JPH04173746A - Medicine-polymer complex having sustained release function - Google Patents
Medicine-polymer complex having sustained release functionInfo
- Publication number
- JPH04173746A JPH04173746A JP30552090A JP30552090A JPH04173746A JP H04173746 A JPH04173746 A JP H04173746A JP 30552090 A JP30552090 A JP 30552090A JP 30552090 A JP30552090 A JP 30552090A JP H04173746 A JPH04173746 A JP H04173746A
- Authority
- JP
- Japan
- Prior art keywords
- drug
- poly
- sustained release
- polymer
- copolymer
- 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.)
- Pending
Links
- 229920000642 polymer Polymers 0.000 title claims abstract description 21
- 238000013268 sustained release Methods 0.000 title claims abstract description 20
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 50
- 229940079593 drug Drugs 0.000 claims abstract description 46
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 38
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229920001577 copolymer Polymers 0.000 claims abstract description 19
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 19
- 239000004310 lactic acid Substances 0.000 claims abstract description 19
- 229920001610 polycaprolactone Polymers 0.000 claims abstract description 11
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims abstract description 7
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 5
- 229920002959 polymer blend Polymers 0.000 abstract description 18
- 238000002156 mixing Methods 0.000 abstract description 13
- 239000000203 mixture Substances 0.000 abstract description 12
- 150000002596 lactones Chemical class 0.000 abstract description 5
- 239000003905 agrochemical Substances 0.000 abstract description 4
- 239000002220 antihypertensive agent Substances 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract description 3
- 229940088597 hormone Drugs 0.000 abstract description 2
- 239000005556 hormone Substances 0.000 abstract description 2
- 230000006870 function Effects 0.000 abstract 1
- 239000010419 fine particle Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000011859 microparticle Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- -1 analgesic Substances 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 229920001519 homopolymer Polymers 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000002131 composite material Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000007334 copolymerization reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- ACGDKVXYNVEAGU-UHFFFAOYSA-N guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 2
- 229960003602 guanethidine Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 2
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 229930192334 Auxin Natural products 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 229930182843 D-Lactic acid Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- XACAZEWCMFHVBX-UHFFFAOYSA-N [C].[Mo] Chemical compound [C].[Mo] XACAZEWCMFHVBX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 229940124339 anthelmintic agent Drugs 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000002363 auxin Substances 0.000 description 1
- 229920005601 base polymer Polymers 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 239000000731 choleretic agent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 229940079919 digestives enzyme preparation Drugs 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 208000010824 fish disease Diseases 0.000 description 1
- 239000004083 gastrointestinal agent Substances 0.000 description 1
- 229940125695 gastrointestinal agent Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 239000002799 interferon inducing agent Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 208000022196 parasitic skin disease Diseases 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 239000003016 pheromone Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000003375 plant hormone Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 238000006068 polycondensation reaction Methods 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、医薬品、農薬等の薬剤の徐放性機能を有する
薬剤・ポリマー複合体に関するものである。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a drug/polymer complex having a sustained release function for drugs such as pharmaceuticals and agricultural chemicals.
（従来の技術）
近年１分解性ポリマーは、医薬品、農薬等の薬剤の放出
を制御するためのシステム（Ｄ Ｄ Ｓ ；Ｄｒａｇｄ
ｅｌｉｖｅｒｙ Ｓｙｓｔｅｍ）用の基剤として種々の
検討が試みられている。(Prior Art) In recent years, monodegradable polymers have been developed into systems for controlling the release of drugs such as pharmaceuticals and agricultural chemicals (DDS; DragD).
Various studies have been attempted as a base material for the ``everyday system''.
従来より３ これらＤＤＳ基剤として９例えば。Conventionally, there are 3 and 9 examples of these DDS bases.
特開昭６２−２５１２１号公報に示されたごとくのポリ
乳酸、ポリグリコール酸等のホモポリマーが知られてい
る。しかし、これらホモポリマーは。Homopolymers such as polylactic acid and polyglycolic acid are known as disclosed in JP-A-62-25121. However, these homopolymers.
−ＩＩＩＱに結晶性であり、ＤＤＳＭ剤としては次のよ
うな問題点が残る。すなわち、結晶性ポリマーは。-IIIQ is crystalline, and the following problems remain as a DDSM agent. That is, crystalline polymers.
分解速度が遅いため、■薬剤が放出してくるまでの時間
が長すぎる。■薬剤の放出速度が遅すぎる等である。Because the decomposition rate is slow, it takes too long for the drug to be released. ■The drug release rate is too slow.
これらのホモポリマーよりなる基剤における問題点を解
決するため１例えば、特開昭６３−２１８６３２号公報
に示されたごとくの乳酸とグリコール酸との共重合体が
開発された。さらに９例えば、特開平１−９６１３９号
公報に示されたごとくの乳酸・グリコール酸・ラクトン
類の三成分の共重合体も開発されている。In order to solve the problems associated with these homopolymer bases, a copolymer of lactic acid and glycolic acid was developed, as disclosed in, for example, Japanese Patent Application Laid-Open No. 63-218632. Furthermore, for example, a three-component copolymer of lactic acid, glycolic acid, and lactones has been developed as shown in JP-A-1-96139.
（発明が解決しようとする課題）
しかしながら、上記のような共重合体においても、いく
つかの問題点があり、未だ満足すべきＤＤＳ基剤が見出
されていないのが現状である。(Problems to be Solved by the Invention) However, even the copolymers described above have some problems, and at present no satisfactory DDS base has yet been found.
この問題点とは、すなわち、■得られた共重合体は大部
分が非品性部分であるため、薬剤の放出速度が速すぎる
。特に、初期のうちに多くの薬剤が放出されてしまう。These problems are as follows: (1) Since most of the obtained copolymer is a non-quality portion, the drug release rate is too fast. In particular, a large amount of drug is released in the early stages.
■共重合組成すなわち、乳酸／グリコール酸あるいは乳
酸／グリコール酸／ラクトン類の混合割合のわずかな変
化により薬剤の放出速度が栄、激に変動するため、望ま
しい放出速度を得ることが非常に困難である。■さらに
。■It is extremely difficult to obtain the desired release rate because the drug release rate fluctuates dramatically due to slight changes in the copolymer composition, that is, the mixing ratio of lactic acid/glycolic acid or lactic acid/glycolic acid/lactones. be. ■Furthermore.
得られる共重合体の共重合組成は、必ずしも仕込みのモ
ノマーの組成と一致しないため、所定の共重合組成の基
剤を得ることが困難である等である。Since the copolymerization composition of the obtained copolymer does not necessarily match the composition of the monomers used, it is difficult to obtain a base having a predetermined copolymerization composition.
（課題を解決するための手段）
本発明者らは、上記の問題点を解決し、所望される薬剤
放出挙動を示すＤＤＳ基剤を得るべく鋭意研究を重ねた
結果、乳酸・グリコール酸共重合体とラクトン類の重合
体との混合物がＤＤＳ基剤として優れているという事実
を見出し２本発明に至ったものである。(Means for Solving the Problems) As a result of intensive research to solve the above-mentioned problems and obtain a DDS base exhibiting the desired drug release behavior, the present inventors have developed a lactic acid/glycolic acid copolymer. The present invention was based on the discovery that a mixture of a polymer and a lactone polymer is excellent as a DDS base.
すなわち１本発明は、 （Ａ）乳酸およびグリコール酸
の共重合体と（Ｂ）ポリ−γ−ブチロラクトン、ポリ−
δ−バレロラクトンおよび／またはポリ−ε−カプロラ
クトンとが重量比として（Ａ）／（Ｂ）＝１０／９０〜
９０／１０の範囲で混合されたポリマー混合物に薬剤を
含有させた徐放性機能を有する薬剤・ポリマー複合体を
要旨とするものである。That is, 1 the present invention comprises (A) a copolymer of lactic acid and glycolic acid, and (B) poly-γ-butyrolactone, poly-
The weight ratio of δ-valerolactone and/or poly-ε-caprolactone is (A)/(B)=10/90~
The gist of the invention is a drug-polymer composite having a sustained release function in which a drug is contained in a polymer mixture having a ratio of 90/10.
以下に９本発明の詳細な説明する。Below, nine detailed explanations of the present invention will be given.
本発明における（Ａ）乳酸およびグリコール酸の共重合
体に用いられる乳酸としては、Ｄ体、Ｌ体、ＤＬ体ある
いはそれらの任意の混合物のいずれであってもよい。ま
た、（Ａ）成分の組成比としては、乳酸／グリコール酸
モル比が１０／９０〜９０／１０のものが望ましい。こ
の範囲を逸脱すると、 （Ａ）および（Ｂ）の混合によ
り得られるポリマー混合物の結晶性が高く１分解速度が
遅くなり、含有させた薬剤の放出速度が著しく遅くなる
ので望ましくない。さらに、（Ａ）の数平均分子量につ
いては、ｉ、ｏｏｏ以上とすることが望ましい。この数
平均分子量が１． ＯＯＯを下回ると。The lactic acid used in the copolymer of lactic acid and glycolic acid (A) in the present invention may be D-form, L-form, DL-form, or any mixture thereof. Further, as for the composition ratio of component (A), it is desirable that the lactic acid/glycolic acid molar ratio is 10/90 to 90/10. If it deviates from this range, the polymer mixture obtained by mixing (A) and (B) will have high crystallinity and the decomposition rate will be slow, which is undesirable since the release rate of the contained drug will be extremely slow. Furthermore, the number average molecular weight of (A) is preferably i,ooo or more. This number average molecular weight is 1. When it falls below OOO.
（Ａ）および（Ｂ）の混合により得られるポリマー混合
物の分解速度が速くなり、含有させた薬剤の放出速度が
極端に速くなるので好ましくない。Mixing (A) and (B) increases the decomposition rate of the polymer mixture obtained, and the release rate of the contained drug becomes extremely rapid, which is not preferable.
上記した（Ａ）を得るための方法としては、乳酸とグリ
コール酸とを強酸性イオン交換樹脂または無機固体酸触
媒の存在下に重縮合させるか、あるいは無触媒で縮合さ
せ水を除去した後重縮合させる方法などが挙げられる。As a method for obtaining the above-mentioned (A), lactic acid and glycolic acid are polycondensed in the presence of a strongly acidic ion exchange resin or an inorganic solid acid catalyst, or they are condensed without a catalyst, water is removed, and then polycondensation is performed. Examples include a method of condensation.
本発明で用いられる（Ｂ）ポリーγ−ブチロラクトン、
ポリ−δ−バレロラクトンおよび／またはポリ−ε−カ
プロラクトンとしては、これら三種類のポリマーの任意
のものでよいが、ポリ−ε−カプロラクトンが特に好ま
しく用いられる。これらラクトン系の数平均分子量とし
ては、６，０００以上のものが望ましい。この数平均分
子量が６゜０００を下回ると、 （Ａ）および（Ｂ）の
混合により得られるポリマー混合物の分解速度が速くな
るため、含有させた薬剤の放出速度が著しく速くなるた
め望ましくない。(B) poly γ-butyrolactone used in the present invention,
As poly-[delta]-valerolactone and/or poly-[epsilon]-caprolactone, any of these three types of polymers may be used, but poly-[epsilon]-caprolactone is particularly preferably used. The number average molecular weight of these lactones is preferably 6,000 or more. If the number average molecular weight is less than 6.000, the decomposition rate of the polymer mixture obtained by mixing (A) and (B) will increase, which is undesirable because the release rate of the contained drug will increase significantly.
（Ｂ）としてポリーγ−ブチロラクトン、ポリ−δ−バ
レロラクトンおよび／またはポリ−ε−カプロラクトン
のうちの２種類または３種類を混合する場合の混合比は
特に限定されないが、ポリ−ε−カプロラクトンが重量
比として５０％以上含有されることが望ましい。The mixing ratio when mixing two or three of poly-γ-butyrolactone, poly-δ-valerolactone and/or poly-ε-caprolactone as (B) is not particularly limited, but poly-ε-caprolactone is It is desirable that the content is 50% or more by weight.
上記の（Ｂ）を得るための方法としては、 Ｔ −ブ
チロラクトン、δ−バレロラクトンまたはε−カプロラ
クトンをモリブデンの炭素化合物やハロゲン化第１スズ
の存在下て゛開環重合させる方法などが挙げられる。Examples of the method for obtaining the above (B) include a method in which T-butyrolactone, δ-valerolactone or ε-caprolactone is subjected to ring-opening polymerization in the presence of a molybdenum carbon compound or stannous halide.
本発明で用いられるポリマー混合物は、上記した（Ａ）
と（Ｂ）とが重量比として１０／９０〜９０／１０の範
囲で混合されていることが必要である。この場合に、こ
の重量比が９０／１０を上回り（Ａ）が多くなると、得
られたポリマー混合物は、大部分が非結晶性部分である
ため１分解速度が速（、含有させた薬剤の放出速度が速
すぎて好ましくないものとなる。反対に９重量比が１０
／９０を下回り（Ｂ）が多くなると、得られたボリマー
混合物は、乳酸、グリコール酸等のホモポリマーと同様
、結晶性部分が多くなりすぎるため。The polymer mixture used in the present invention is the above-mentioned (A)
and (B) must be mixed in a weight ratio of 10/90 to 90/10. In this case, if the weight ratio exceeds 90/10 and the amount of (A) increases, the resulting polymer mixture will have a high decomposition rate (i.e., release of the contained drug) because most of the polymer mixture is amorphous. The speed is too high and becomes undesirable.On the other hand, if the weight ratio of 9 is 10
If (B) is less than /90 and increases, the resulting polymer mixture will have too many crystalline portions, similar to homopolymers such as lactic acid and glycolic acid.
分解速度が遅く、含有させた薬剤の放出速度が遅すぎて
好ましくないものとなる。The rate of decomposition is slow, and the rate of release of the contained drug is too slow, making it undesirable.
本発明で用いられる薬剤としては、薬剤の＃１類には特
に限定されるものではないが、好ましくは。The drugs used in the present invention are not particularly limited to #1 drugs, but are preferred.
ホルモン剤、抗癌剤、抗生物質、血圧降下剤、血管拡張
剤、血管補強剤、健胃消化剤、整腸剤、避妊剤、外皮用
殺菌消毒剤、寄生性皮膚疾患用剤。Hormone agents, anti-cancer agents, antibiotics, antihypertensive agents, vasodilators, vascular reinforcing agents, gastrointestinal agents, intestinal regulation agents, contraceptives, disinfectants for the skin, and agents for parasitic skin diseases.
消炎剤、鎮痛剤、利胆剤、抗リウマチ剤１強心剤。Anti-inflammatory agent, analgesic, choleretic agent, anti-rheumatic agent, 1 cardiotonic agent.
病治療剤２便秘治療剤、ビタミン剤、各種酵素製剤、ワ
クチン類、抗原虫剤、インターフェロン誘起物質、駆虫
剤、魚病薬、農薬、オーキシン、植物ホルモン、昆虫フ
ェロモン等の薬物があげられる。これらの薬剤のうち、
特に抗癌剤、ホルモン剤、抗生物質、血圧降下剤が好ま
しく用いられる。Disease Treatment Agents 2 Drugs include constipation treatment agents, vitamin preparations, various enzyme preparations, vaccines, antiprotozoal agents, interferon inducers, anthelmintics, fish disease drugs, agricultural chemicals, auxins, plant hormones, and insect pheromones. Of these drugs,
In particular, anticancer agents, hormonal agents, antibiotics, and antihypertensive agents are preferably used.
以下１本発明の薬剤・ポリマー複合体の製造法を説明す
る。A method for producing the drug-polymer complex of the present invention will be described below.
本発明の薬剤・ポリマー複合体は、（Ａ）と（Ｂ）の混
合物に薬剤が含有されておればよく。The drug/polymer complex of the present invention only needs to contain the drug in a mixture of (A) and (B).
その製造方法は特に限定されるものではないが。The manufacturing method is not particularly limited.
例えば、（Ａ）と（Ｂ）とを混合してポリマーの混合物
を作製した後、これに薬剤を含有させることにより製造
することができる。For example, it can be produced by mixing (A) and (B) to prepare a polymer mixture, and then adding a drug to the polymer mixture.
（Ａ）と（Ｂ）を混合するためには、ニーダ−。A kneader is used to mix (A) and (B).
エクストルーダー等を使用して、１５０〜２００°Ｃで
１〜３時間溶融混合するか、 （Ａ）および（Ｂ）を常
温で共通溶媒中で１０〜３０分攪拌して溶解させた後、
有機溶媒を除去すればよい。ここで用いられる共通溶媒
としては、ジクロロメタン、 １，１，１，３，３．３
−ヘキサフルオロイソプロパツール等の有機溶媒が挙げ
られる。Using an extruder or the like, melt and mix at 150 to 200°C for 1 to 3 hours, or stir and dissolve (A) and (B) in a common solvent at room temperature for 10 to 30 minutes, and then
The organic solvent may be removed. Common solvents used here include dichloromethane, 1,1,1,3,3.3
-Organic solvents such as hexafluoroisopropanol.
上記のようにして得られるポリマー混合物の形状として
は、結晶性固体、ワックス状、ペースト状などが挙げら
れる。The shape of the polymer mixture obtained as described above includes crystalline solid, waxy, pasty, and the like.
次に、上記のような方法により得られたポリマーの混合
物に薬剤を含有させる方法としては、ポリマー混合物を
薬剤溶液に浸漬する方法や、ポリマー混合物を再び溶融
あるいは（Ａ）と（Ｂ）との共通溶媒中に溶解させたも
のに、薬剤または薬剤溶液を混合、攪拌した後、冷却あ
るいは共通溶媒を除去する方法などが挙げられる。この
ような方法によって得られる薬剤・ポリマー複合体の形
状は、微粒子状、ペレット状、シート状、ペースト状な
どになる。Next, methods for incorporating a drug into the polymer mixture obtained by the above method include immersing the polymer mixture in a drug solution, melting the polymer mixture again, or combining (A) and (B). Examples include a method in which a drug or drug solution is mixed with something dissolved in a common solvent, stirred, and then cooled or the common solvent is removed. The shape of the drug/polymer complex obtained by such a method is fine particles, pellets, sheets, pastes, etc.
このようにして得られる本発明の徐放性機能を有する薬
剤・ポリマー複合体は、徐放特性に優れ。The drug/polymer complex having a sustained release function of the present invention thus obtained has excellent sustained release properties.
広範な用途に適用し得るものである。本発明の薬剤・ポ
リマー複合体を１例えば疾患の治療薬を徐放化させる目
的で使用する場合には、これを微粒子状として作製した
ものを懸濁注射液などに分散した後、皮下あるいは筋肉
注射するか、ペレット状として作製したものを患部に埋
め込むことなどによって使用することができる。It can be applied to a wide range of applications. When the drug/polymer complex of the present invention is used for the purpose of sustained release of a therapeutic drug for a disease, for example, it is prepared in the form of fine particles and dispersed in a suspension injection solution, then subcutaneously or intramuscularly. It can be used by injecting it or by making it into a pellet and embedding it in the affected area.
（実施例）
以下に１本発明の実施例を掲げてさらに説明する。なお
、実施例中、微粒子の平均粒子径の測定法及び微粒子中
の薬剤の含有量（重量％）の測定は以下のようにして行
った。すなわち、微粒子の平均粒子径は、レーザー回折
弐粒度分布測定装置（堀場製作所製）により測定した。(Example) Below, an example of the present invention will be further explained. In the Examples, the method for measuring the average particle diameter of the fine particles and the content (wt%) of the drug in the fine particles were carried out as follows. That is, the average particle diameter of the fine particles was measured using a laser diffraction particle size distribution measuring device (manufactured by Horiba, Ltd.).
また、微粒子中の薬剤の含有量（重量％）は、塩化メチ
レン／水あるいはアセトニトリル／水混液に所定量の微
粒子を添加して薬剤を抽出させた後、抽出液中の薬剤量
を高速液体クロマトグラフィー（日立製作所型、Ｌ−５
０００）を用いて定量することにより求めた。The content (wt%) of the drug in the microparticles can be determined by adding a predetermined amount of microparticles to a methylene chloride/water or acetonitrile/water mixture to extract the drug, and then measuring the amount of the drug in the extract using high-performance liquid chromatography. Graphy (Hitachi model, L-5
000).
実施例１
乳酸・グリコール酸共重合体（和光純薬工業■製；モル
比７５／２５．平均分子量１０，０００）およびポリ−
ε−カプロラクトン（開環重合法。Example 1 Lactic acid/glycolic acid copolymer (manufactured by Wako Pure Chemical Industries, Ltd.; molar ratio 75/25, average molecular weight 10,000) and poly-
ε-caprolactone (ring-opening polymerization method.
平均分子１８０，０００）を０．６ｇずつジクロロメタ
ン８Ｉ１１に溶解させた。他方、インシュリン（抗生物
質）１００■を２０％ゼラチン水溶液０．８ ｄに溶解
させた。両者を混合して、ホモジナイザー（ヤマト科学
製；ＬＫ−２２）を用い、８０００ｒｐｍにて１分間攪
拌した。(average molecular weight 180,000) was dissolved in 0.6 g portions in dichloromethane 8I11. On the other hand, 100 ml of insulin (antibiotic) was dissolved in 0.8 d of a 20% gelatin aqueous solution. Both were mixed and stirred for 1 minute at 8000 rpm using a homogenizer (LK-22, manufactured by Yamato Kagaku).
得られたＷ１０型エマルジョン８ｍを０．２５ ｗ／Ｖ
％ポリビニルアルコール（ユニチカ■製；平均分子！８
８，０００．ケン化度８８モル％）水溶液５００−に投
入し、ラボスターラー（東京理化器械■製；ＤＣ−２３
）を用い、５００ｒｐｍにて２４時間撹拌して、液中乾
燥を行った。これを凍結乾燥し１本発明の徐放性を有す
る薬剤・ポリマー複合体よりなる微粒子を得た。8 m of the obtained W10 type emulsion was heated to 0.25 w/V.
% polyvinyl alcohol (manufactured by Unitika ■; average molecule!8
8,000. saponification degree 88 mol%) aqueous solution 500-, and a laboratory stirrer (manufactured by Tokyo Rikakikai ■; DC-23).
) and was stirred at 500 rpm for 24 hours to perform in-liquid drying. This was freeze-dried to obtain microparticles of the drug/polymer complex having sustained release properties according to the present invention.
この微粒子の平均粒子径は８０μｍ、微粒子全重量に対
する含有薬剤の重量％は５．１％であった。The average particle diameter of the fine particles was 80 μm, and the weight percent of the drug contained in the fine particles was 5.1% based on the total weight of the fine particles.
この微粒子の混合比、（Ａ）と（Ｂ）の平均分子量等を
表１に示す。The mixing ratio of the fine particles, the average molecular weights of (A) and (B), etc. are shown in Table 1.
参考例１
実施例１で得られた薬剤・ポリマー複合体からのインシ
ュリンのｉｎνｉ ｔｒｏにおける溶出挙動を測定した
。溶出試験において、媒液は生理食塩水を用い、ウォー
ターバスインキュベーター（ヤマト科学■製；ＢＴ−４
７）中で３７°ｃ、ｔｏｏ回／分の振盪条件にて溶出さ
せた。この結果を図１に示す。Reference Example 1 The in vitro elution behavior of insulin from the drug/polymer complex obtained in Example 1 was measured. In the elution test, physiological saline was used as the medium, and a water bath incubator (manufactured by Yamato Scientific; BT-4) was used.
7) under conditions of shaking at 37°C and too many times/min. The results are shown in FIG.
なお、インシュリンの濃度は、高速液体クロマトグラフ
ィーを用いて測定した。液体クロマトグラフィーによる
測定において、カラムは逆相カラム（旭化成■製造；
Ａｓａｈｉｐａｋ ＯＤ Ｐ −５０） 。Note that the insulin concentration was measured using high performance liquid chromatography. In liquid chromatography measurements, the column is a reverse phase column (manufactured by Asahi Kasei;
Asahipak OD P-50).
移動相にはアセトニトリル／水（３２／６ Ｂ ）混合
溶媒を用いた。An acetonitrile/water (32/6 B) mixed solvent was used as the mobile phase.
実施例２〜８
表１に示すごとくの乳酸およびグリコール酸共重合体の
モル比、平均分子量、ポリ−ε−カプロラクトンの分子
量、乳酸およびグリコール酸共重合体とポリ−ε−カプ
ロラクトンとの混合比（重量比）にて、実施例１と同様
の操作により本発明の徐放性を有する薬剤・ポリマー複
合体よりなる微粒子を得た（実施例２〜８）。Examples 2 to 8 Molar ratio of lactic acid and glycolic acid copolymer, average molecular weight, molecular weight of poly-ε-caprolactone, and mixing ratio of lactic acid and glycolic acid copolymer and poly-ε-caprolactone as shown in Table 1 (weight ratio), microparticles made of the drug/polymer composite having sustained release properties of the present invention were obtained by the same operation as in Example 1 (Examples 2 to 8).
これら微粒子の物性値として、平均粒子径は表１に示し
たとおりであった。さらに、このポリマー混合物微粒子
からのインシュリンのｉｎ ｖｉｔｒ。As for the physical property values of these fine particles, the average particle diameter was as shown in Table 1. Furthermore, in vitro production of insulin from this polymer mixture microparticles.
における徐放挙動を図１．２に示した。図１中の○は実
施剥し・は実施例２．△は実施例３．ムは実施例４の徐
放挙動をそれぞれ示し、また図２中の口は実施例５．■
は実施例６．■は実施例７゜マは実施例８の徐放挙動を
それぞれ示す。Figure 1.2 shows the sustained release behavior. In Figure 1, ○ indicates the actual product was removed, and indicates Example 2. △ indicates Example 3. 2 shows the sustained release behavior of Example 4, and the mouth in FIG. 2 shows the sustained release behavior of Example 5. ■
Example 6. (2) shows the sustained release behavior of Example 7, and (2) shows the sustained release behavior of Example 8.
表 １
表 ２
比較例１〜４
比較のため、乳酸およびグリコール酸の共重合体とポリ
−ε−カプロラクトンの混合比（重量比）が本発明の特
許請求の範囲（１０／９０〜９０／１０）外のポリマー
混合物を、実施例と１同様の操作により作製した。Table 1 Table 2 Comparative Examples 1 to 4 For comparison, the mixing ratio (weight ratio) of the copolymer of lactic acid and glycolic acid to poly-ε-caprolactone was within the claimed range of the present invention (10/90 to 90/10). ) Polymer mixtures were prepared in the same manner as in Example 1.
これら微粒子の物性値として、平均粒子径、基剤ポリマ
ーに対する薬剤の重量％は２表２に示したとおりである
。さらに、このポリマー混合物微粒子からのインシュリ
ンのｉｎ ｖｉｔｒｏにおける徐放挙動を図３に示した
。図３中Ｏは比較例］、０は比較例２．８は比較例３．
Ｑは比較例４の徐放挙動をそれぞれ示す。As for the physical properties of these fine particles, the average particle diameter and the weight percent of the drug relative to the base polymer are as shown in Table 2. Furthermore, the in vitro sustained release behavior of insulin from this polymer mixture microparticle is shown in FIG. In FIG. 3, O is Comparative Example], 0 is Comparative Example 2.8 is Comparative Example 3.
Q indicates the sustained release behavior of Comparative Example 4, respectively.
実施例９〜１２
実施例１と同じ乳酸およびグリコール酸共重合体のモル
比、平均分子量、ポリ−ε−カプロラクトンの分子量、
乳酸およびグリコール酸共重合体とポリ−ε−カプロラ
クトンとの混合比にて、実施例１と同様の操作によって
、薬剋としてアドリアマイシン（抗癌剤、実施例９）、
メトトレキセ−ト（抗ＦｆＡ荊３実施例１０）、エリス
ロマイシン（抗生物質、実施例１１）、グアネチジン（
血圧降下剤、実施例１２）を用いて１本発明の徐放性機
能を有する薬剤・ポリマー複合体よりなる微粒子を得た
。Examples 9 to 12 Same molar ratio of lactic acid and glycolic acid copolymer as in Example 1, average molecular weight, molecular weight of poly-ε-caprolactone,
Adriamycin (anticancer drug, Example 9) as a drug was prepared using the same procedure as in Example 1 using the mixing ratio of lactic acid and glycolic acid copolymer and poly-ε-caprolactone.
Methotrexate (anti-FfA 荊3 Example 10), erythromycin (antibiotic, Example 11), guanethidine (
Using a hypotensive agent (Example 12), microparticles made of a drug/polymer composite having a sustained release function of the present invention were obtained.
アドリアマイシン。メトトレキセート、エリスロマイシ
ン、グアネチジンのｉｎν１ｔｒｏにおける徐放挙動を
図４に示した。図４中＋は実施例９゜×は実施例１０．
０は実施例１１．・は実施例１２の徐放挙動をそれぞれ
示す。Adriamycin. The sustained release behavior of methotrexate, erythromycin, and guanethidine in 1tro is shown in FIG. 4. In FIG. 4, + indicates Example 9. × indicates Example 10.
0 is Example 11. * indicates sustained release behavior of Example 12, respectively.
（発明の効果）
本発明の薬剤・ポリマー複合体は５初朋において象徴な
薬剤放出をみることがなく、シかも作製時に（Ａ）及び
（Ｂ）の組成を変化させることに基づき所望の薬剤放出
挙動を具備させることができる。(Effects of the Invention) The drug-polymer complex of the present invention does not show typical drug release in the first five days, and the desired drug can be produced by changing the compositions of (A) and (B) during production. release behavior.
第１図は１本発明の実施例１〜４における溶出挙動を示
す図である。
挙動を示す図である。
第３０は、本発明の実施例１及び比較例１〜４におりる
溶出挙動を示す図である。
第４図は２本発明の実施例９〜１２における溶出挙動を
示す図である。FIG. 1 is a diagram showing elution behavior in Examples 1 to 4 of the present invention. It is a diagram showing behavior. 30th is a diagram showing elution behavior in Example 1 of the present invention and Comparative Examples 1 to 4. FIG. 4 is a diagram showing elution behavior in Examples 9 to 12 of the present invention.
Claims (1)
）ポリ−γ−ブチロラクトン、ポリ−δ−バレロラクト
ンおよび／またはポリ−ε−カプロラクトンとが重量比
として（Ａ）／（Ｂ）＝１０／９０〜９０／１０の範囲
で混合されたポリマー混合物に薬剤を含有させた徐放性
機能を有する薬剤・ポリマー複合体。(1) (A) copolymer of lactic acid and glycolic acid and (B)
) Poly-γ-butyrolactone, poly-δ-valerolactone and/or poly-ε-caprolactone are mixed in a weight ratio of (A)/(B) in the range of 10/90 to 90/10. A drug/polymer complex that contains a drug and has a sustained release function.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30552090A JPH04173746A (en) | 1990-11-07 | 1990-11-07 | Medicine-polymer complex having sustained release function |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30552090A JPH04173746A (en) | 1990-11-07 | 1990-11-07 | Medicine-polymer complex having sustained release function |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04173746A true JPH04173746A (en) | 1992-06-22 |
Family
ID=17946142
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP30552090A Pending JPH04173746A (en) | 1990-11-07 | 1990-11-07 | Medicine-polymer complex having sustained release function |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04173746A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994011441A1 (en) * | 1992-11-06 | 1994-05-26 | Rijksuniversiteit Te Groningen | Rubber-modified polylactide and/or glycolide composition |
| US5594091A (en) * | 1994-02-21 | 1997-01-14 | Takeda Chemical Industries, Ltd. | Matrix for sustained-release preparation |
| JP2006213600A (en) * | 2005-02-01 | 2006-08-17 | Kawasumi Lab Inc | Sustained release system of medicine |
| JP2009029821A (en) * | 1994-04-08 | 2009-02-12 | Qlt Usa Inc | Liquid delivery composition |
| WO2010026760A1 (en) * | 2008-09-03 | 2010-03-11 | 富士フイルム株式会社 | Compositions wherein bioactive components are stably sealed |
| WO2012171084A1 (en) * | 2011-06-13 | 2012-12-20 | Universidade Federal Do Rio De Janeiro - Ufrj | Polymer insulin encapsulation system, process and use of said system |
-
1990
- 1990-11-07 JP JP30552090A patent/JPH04173746A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994011441A1 (en) * | 1992-11-06 | 1994-05-26 | Rijksuniversiteit Te Groningen | Rubber-modified polylactide and/or glycolide composition |
| US5594091A (en) * | 1994-02-21 | 1997-01-14 | Takeda Chemical Industries, Ltd. | Matrix for sustained-release preparation |
| US5665394A (en) * | 1994-02-21 | 1997-09-09 | Takeda Chemical Industries, Ltd. | Matrix for sustained-release preparation |
| JP2009029821A (en) * | 1994-04-08 | 2009-02-12 | Qlt Usa Inc | Liquid delivery composition |
| JP2006213600A (en) * | 2005-02-01 | 2006-08-17 | Kawasumi Lab Inc | Sustained release system of medicine |
| WO2010026760A1 (en) * | 2008-09-03 | 2010-03-11 | 富士フイルム株式会社 | Compositions wherein bioactive components are stably sealed |
| WO2012171084A1 (en) * | 2011-06-13 | 2012-12-20 | Universidade Federal Do Rio De Janeiro - Ufrj | Polymer insulin encapsulation system, process and use of said system |
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