP 69/48 NRH 69/48 NRH (72) Inventor Shohei Inoue Toyoshima, Tokyo 4-12 Chihaya-cho, Tokyo Canyon Mansion 206, Chihaya-cho (72) Inventor Masayuki Yokoyama 5-26-25 Higashioi, Shinagawa-ku, Tokyo
Claims (7)
せしめた疎水性の薬理機能セグメントとを有するブロッ
ク共重合体からなる水溶性高分子化医薬。1. A water-soluble polymerized drug comprising a block copolymer having a hydrophilic segment and a hydrophobic pharmacologically functional segment having a drug bound to a side chain.
メントを外核とするミセルを形成するものである請求項
１記載の水溶性高分子化医薬。2. The water-soluble polymerized drug according to claim 1, which forms a micelle having a pharmacologically functional segment as an inner core and a hydrophilic segment as an outer core.
溶性高分子化医薬。3. The water-soluble polymerized drug according to claim 1, wherein the drug is an anticancer drug.
項３記載の水溶性高分子化医薬。4. The water-soluble polymerized drug according to claim 3, wherein the anticancer agent is adriamycin.
側鎖を有し、該薬物を結合した場合において疎水性とな
る第２のセグメントとからなるブロック共重合体からな
る薬物担持用担体。5. A drug-supporting carrier comprising a block copolymer composed of a hydrophilic segment and a second segment having a side chain capable of binding to a drug and being hydrophobic when the drug is bound.
を表す。)で示されるブロック共重合体。6. The following formula I: (In the formula, n is 5 to 400, m is 1 to 300, and x is an integer of 0 to 300).
で示されるブロック共重合体をアルカリ加水分解するこ
とを特徴とする請求項６記載のブロック共重合体の製造
方法。7. The following formula II: (In the formula, n represents an integer of 5 to 400 and m represents an integer of 1 to 300.)
7. The method for producing a block copolymer according to claim 6, which comprises subjecting the block copolymer represented by (4) to alkali hydrolysis.
Priority Applications (1)
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|---|---|---|---|
| JP7211596A JP2694923B2 (en) | 1995-08-21 | 1995-08-21 | Water-soluble polymerized pharmaceutical preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7211596A JP2694923B2 (en) | 1995-08-21 | 1995-08-21 | Water-soluble polymerized pharmaceutical preparation |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1116082A Division JP2517760B2 (en) | 1989-05-11 | 1989-05-11 | Water-soluble polymerized pharmaceutical preparation |
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| Publication Number | Publication Date |
|---|---|
| JPH08310970A JPH08310970A (en) | 1996-11-26 |
| JP2694923B2 true JP2694923B2 (en) | 1997-12-24 |
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ID=16608388
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7211596A Expired - Lifetime JP2694923B2 (en) | 1995-08-21 | 1995-08-21 | Water-soluble polymerized pharmaceutical preparation |
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| JP (1) | JP2694923B2 (en) |
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