JPH11286439A - Biodegradable polymer-type drug release system - Google Patents
Biodegradable polymer-type drug release systemInfo
- Publication number
- JPH11286439A JPH11286439A JP10537098A JP10537098A JPH11286439A JP H11286439 A JPH11286439 A JP H11286439A JP 10537098 A JP10537098 A JP 10537098A JP 10537098 A JP10537098 A JP 10537098A JP H11286439 A JPH11286439 A JP H11286439A
- Authority
- JP
- Japan
- Prior art keywords
- release
- polylactic acid
- molecular weight
- average molecular
- drug release
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 62
- 229940079593 drug Drugs 0.000 title claims abstract description 62
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 78
- 239000004626 polylactic acid Substances 0.000 claims abstract description 78
- 238000000034 method Methods 0.000 claims abstract description 65
- 238000013268 sustained release Methods 0.000 claims abstract description 29
- 239000012730 sustained-release form Substances 0.000 claims abstract description 29
- 239000004480 active ingredient Substances 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 229920002988 biodegradable polymer Polymers 0.000 claims abstract description 14
- 239000004621 biodegradable polymer Substances 0.000 claims abstract description 14
- 238000002844 melting Methods 0.000 claims description 50
- 230000008018 melting Effects 0.000 claims description 49
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 230000003111 delayed effect Effects 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- 102000036639 antigens Human genes 0.000 claims description 4
- 108091007433 antigens Proteins 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 239000000427 antigen Substances 0.000 claims description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 2
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 2
- 229940124428 anticataract agent Drugs 0.000 claims description 2
- 239000000030 antiglaucoma agent Substances 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 238000010298 pulverizing process Methods 0.000 claims description 2
- 229960005486 vaccine Drugs 0.000 claims description 2
- 229940088623 biologically active substance Drugs 0.000 claims 2
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 claims 1
- 239000003443 antiviral agent Substances 0.000 claims 1
- 230000003115 biocidal effect Effects 0.000 claims 1
- 239000011159 matrix material Substances 0.000 abstract description 8
- 238000000465 moulding Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- 238000002255 vaccination Methods 0.000 description 7
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000013543 active substance Substances 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- 229960000448 lactic acid Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000002051 biphasic effect Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- 229920001710 Polyorthoester Polymers 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- 238000012382 advanced drug delivery Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000748 compression moulding Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000002745 poly(ortho ester) Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 1
- -1 anti-cataract agents Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000012489 doughnuts Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013269 sustained drug release Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、生分解性の埋め込
み型薬物放出システムの製造方法に関する。更に詳しく
は、本発明はポリ乳酸に基づく、徐放型、放出遅延型、
又は初期放出−放出中断−持続放出型の放出パターンを
備えた、生分解性の埋め込み型薬物放出システムの製造
方法に関する。The present invention relates to a method for producing a biodegradable implantable drug release system. More specifically, the present invention is based on polylactic acid, controlled release, delayed release,
Or, a method of making a biodegradable implantable drug release system with an initial release-interruption-sustained release pattern.
【０００２】[0002]
【従来の技術】ポリ乳酸等のような生分解性のポリマー
に基づく薬物放出が長らく検討されている。これらは、
主として長期間にわたる薬物の持続的放出を求めるもの
である。他方、２段階の放出パターン（パルス型放出パ
ターン）を作り出すための方法も試みられており、Adva
nced Drug Delivery Reviews, 1: 19-39, 1987. には乳
酸とグリコール酸との併用によるロッド型のマトリック
スが、ＷＯ ９３／００３８３には、複数のポリ（オル
トエステル）ポリマーよりなる組成物が記載されてい
る。複数のパルス状の放出パターンは、例えばワクチン
接種に適用する場合に特に好ましいと考えられている。
即ち、通常ワクチン接種には、初回接種後一定期間をあ
けて２回目の接種が行なわれるものが多く、２回目の接
種はこの場合十分な強さ及び持続性の免疫を獲得するた
めに必要である。２回目の接種は、一定の時期に行なわ
なければならず、これは接種を受ける側にとって煩わし
いことであるのみならず、地理的、経済的その他の状況
によっては、２回目の接種の機会を確保するのが困難な
場合もある。従って、１回接種すれば、所定の期間経過
後に２回目の接種も自動的に行われるよう２回又はそれ
以上に分けて抗原タンパク質を放出することのできるパ
ルス型の薬物放出システムは、感染性疾患の頻度が依然
高い地域において、予防接種に取り分け有用である。2. Description of the Related Art Drug release based on biodegradable polymers such as polylactic acid has been studied for a long time. They are,
It primarily seeks a sustained release of the drug over an extended period of time. On the other hand, a method for creating a two-step release pattern (pulse-type release pattern) has also been attempted, and Adva
nced Drug Delivery Reviews, 1: 19-39, 1987. describes a rod-type matrix using a combination of lactic acid and glycolic acid, and WO 93/00383 describes a composition comprising a plurality of poly (orthoester) polymers. Have been. Multiple pulsed release patterns are believed to be particularly preferred, for example, as applied to vaccination.
That is, most vaccinations are usually given a second time after a certain period after the first vaccination, and the second vaccination is necessary in this case to obtain sufficient strength and sustained immunity. is there. The second vaccination must be given at a certain time, which is not only troublesome for the recipient, but also depends on geographical, economic and other circumstances to secure the opportunity for the second vaccination. It can be difficult to do. Therefore, a pulse-type drug release system that can release antigen protein twice or more so that once inoculation is performed and the second inoculation is automatically performed after a predetermined period of time, the infectious It is particularly useful for vaccinations in areas where the frequency of the disease is still high.
【０００３】ポリ乳酸、ポリペプチド又はタンパク質を
薬物担体とする薬理活性物質の放出システムの製造方法
は種々報告されている。例えば特開昭６１−１７２８１
３には、生理活性物質と分子量１０００〜４０００のＤ
Ｌ−ポリ乳酸又は分子量１０００のＬ−若しくはＤ−ポ
リ乳酸を機械的に混合し、２００ｋｇ／ｃｍ2 の圧力
下、３０℃の温度において担体を加熱軟化させて得られ
る円柱状の複合体が記載されている。これにより得られ
た徐放性複合体は、生理活性物質をほぼ一定した速度で
放出する持続的放出型のシステムである（実施例２、
３、５、８、９）。また特開昭５８−１５４５０９に
は、ポリペプチドをマトリックスとして用いこれに生理
活性物質を包括させた形の持続的放出型の徐放性複合体
が開示されている。この方法により得られるものとし
て、生理活性物質の放出に100日以上を有する持続的放
出型のシステムが例示されている。特開昭５８−１７０
７１１及び特開昭５８−２２５００８にも、タンパク質
又はポリペプチドをマトリックスとして用いた、生理活
性物質の長期にわたる持続的放出型のシステムが開示さ
れている。また特開昭６２−２０７２２７は、ポリ（Ｄ
Ｌ−乳酸）（Ｍｎ＝15000）を５０ｋｇ／ｃｍ2の圧力下
で４０℃、１０秒間加熱処理して得られる放出システム
を開示しており（同公報中実施例４）、このシステム
は、約６０日程度にわたって薬物を持続的に放出する
（同公報中第４図）。更に、Drug Design and Deliver
y, 5: 301-320 (1990) は、数平均分子量（Ｍｎ）１４
００〜１６９００のポリ（ＤＬ−乳酸）を用いた薬物放
出システムを報告しており、Ｍｎ＝１６００以下ではい
わゆる放物線型の分解パターン、Ｍｎ＝２０００以上で
はＳ字型の分解パターンを示すとしている。[0003] Various methods for producing a pharmacologically active substance release system using polylactic acid, polypeptide or protein as a drug carrier have been reported. For example, JP-A-61-17281
No. 3 contains a physiologically active substance and D having a molecular weight of 1,000 to 4,000.
A columnar complex obtained by mechanically mixing L-polylactic acid or L- or D-polylactic acid having a molecular weight of 1,000 and heating and softening the support at a temperature of 30 ° C. under a pressure of 200 kg / cm 2 is described. Have been. The sustained-release complex thus obtained is a sustained-release system that releases a physiologically active substance at a substantially constant rate (Example 2,
3, 5, 8, 9). JP-A-58-154509 discloses a sustained-release sustained-release complex in which a polypeptide is used as a matrix and a physiologically active substance is included in the matrix. As a product obtained by this method, a sustained-release system having more than 100 days for releasing a bioactive substance is exemplified. JP-A-58-170
711 and JP-A-58-225008 also disclose a long-term sustained-release system of a physiologically active substance using a protein or polypeptide as a matrix. Japanese Patent Application Laid-Open No. 62-207227 discloses poly (D
A release system obtained by heat-treating L-lactic acid) (Mn = 15000) under a pressure of 50 kg / cm 2 at 40 ° C. for 10 seconds is disclosed (Example 4 in the same publication). The drug is continuously released for about 60 days (FIG. 4 in the publication). Furthermore, Drug Design and Deliver
y, 5: 301-320 (1990) has a number average molecular weight (Mn) of 14
A drug release system using a poly (DL-lactic acid) of 00 to 16900 has been reported, and a so-called parabolic decomposition pattern is shown when Mn is 1600 or less, and an S-shaped decomposition pattern is shown when Mn is 2000 or more.
【０００４】上記Advanced Drug Delivery Reviews, 1:
19-39, 1987に記載のマトリックスはポリ乳酸とポリグ
リコール酸との共重合体よりなるものであり、また上記
ＷＯ９３／００３８３は、複数の種類のポリ（オルトエ
ステル）ポリマー組成物を使用するものである。即ち、
これらの先行技術文献には、手術用縫合糸などで生体に
対する使用実績の豊富なポリ乳酸のみを用いて、２相性
の薬物放出、即ち、含有する薬物を、持続的な放出では
なく中間の休止期間を挟んで２回に分けて放出できるタ
イプのシステムは報告されていない。The above-mentioned Advanced Drug Delivery Reviews, 1:
The matrix described in 19-39, 1987 is composed of a copolymer of polylactic acid and polyglycolic acid, and the above-mentioned WO 93/00383 uses a plurality of types of poly (orthoester) polymer compositions. It is. That is,
In these prior art documents, biphasic drug release, that is, containing the drug at an intermediate pause rather than a sustained release, using only polylactic acid, which has been used for the living body such as a surgical suture, is used. No systems have been reported that can be released in two separate periods.
【０００５】一方、ポリ乳酸を用いた場合、時間経過に
ともなうポリマー内部の全体分解（bulk erosion）のた
め、含有されている薬物が相当時間経過後に急激に放出
される現象があることが認められている。その結果、あ
る時間まで持続的に放出されていた薬物がある時点から
突然急激に放出されてしまい、最後まで持続的な放出状
態を維持することが困難であった。また全体分解の起こ
る時間を制御する事も困難であり、それらが、ポリ乳酸
を用いて制御可能な所望の設計された薬物放出パターン
を達成するシステムを作り上げる上で障害となってい
た。[0005] On the other hand, when polylactic acid is used, it is recognized that there is a phenomenon that the contained drug is rapidly released after a considerable time has elapsed due to the bulk erosion of the inside of the polymer over time. ing. As a result, a drug that has been continuously released until a certain time is suddenly released from a certain point in time, and it is difficult to maintain a continuous release state until the end. Also, it is difficult to control the time at which total degradation occurs, which has been an obstacle in creating a system that achieves the desired designed drug release pattern that can be controlled using polylactic acid.
【０００６】また、持続的薬物放出のためのシステムと
しては、一般には生体内への埋め込み等の直後から薬物
を持続的に放出することが求められるが、用途によって
は、埋め込みから一定期間を経た後に薬物の放出を開始
させ且つ放出が一定期間内に行われるものが望ましい場
合もある。例えば時間的に間隔を開けて投与すべき２種
類の薬物がある場合、後で放出させるべき薬物について
は、放出の遅れを目的とした、放出遅延型のシステムが
あれば好都合である。[0006] In addition, a system for sustained drug release is generally required to release a drug continuously immediately after implantation in a living body or the like. However, depending on the application, a certain period of time has passed since implantation. It may be desirable to initiate the release of the drug at a later time and release within a certain period of time. For example, when there are two types of drugs to be administered at a time interval, it is advantageous to provide a delayed release system for delaying release of a drug to be released later.
【０００７】[0007]
【発明が解決しようとする課題】このような背景のも
と、本発明は、制御された２相性の放出、徐放、及び遅
延型の放出の何れかを選択して行わせることができる薬
物放出システムを、生分解性ポリマーであるポリ乳酸の
みをマトリクスとして用いることによって作り出すこと
を目的とする。SUMMARY OF THE INVENTION Under these circumstances, the present invention relates to a drug which can be selected from controlled biphasic release, sustained release, and delayed release. The aim is to create a release system by using only the biodegradable polymer polylactic acid as matrix.
【０００８】本発明者らは、ポリ乳酸成形物の全体分解
の開始を適切に制御することによって、２相性の薬物放
出を可能にするシステムや、徐放及び放出遅延の可能な
システムが得られるであろうと仮定し、材料及び製造方
法につき検討した。その結果、薬物放出システムの成形
を所定の工程に従って行い、これとポリ乳酸のタイプと
を組み合わせることにより、これら目的とする制御され
た薬物放出を可能にするシステムが再現性よく得られる
ことを見出し、更に検討を重ねて本発明を完成させた。By appropriately controlling the onset of the total degradation of the polylactic acid molded product, the present inventors can obtain a system capable of biphasic drug release and a system capable of sustained release and delayed release. Therefore, the material and the manufacturing method were examined. As a result, they found that a drug release system can be molded in accordance with a predetermined process, and by combining this with a type of polylactic acid, a system capable of controlling and releasing the intended drug can be obtained with good reproducibility. After further study, the present invention was completed.
【０００９】[0009]
【課題を解決するための手段】即ち本発明は、重量平均
分子量（Ｍｗ）３０００〜４００００を有する粉砕した
ポリ乳酸を粉末状の生物学的活性成分と混合し、混合物
を型に入れ、５０〜１００℃の範囲の温度に加熱してポ
リ乳酸を軟化させつつかさ密度７００〜４０００ｍｇ／
ｃｍ3に圧縮して所定の形状に成形することを含む、生
分解性ポリマー型薬物放出システムの製造方法を提供す
る。この方法においては、ポリ乳酸は生物学的活性成分
と混合された後完全に融解されることがなく、圧縮成形
に際して軟化させられるにとどまる（「非溶融法」）。
この方法で成形を行うことにより、薬物放出が非常に再
現性よく制御可能となる。That is, the present invention relates to a method of mixing ground polylactic acid having a weight-average molecular weight (Mw) of 3000 to 40000 with a powdered biologically active ingredient, placing the mixture in a mold, and mixing the mixture with a powder. While heating to a temperature in the range of 100 ° C. to soften the polylactic acid, the bulk density is 700 to 4000 mg /
Provided is a method for producing a biodegradable polymer-based drug release system, which comprises compressing to a predetermined shape by compressing to a cm 3 . In this method, the polylactic acid is not completely melted after being mixed with the biologically active ingredient, but is only softened during compression molding ("non-melting method").
By performing molding in this manner, drug release can be controlled very reproducibly.
【００１０】更に本発明は、重量平均分子量３０００〜
４００００を有する粉砕したポリ乳酸を粉末状の生物学
的活性成分と混合し、混合物を加熱溶融し、冷却後粉砕
し、これを型に入れ、５０〜１００℃の範囲の温度に加
熱してポリ乳酸を軟化させつつかさ密度７００〜４００
０ｍｇ／ｃｍ3に圧縮して所定の形状に成形することを
含む、生分解性ポリマー型薬物放出システムの製造方法
をも供する。即ちこの方法（「溶融法」）は、粉砕した
ポリ乳酸と粉末状の生物学的活性成分との混合物を型に
入れる前に、該混合物を加熱溶融し冷却後粉砕する工程
を更に含んでいる。この方法において「溶融」とは、混
合物を構成するポリ乳酸を溶融させることを意味し、生
物学的活性成分を溶融させることを要しない。[0010] The present invention further provides a weight average molecular weight of 3,000 to 3,000.
The ground polylactic acid having a molecular weight of 40,000 is mixed with the powdered biologically active ingredient, the mixture is heated and melted, cooled and ground, put into a mold and heated to a temperature in the range of 50-100 ° C. Lactic acid is softened and bulk density is 700-400
There is also provided a method for producing a biodegradable polymer-based drug release system, comprising compressing to 0 mg / cm 3 and shaping into a predetermined shape. That is, this method ("melting method") further includes the step of heating and melting the mixture of the ground polylactic acid and the powdered biologically active component before cooling the mixture into a mold, followed by cooling and grinding. . In this method, “melting” means melting the polylactic acid constituting the mixture, and does not require melting the biologically active ingredient.
【００１１】本明細書にいう「かさ密度」とは、成形し
たシステムの単位体積（ｃｍ3）当たりの重量（ｍｇ）
を表す。粉砕されたポリ乳酸と生物学的活性成分とから
なる混合物は、成形に際して加熱軟化させることにより
広い範囲で圧縮度合いを決定することができ、それに応
じてかさ密度を調節することができる。通常はかさ密度
７００〜４０００ｍｇ／ｃｍ3の範囲、より好ましくは
かさ密度９５０〜１５００ｍｇ／ｃｍ3とする。As used herein, "bulk density" refers to the weight (mg) per unit volume (cm 3 ) of a molded system.
Represents The degree of compression of the mixture of the ground polylactic acid and the biologically active component can be determined over a wide range by heating and softening during molding, and the bulk density can be adjusted accordingly. Usually, the bulk density is in the range of 700 to 4000 mg / cm 3 , more preferably 950 to 1500 mg / cm 3 .
【００１２】溶融法において粉砕ポリ乳酸と生物学的活
性成分粉末の混合物を溶融させるには、混合物が溶解す
るように適宜加熱すればよく、溶融温度は通常は１４０
〜１６０℃である。In order to melt the mixture of the ground polylactic acid and the powder of the biologically active ingredient in the melting method, the mixture may be heated appropriately so as to dissolve the mixture.
１６０160 ° C.
【００１３】更にまた、上記非溶融法又は溶融法におい
て、ポリ乳酸としてＤＬ−ポリ乳酸を使用することによ
り、所定の無放出期間の経過後に生物学的活性成分の放
出を行なう、放出遅延型の生分解性ポリマー型薬物放出
システムを製造することができ、本発明はそのような製
造方法も提供する。Furthermore, in the above-mentioned non-melting method or melting method, by using DL-polylactic acid as the polylactic acid, a biologically active ingredient is released after a predetermined non-release period, so that a delayed release type is used. Biodegradable polymer-based drug release systems can be manufactured, and the present invention also provides such manufacturing methods.
【００１４】更には、非溶融法において、ポリ乳酸とし
てＬ−又はＤ−ポリ乳酸を使用することにより、初期放
出後、所定の放出中断期間の経過後に生物学的活性成分
の持続的放出を行なう、初期放出−放出中断−持続放出
型の生分解性ポリマー型薬物放出システムを製造するこ
とができ、本発明はそのような製造方法をも提供する。Furthermore, by using L- or D-polylactic acid as the polylactic acid in the non-melting method, a sustained release of the biologically active ingredient is carried out after a predetermined release interruption period after the initial release. In addition, a biodegradable polymer-based drug release system of an initial release-interrupted release-sustained release type can be manufactured, and the present invention also provides such a manufacturing method.
【００１５】尚も更には、溶融法において、ポリ乳酸と
してＬ−又はＤ−ポリ乳酸を使用することにより、持続
放出型の生分解性ポリマー型薬物放出システムを製造す
ることができ、本発明はそのような製造方法をも提供す
る。Still further, by using L- or D-polylactic acid as the polylactic acid in the melting method, a sustained-release biodegradable polymer-type drug release system can be produced. Such a manufacturing method is also provided.
【００１６】[0016]
【発明の実施の形態】上記において、重量平均分子量３
０００〜４００００を有するポリ乳酸が使用できるが、
更に好ましくは重量平均分子量３０００〜３００００、
取り分け好ましくは重量平均分子量５０００〜２０００
０のポリ乳酸が用いられる。BEST MODE FOR CARRYING OUT THE INVENTION In the above, the weight average molecular weight is 3
Although polylactic acid having 000 to 40,000 can be used,
More preferably, the weight average molecular weight is 3,000 to 30,000,
Particularly preferably, the weight average molecular weight is 5,000 to 2,000.
0 polylactic acid is used.
【００１７】非溶融法において、Ｌ−又はＤ−ポリ乳酸
を用いるとき、初期放出−放出中断−持続放出型の生分
解性ポリマー型薬物放出システムにおける放出中断後の
持続的放出期間（本明細書において「第２相放出期間」
という。）は、用いるポリ乳酸の重量平均分子量により
制御することができる。例えば、基準溶媒として用いる
０．０５Ｍリン酸緩衝液（ｐＨ７．２）中において、非
溶融法によるシステム（長さ３ｍｍ×外径１ｍｍの円柱
状：かさ密度約１２７０ｍｇ／ｃｍ3）は、重量平均分
子量５０００のものを用いたときは、第２相放出期間は
試験開始の約８日後から２０日後までの期間であり、重
量平均分子量１００００のものを用いたときは、約３０
日後から８０日後までの期間であり、重量平均分子量２
００００のものを用いたときは、約１４０日後から第２
相放出期間が始まる。従って、これらを目安として、第
２相放出期間が所定の時に開始するよう分子量を定める
ことができる。When L- or D-polylactic acid is used in the non-melting method, the sustained release period after the release is interrupted in the initial release-interrupted-extended release biodegradable polymer-based drug release system (refer to the present specification). In the "second phase release period"
That. ) Can be controlled by the weight average molecular weight of the polylactic acid used. For example, in a 0.05 M phosphate buffer (pH 7.2) used as a reference solvent, a system by a non-melting method (a column having a length of 3 mm and an outer diameter of 1 mm: a bulk density of about 1270 mg / cm 3 ) has a weight average When a molecular weight of 5000 was used, the second phase release period was from about 8 days to 20 days after the start of the test, and about 30 days when a weight average molecular weight of 10,000 was used.
The period from the day to the 80th day, the weight average molecular weight 2
0000, the second
The phase release period begins. Therefore, using these as a guide, the molecular weight can be determined so that the second phase release period starts at a predetermined time.
【００１８】溶融法において、Ｌ−又はＤ−ポリ乳酸を
用いるとき、持続放出型の生分解性ポリマー型薬物放出
システムにおける放出持続時間は、用いるポリ乳酸の重
量平均分子量により制御することができる。例えば、基
準溶媒として用いる０．０５Ｍリン酸緩衝液（ｐＨ７．
２）中において、溶融法によるシステム（長さ３ｍｍ×
外径１ｍｍの円柱状：かさ密度約１２７０ｍｇ／ｃ
ｍ3）は、重量平均分子量５０００のものを用いたとき
は、持続的放出期間は約２５日間であり、重量平均分子
量１００００のものではおよそ７日後から６０日後まで
の約５３日間であり、重量平均分子量２００００のもの
でおよそ５０日後から１２０日後にかけての約７０日間
である。When L- or D-polylactic acid is used in the melting method, the release duration in the sustained-release biodegradable polymer-type drug release system can be controlled by the weight average molecular weight of the polylactic acid used. For example, a 0.05 M phosphate buffer (pH 7.
In 2), a system (3 mm length ×
Cylindrical shape with outer diameter of 1mm: bulk density about 1270mg / c
m 3 ) is about 25 days when the substance having a weight average molecular weight of 5000 is used, and about 53 days from about 7 days to about 60 days after the substance having a weight average molecular weight of 10,000 is used. About 70 days from about 50 days to 120 days with an average molecular weight of 20,000.
【００１９】溶融法又は非溶融法において、ＤＬ−ポリ
乳酸を用いるときは、生物活性成分の無放出期間は、用
いるポリ乳酸の分子量及び溶融法・非溶融法の選択の組
み合わせによって制御することができる。例えば、基準
溶媒として用いる０．０５Ｍリン酸緩衝液（ｐＨ７．
２）中において、溶融法によるシステム（長さ３ｍｍ×
外径１ｍｍの円柱状：かさ密度約１２７０ｍｇ／ｃ
ｍ3）は、重量平均分子量１００００のものでは、生物
学的活性成分の放出開始までに約１０日を要し、重量平
均分子量２００００のものでは約２５日を要する。また
非溶融法によれば、重量平均分子量１００００のもので
は、生物活性成分の放出開始までに約１５日を要し、重
量平均分子量２００００のものでは約３５日を要する。
放出開始から放出完了までに要する期間は何れの場合も
約１０日間と一定しており比較的短い。これらを目安に
して、システムの目的に合うように分子量及び製造方法
を選択することができる。例えば重量平均分子量８００
０〜３００００の範囲で選択してよい。When DL-polylactic acid is used in the melting method or the non-melting method, the non-release period of the biologically active ingredient can be controlled by a combination of the molecular weight of the polylactic acid used and the selection of the melting method and the non-melting method. it can. For example, a 0.05 M phosphate buffer (pH 7.
In 2), a system (3 mm length ×
Cylindrical shape with outer diameter of 1mm: bulk density about 1270mg / c
m 3 ) requires about 10 days before the release of the biologically active ingredient for a substance having a weight average molecular weight of 10,000 and about 25 days for a substance having a weight average molecular weight of 20,000. According to the non-melting method, about 15 days are required until the release of the biologically active ingredient starts when the weight average molecular weight is 10,000, and about 35 days when the weight average molecular weight is 20,000.
The period required from the start of release to the completion of release is constant at about 10 days in each case, which is relatively short. With these as a guide, the molecular weight and production method can be selected to suit the purpose of the system. For example, weight average molecular weight 800
You may select in the range of 0-30000.
【００２０】十分な再現性を有する薬物放出システムを
得るには、加える生物学的活性成分の量は、ポリ乳酸の
分解特性に影響の無い範囲とするのが望ましい。好まし
くは、ポリ乳酸の重量に対し、添加する生物学的活性成
分の重量比率は０．２まで、より好ましくは０．１まで
である。この重量比率には特に下限はなく、微量で効果
を発揮する生物学的活性成分の場合は、それに対応して
重量比率を下げればよい。In order to obtain a drug release system with sufficient reproducibility, the amount of the biologically active ingredient to be added is desirably within a range that does not affect the degradation characteristics of polylactic acid. Preferably, the weight ratio of added biologically active ingredient to the weight of polylactic acid is up to 0.2, more preferably up to 0.1. There is no particular lower limit to this weight ratio, and in the case of a biologically active ingredient that exerts its effect in a very small amount, the weight ratio may be reduced correspondingly.
【００２１】システムの形状は任意であり、例えば円柱
状、平たい円柱状（即ちタブレット状）、角柱状、球
状、ドーナツ状等であってよい。何れも対応した筒状の
型内で材料を加熱軟化させつつ軸方向に圧縮することに
より成形できる。The shape of the system is arbitrary and may be, for example, a cylinder, a flat cylinder (ie, a tablet), a prism, a sphere, a donut, or the like. Each of them can be formed by compressing the material in the axial direction while heating and softening the material in the corresponding cylindrical mold.
【００２２】本発明において生物学的活性成分として添
加することのできる成分は、製造中における安定性が維
持できるものである限り特に制限はなく、例えば、抗生
物質、抗菌剤、抗炎症剤、抗ウイルス剤、血管新生抑制
剤、抗緑内障剤、抗白内障剤、制癌剤及びワクチン用抗
原その他の種々の薬剤から適宜選択して用いてよい。The components which can be added as biologically active components in the present invention are not particularly limited as long as they can maintain stability during the production. Examples thereof include antibiotics, antibacterial agents, anti-inflammatory agents, anti-inflammatory agents, and the like. Viral agents, angiogenesis inhibitors, anti-glaucoma agents, anti-cataract agents, anti-cancer agents, vaccine antigens and other various agents may be appropriately selected and used.
【００２３】本発明は、放出遅延型の生分解性ポリマー
型薬物放出システム、初期放出−放出中断−持続放出型
の生分解性ポリマー型薬物放出システム、及び持続放出
型の生分解性ポリマー型薬物放出システムを、マトリッ
クスとしてポリ乳酸を用いて自在に作り出すことを可能
にする。放出遅延型及び初期放出−放出中断−持続放出
型の生分解性ポリマー型薬物放出システムの場合には、
２度に分けた投与を必要とするような生物学的活性成
分、例えば免疫付与のための抗原の投与などに、有利に
用いることができる。The present invention relates to a delayed release type biodegradable polymer drug release system, an initial release-interruption-sustained release type biodegradable polymer type drug release system, and a sustained release type biodegradable polymer type drug. The release system can be created freely using polylactic acid as matrix. In the case of a delayed release and initial release-release interrupted-sustained release biodegradable polymer-based drug release system,
It can be advantageously used for the administration of biologically active ingredients which require two separate doses, such as the administration of antigens for immunization.
【００２４】非溶融法及び溶融法は例えば次のようにし
て行なうことができる。 （非溶融法）生物学的活性成分０．０１〜１０ｇ及びポ
リ乳酸０．０１〜１００ｇを乳鉢（内径７０〜１００ｍ
ｍ×深さ４０×６０ｍｍ）を用いて１分間に１００〜１
２０サイクル程度で機械的に混合粉砕する。混合粉砕物
の所定量を秤取して所望の型に入れ、約６０〜８０℃に
加熱して軟化させつつ所定の形状に圧縮成形する。The non-melting method and the melting method can be performed, for example, as follows. (Non-melting method) 0.01 to 10 g of biologically active ingredient and 0.01 to 100 g of polylactic acid are mortared (inner diameter of 70 to 100 m).
mx 40 x 60 mm) for 100-1 minutes per minute.
It is mechanically mixed and pulverized in about 20 cycles. A predetermined amount of the mixed and pulverized material is weighed and put into a desired mold, and is compression-molded into a predetermined shape while being softened by heating to about 60 to 80 ° C.
【００２５】（溶融法）生物学的活性成分０．０１〜１
０ｇ及びポリ乳酸０．０１〜１００ｇを乳鉢（内径７０
〜１００ｍｍ×深さ４０×６０ｍｍ）を用いて１分間に
１００〜１２０サイクル程度で機械的に混合粉砕する。
混合粉砕物を約１４０〜１６０℃に加熱し完全溶融す
る。得られた混合塊を再度乳鉢で粉砕し、所定量を秤取
して所望の型に入れ、約６０〜８０℃に加熱して軟化さ
せつつ所定の形状に圧縮成形する。(Melting method) Biologically active ingredient 0.01-1
0 g and 0.01-100 g of polylactic acid in a mortar (inner diameter 70
１００100 mm × depth 40 × 60 mm) and mechanically mixing and pulverizing at about 100 to 120 cycles per minute.
The mixed and pulverized material is heated to about 140 to 160 ° C. and completely melted. The obtained mixed mass is pulverized again in a mortar, a predetermined amount is weighed and placed in a desired mold, and the mixture is heated to about 60 to 80 ° C. and softened and compression-molded into a predetermined shape.
【００２６】[0026]
【実施例】以下に実施例を示して本発明を更に具体的に
説明する。The present invention will be described more specifically with reference to the following examples.
【００２７】（実施例１）生物学的活性成分としてイン
ドメタシン０．１ｇ、重量平均分子量１００００のＤＬ
−ポリ乳酸１ｇを機械的に混合粉砕後、その３ｍｇを秤
取し、内径１ｍｍのテフロンチューブに入れ、約７０℃
に加熱しつつ、両側から外径約１ｍｍのステンレス棒に
より圧縮して、直径１ｍｍ、長さ３ｍｍのロッド状に圧
縮成形することにより、非溶融法による薬物放出システ
ムを作製した。このシステムのかさ密度は約１２７０ｍ
ｇ／ｃｍ3である。Example 1 0.1 g of indomethacin as a biologically active ingredient, DL having a weight average molecular weight of 10,000
-After mechanically mixing and crushing 1 g of polylactic acid, 3 mg of the lactic acid is weighed and placed in a Teflon tube having an inner diameter of 1 mm.
While heating the mixture, it was compressed from both sides with a stainless steel rod having an outer diameter of about 1 mm to form a rod having a diameter of 1 mm and a length of 3 mm, thereby producing a drug release system by a non-melting method. The bulk density of this system is about 1270m
g / cm 3 .
【００２８】（実施例２）重量平均分子量２００００の
ＤＬ−ポリ乳酸を用いる以外は実施例１と同様にして、
非溶融法による薬物放出システムを作製した。かさ密度
約１２７０ｍｇ／ｃｍ3である。Example 2 The procedure of Example 1 was repeated except that DL-polylactic acid having a weight average molecular weight of 20,000 was used.
A drug release system by a non-melting method was fabricated. The bulk density is about 1270 mg / cm 3 .
【００２９】（実施例３）生物学的活性成分としてイン
ドメタシン０．１ｇ、重量平均分子量１００００のＤＬ
−ポリ乳酸１ｇを機械的に混合粉砕後、混合物を約１５
０℃に加熱して溶融させ、冷却後再度乳鉢で粉砕した。
粉砕物の３ｍｇを秤取し、内径１ｍｍのテフロンチュー
ブに入れ、約７０℃に加熱しつつ、両側から外径約１ｍ
ｍのステンレス棒により圧縮して、直径１ｍｍ、長さ３
ｍｍのロッド状に圧縮成形することにより、溶融法によ
る薬物放出システムを作製した。かさ密度約１２７０ｍ
ｇ／ｃｍ3。Example 3 0.1 g of indomethacin as a biologically active ingredient and DL having a weight average molecular weight of 10,000
-After mechanically mixing and grinding 1 g of polylactic acid, the mixture is
The mixture was heated to 0 ° C. and melted. After cooling, the mixture was ground again in a mortar.
3 mg of the pulverized material is weighed, placed in a Teflon tube having an inner diameter of 1 mm, and heated to about 70 ° C. while an outer diameter of about 1 m from both sides.
m, stainless steel rod, diameter 1mm, length 3
A drug release system by a melting method was manufactured by compression molding into a rod shape of mm. Bulk density about 1270m
g / cm 3 .
【００３０】（実施例４）重量平均分子量２００００の
ＤＬ−ポリ乳酸を用いる以外は実施例３と同様にして、
溶融法による薬物放出システムを作製した。かさ密度約
１２７０ｍｇ／ｃｍ3。Example 4 The procedure of Example 3 was repeated except that DL-polylactic acid having a weight average molecular weight of 20,000 was used.
A drug release system by the melting method was fabricated. The bulk density is about 1270 mg / cm 3 .
【００３１】（実施例５）重量平均分子量５０００のＬ
−ポリ乳酸を用いる以外は実施例１と同様にして非溶融
法による薬物放出システムを作製した。かさ密度約１２
７０ｍｇ／ｃｍ3。Example 5 L having a weight average molecular weight of 5000
-A drug release system was produced in the same manner as in Example 1 except that polylactic acid was used. Bulk density about 12
70 mg / cm 3 .
【００３２】（実施例６）重量平均分子量１００００の
Ｌ−ポリ乳酸を用いる以外は実施例１と同様にして、非
溶融法による薬物放出システムを作製した。かさ密度約
１２７０ｍｇ／ｃｍ3。Example 6 A drug release system was produced in the same manner as in Example 1 except that L-polylactic acid having a weight average molecular weight of 10,000 was used. The bulk density is about 1270 mg / cm 3 .
【００３３】（実施例７）重量平均分子量２００００の
Ｌ−ポリ乳酸を用いる以外は実施例１と同様にして、非
溶融法による薬物放出システムを作製した。かさ密度約
１２７０ｍｇ／ｃｍ3。Example 7 A drug release system was produced in the same manner as in Example 1 except that L-polylactic acid having a weight average molecular weight of 20,000 was used. The bulk density is about 1270 mg / cm 3 .
【００３４】（実施例８）重量平均分子量５０００のＬ
−ポリ乳酸を用いる以外は実施例３と同様にして、溶融
法による薬物放出システムを作製した。かさ密度約１２
７０ｍｇ／ｃｍ3。Example 8 L having a weight average molecular weight of 5000
-A drug release system by a melting method was prepared in the same manner as in Example 3 except that polylactic acid was used. Bulk density about 12
70 mg / cm 3 .
【００３５】（実施例９）重量平均分子量１００００の
Ｌ−ポリ乳酸を用いる以外は実施例３と同様にして、溶
融法による薬物放出システムを作製した。かさ密度約１
２７０ｍｇ／ｃｍ3。Example 9 A drug release system by a melting method was prepared in the same manner as in Example 3 except that L-polylactic acid having a weight average molecular weight of 10,000 was used. Bulk density about 1
270 mg / cm 3 .
【００３６】（実施例１０）重量平均分子量２００００
のＬ−ポリ乳酸を用いる以外は実施例３と同様にして、
溶融法による薬物放出システムを作製した。かさ密度約
１２７０ｍｇ／ｃｍ3。(Example 10) Weight average molecular weight 20,000
In the same manner as in Example 3 except that L-polylactic acid was used,
A drug release system by the melting method was fabricated. The bulk density is about 1270 mg / cm 3 .
【００３７】＜薬物放出試験＞実施例１〜１０の薬物放
出システムの各々を、遮光瓶（５ｍＬ）に入れ、０．０
５Ｍリン酸緩衝液（ｐＨ７．２）を５ｍＬ加えた。これ
を３７℃にて震盪し、経時的にサンプリングを行い、溶
液中のインドメタシン濃度をＨＰＬＣで定量した。実験
はシンク条件で行い、サンプリング後は全液量交換し
た。ＨＰＬＣ条件は次の通りとした。 カラム： ＴＯＳＯＨ ＴＳＫｇｅｌ ＯＤＳ−８０Ｔ
ｓ，内径４．６ｍｍ×長さ１５０ｍｍ 検出器： ＵＶ−２５４ｎｍ 移動相： ０．０５Ｍリン酸緩衝液：メタノール＝３：
７ 流速： ０．７ｍＬ／分 温度： ４０℃ 注入液量： ５０μＬ 保持時間： ７分<Drug Release Test> Each of the drug release systems of Examples 1 to 10 was placed in a light-shielding bottle (5 mL),
5 mL of 5M phosphate buffer (pH 7.2) was added. This was shaken at 37 ° C., sampling was performed over time, and the concentration of indomethacin in the solution was quantified by HPLC. The experiment was performed under sink conditions, and after the sampling, the entire liquid volume was exchanged. HPLC conditions were as follows. Column: TOSOH TSKgel ODS-80T
s, inner diameter 4.6 mm x length 150 mm Detector: UV-254 nm Mobile phase: 0.05 M phosphate buffer: methanol = 3:
7 Flow rate: 0.7 mL / min Temperature: 40 ° C. Injection volume: 50 μL Retention time: 7 minutes
【００３８】（結果）実施例１〜４についての結果を図
１に、実施例５〜７についての結果を図２に、そして実
施例８〜１０についての結果を図３に、それぞれ示す。(Results) The results for Examples 1 to 4 are shown in FIG. 1, the results for Examples 5 to 7 are shown in FIG. 2, and the results for Examples 8 to 10 are shown in FIG.
【００３９】図１〜３を比較すると明らかなように、Ｄ
Ｌ−ポリ乳酸を用いるときは溶融法又は非溶融法の何れ
においても、薬物放出が開始するまでの時間を遅らせる
ことができる。試験開始から薬物放出が開始するまでの
無放出期間は、用いるポリ乳酸の分子量及び溶融法・非
溶融法の双方に応じて変化しており、実施例１の非溶融
法による分子量１００００のＤＬ−ポリ乳酸は、約１５
日、実施例２の非溶融法による分子量２００００のＤＬ
−ポリ乳酸は、約３５日であり、実施例３の溶融法によ
る分子量１００００のＤＬ−ポリ乳酸では約１０日、実
施例４の溶融法による分子量２００００のポリ乳酸では
約２５日である。放出が開始してから放出が完了するま
での期間は、何れも約１０日間と同等である。無放出期
間が重量平均分子量の増大とともに延長することから、
これらのデータに基づき、重量平均分子量を選択するこ
とにより、ＤＬ−ポリ乳酸を用いて非溶融法又は溶融法
で、所定の無放出期間を有する薬物放出システムを作製
することが可能である。そのためには例えば、分子量を
横軸、無放出期間を縦軸として非溶融法及び溶融法につ
いて別個にプロットし、直線で結んでグラフ化し、１０
日〜３５日の範囲又はそのある程度前後に相当する所望
の無放出期間に対応する分子量を、非溶融法及び溶融法
それぞれにつき求め、何れかを所望により使用すればよ
い。As is apparent from a comparison of FIGS.
When L-polylactic acid is used, the time until drug release starts can be delayed in either the melting method or the non-melting method. The non-release period from the start of the test to the start of drug release varies depending on the molecular weight of the polylactic acid used and both the melting method and the non-melting method. Polylactic acid is about 15
DL of 20,000 molecular weight by the non-melting method of Example 2
Polylactic acid is about 35 days, DL-polylactic acid having a molecular weight of 10,000 by the melting method of Example 3 is about 10 days, and polylactic acid having a molecular weight of 20,000 by the melting method of Example 4 is about 25 days. The period from the start of the release to the completion of the release is equivalent to about 10 days. Since the non-release period increases with the increase of the weight average molecular weight,
By selecting the weight average molecular weight based on these data, it is possible to produce a drug release system having a predetermined non-release period by a non-melting method or a melting method using DL-polylactic acid. For this purpose, for example, the molecular weight is plotted on the horizontal axis and the non-discharge period is plotted on the vertical axis for the non-melting method and the melting method, and the graph is plotted by connecting with a straight line.
The molecular weight corresponding to the desired non-release period corresponding to the range of days to 35 days, or to some extent around that, may be determined for each of the non-melting method and the melting method, and either may be used as desired.
【００４０】図２を他の図と比較すると明らかなよう
に、Ｌ−ポリ乳酸を用いた非溶融法による薬物放出シス
テムは、分子量の大小に関りなく初期放出を示してい
る。初期放出の後、何れのシステムも放出がある期間実
質的に中断し、その期間の経過後に持続的放出が開始し
ていることがわかる。持続的放出の開始時期は、分子量
５０００では開始後約８日から２０日まで、分子量１０
０００では約３０日から８０日までであり、分子量２０
０００では試験開始後約１４０日から放出が開始する。
このように、Ｌ−ポリ乳酸を用いた非溶融法による薬物
放出システムは、初期放出−放出中断−持続放出型のシ
ステムを与え、その放出プロフィールは重量平均分子量
に依存しているから、これらのデータをプロットするこ
とにより、所望の放出中断期間を有する、初期放出−放
出中断−持続放出型のシステムを作製することができ
る。尚、ここではＬ−ポリ乳酸を用いているが、分解特
性については鏡像関係にあるＤ−ポリ乳酸と差がある筈
はないから、Ｄ−ポリ乳酸を用いても同様の結果を得る
ことができるのは明らかである。As is clear from comparison of FIG. 2 with other figures, the drug release system by the non-melting method using L-polylactic acid shows an initial release regardless of the molecular weight. After the initial release, it can be seen that both systems have substantially discontinued the release for a period of time, after which time a sustained release has begun. The onset of sustained release is from about 8 to 20 days after initiation at 5000 molecular weight, with a molecular weight of 10
000 is about 30 to 80 days and has a molecular weight of 20.
000, the release starts about 140 days after the start of the test.
Thus, the non-melting drug release system using L-polylactic acid provides an initial release-interruption-sustained release system, whose release profile depends on the weight average molecular weight. By plotting the data, an initial release-interruption-sustained release system can be created having the desired release interruption period. Although L-polylactic acid is used here, there is no difference in the decomposition characteristics from D-polylactic acid which is in a mirror image relationship. Therefore, similar results can be obtained using D-polylactic acid. Obviously you can.
【００４１】図３を図２と比較すると明らかなように、
Ｌ−ポリ乳酸を用いた溶融法による薬物放出システムは
持続放出型のシステムを与え、非溶融法のように初期放
出と持続的放出との間に放出中断期間を挟むような放出
パターンをとらないことがわかる。また図１のＤＬ−ポ
リ乳酸を用いたシステムと異なり、放出の開始から終了
まで徐々に薬物を放出する。またその放出期間は分子量
の増大とともに延長し、重量平均分子量５０００のもの
を用いたときは約２５日間であり、重量平均分子量１０
０００のものではおよそ７日後から６０日後までの約５
３日間であり、重量平均分子量２００００のものでおよ
そ５０日後から１２０日後にかけての約７０日間であ
る。従って、これら重量平均分子量と放出開始、放出終
了日数のデータをグラフにプロットすることにより、所
望の徐放特性を有する薬物放出システムを容易に作り出
すことができる。As is apparent from a comparison of FIG. 3 with FIG.
The drug release system by the melting method using L-polylactic acid provides a sustained-release type system, and does not have a release pattern in which a release interruption period is interposed between the initial release and the sustained release unlike the non-melting method. You can see that. Also, unlike the system using DL-polylactic acid in FIG. 1, the drug is gradually released from the start to the end of the release. The release period is extended with an increase in the molecular weight, and is about 25 days when a substance having a weight average molecular weight of 5000 is used.
000, about 5 days from about 7 days to 60 days
3 days, and about 70 days from about 50 days to 120 days after the weight average molecular weight is 20,000. Therefore, by plotting the data of the weight average molecular weight and the release start and release end days on a graph, a drug release system having desired sustained release characteristics can be easily created.
【００４２】[0042]
【発明の効果】本発明は、ポリ乳酸のみを用いて、生物
学的活性成分の放出を確実に制御し、且つ種々の所望の
放出パターンを設計することを可能にする。The present invention makes it possible to control the release of a biologically active ingredient using only polylactic acid and to design various desired release patterns.
【図１】 ＤＬ−ポリ乳酸に基づくシステムの薬物放出FIG. 1. Drug release of a system based on DL-polylactic acid
【図２】 Ｌ−ポリ乳酸に基づく非溶融法によるシステ
ムの薬物放出FIG. 2. Drug release of the system by a non-melting method based on L-polylactic acid
【図３】 Ｌ−ポリ乳酸に基づく溶融法によるシステム
の薬物放出FIG. 3. Drug release of the system by a melting method based on L-polylactic acid
Claims (11)
する粉砕したポリ乳酸を粉末状の生物学的活性成分と混
合し、混合物を型に入れ、５０〜１００℃の範囲の温度
に加熱してポリ乳酸を軟化させつつかさ密度７００〜４
０００ｍｇ／ｃｍ3に圧縮して所定の形状に成形するこ
とを含む、生分解性ポリマー型薬物放出システムの製造
方法。A polylactic acid having a weight average molecular weight of 3,000 to 40,000 is mixed with a powdered biologically active ingredient, the mixture is placed in a mold and heated to a temperature in the range of 50 to 100 ° C. Bulk density of 700-4 while softening
A method for producing a biodegradable polymer-type drug release system, comprising compressing to a predetermined shape by compressing to 000 mg / cm 3 .
後粉砕する工程を更に含む、請求項１の製造方法。2. The method according to claim 1, further comprising a step of heating and melting the mixture before putting it in a mold, and cooling and pulverizing the mixture.
乳酸としてＤＬ−ポリ乳酸を使用することを特徴とす
る、所定の無放出期間の経過後に生物学的活性成分の放
出を行なう、放出遅延型の生分解性ポリマー型薬物放出
システムの製造方法。3. The method according to claim 1, wherein the biologically active ingredient is released after a predetermined non-release period has elapsed, wherein DL-polylactic acid is used as the polylactic acid. And a method for producing a delayed-release biodegradable polymer-based drug release system.
ある、請求項３の製造方法。4. The method according to claim 3, wherein the weight average molecular weight is 8,000 to 30,000.
してＬ−又はＤ−ポリ乳酸を使用することを特徴とす
る、初期放出後、所定の放出中断期間の経過後に生物学
的活性成分の持続的放出を行なう、初期放出−放出中断
−持続放出型の生分解性ポリマー型薬物放出システムの
製造方法。5. The method according to claim 1, wherein L- or D-polylactic acid is used as the polylactic acid, after the initial release and after a predetermined release interruption period. A method for producing an initial release-interruption-sustained release biodegradable polymer-based drug release system that provides sustained release of components.
してＬ−又はＤ−ポリ乳酸を使用することを特徴とす
る、徐放型の生分解性ポリマー型薬物放出システムの製
造方法。6. The method according to claim 2, wherein L- or D-polylactic acid is used as the polylactic acid.
ある、請求項５又は６の製造方法。7. The method according to claim 5, wherein the weight average molecular weight is 3,000 to 30,000.
である請求項１乃至７の何れかの製造方法。8. A bulk density of 700 to 4000 mg / cm 3.
The method according to claim 1, wherein
比が０．２までである、請求項１乃至８の何れかの製造
方法。9. The process according to claim 1, wherein the weight ratio of biologically active substance to polylactic acid is up to 0.2.
向に圧縮されるものである、請求項１乃至９の何れかの
製造方法。10. The method according to claim 1, wherein the mold is cylindrical and the mixture is compressed in the axial direction of the mold.
抗炎症剤、抗ウイルス剤、血管新生抑制剤、抗緑内障
剤、抗白内障剤、制癌剤及びワクチン用抗原よりなる群
より選ばれるものである、請求項１乃至１０の何れかの
製造方法。11. The biologically active substance is an antibiotic, an antibacterial agent,
The method according to any one of claims 1 to 10, which is selected from the group consisting of an anti-inflammatory agent, an antiviral agent, an angiogenesis inhibitor, an anti-glaucoma agent, an anti-cataract agent, an anticancer agent, and an antigen for vaccine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10537098A JPH11286439A (en) | 1998-04-01 | 1998-04-01 | Biodegradable polymer-type drug release system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10537098A JPH11286439A (en) | 1998-04-01 | 1998-04-01 | Biodegradable polymer-type drug release system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH11286439A true JPH11286439A (en) | 1999-10-19 |
Family
ID=14405828
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10537098A Pending JPH11286439A (en) | 1998-04-01 | 1998-04-01 | Biodegradable polymer-type drug release system |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH11286439A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002003406A (en) * | 2000-06-21 | 2002-01-09 | Sankyo Co Ltd | Cerebrovascular spasm prophylactic preparation |
| WO2002067993A1 (en) * | 2001-02-27 | 2002-09-06 | Senju Pharmaceutical Co., Ltd. | Drug-releasing system of biodegradable polymer type |
| WO2010143689A1 (en) | 2009-06-10 | 2010-12-16 | 久光製薬株式会社 | Microneedle device |
| WO2011010605A1 (en) | 2009-07-23 | 2011-01-27 | 久光製薬株式会社 | Microneedle array |
| US8771781B2 (en) | 2007-05-15 | 2014-07-08 | Hisamitsu Pharmaceutical Co., Inc. | Method of coating microneedle |
| JP2021504487A (en) * | 2017-11-30 | 2021-02-15 | ベーイーテー ファルマ ゲーエムベーハー | Methods and equipment for preparing solid dispersions |
-
1998
- 1998-04-01 JP JP10537098A patent/JPH11286439A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002003406A (en) * | 2000-06-21 | 2002-01-09 | Sankyo Co Ltd | Cerebrovascular spasm prophylactic preparation |
| WO2002067993A1 (en) * | 2001-02-27 | 2002-09-06 | Senju Pharmaceutical Co., Ltd. | Drug-releasing system of biodegradable polymer type |
| US8771781B2 (en) | 2007-05-15 | 2014-07-08 | Hisamitsu Pharmaceutical Co., Inc. | Method of coating microneedle |
| WO2010143689A1 (en) | 2009-06-10 | 2010-12-16 | 久光製薬株式会社 | Microneedle device |
| US8747362B2 (en) | 2009-06-10 | 2014-06-10 | Hisamitsu Pharmaceutical Co., Inc | Microneedle device |
| WO2011010605A1 (en) | 2009-07-23 | 2011-01-27 | 久光製薬株式会社 | Microneedle array |
| KR20120037910A (en) | 2009-07-23 | 2012-04-20 | 도판 인사츠 가부시키가이샤 | Microneedle array |
| US8696638B2 (en) | 2009-07-23 | 2014-04-15 | Hisamitsu Pharmaceutical Co., Inc. | Microneedle array |
| JP2021504487A (en) * | 2017-11-30 | 2021-02-15 | ベーイーテー ファルマ ゲーエムベーハー | Methods and equipment for preparing solid dispersions |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100413581B1 (en) | PHARMACEUTICAL COMPOSITION COMPRISING A FUSIBLE CARRIER AND PROCESS FOR PRODUCING THE SAME | |
| NL195056C (en) | Process for the preparation of preparations containing salts of peptides with carboxy terminated polyesters. | |
| Shi et al. | Current advances in sustained-release systems for parenteral drug delivery | |
| US8409621B2 (en) | Microparticles | |
| AU718866B2 (en) | Method for fabricating polymer-based controlled-release devices | |
| JP4121372B2 (en) | Biodegradable polymer-type drug release system | |
| MX2014000891A (en) | Biodegradable, semi-crystalline, phase separated, thermoplastic multi block copolymers for controlled release of biologically active compounds. | |
| JP2003534268A (en) | Method for preparing microparticles with selected polymer molecular weight | |
| Qi et al. | Goserelin acetate loaded poloxamer hydrogel in PLGA microspheres: Core–shell di-depot intramuscular sustained release delivery system | |
| HU211845A9 (en) | Orally administrated solvent-free pharmaceutical composition with delayed active-substance release and a method for preparing thereof | |
| AU2018305161A1 (en) | Drug delivery composition | |
| JP7737981B2 (en) | Biodegradable phase-separated thermoplastic multiblock copolymers | |
| Jiang et al. | Pulsatile protein release from a laminated device comprising of polyanhydrides and pH-sensitive complexes | |
| Jerbic | Biodegradable synthetic polymers and their application in advanced drug delivery systems (DDS) | |
| JPH11286439A (en) | Biodegradable polymer-type drug release system | |
| JP2025128118A (en) | Sustained-release formulations using non-aqueous emulsions | |
| Pekarek et al. | In vitro and in vivo degradation of double-walled polymer microspheres | |
| CN107698747B (en) | A kind of micro- block polymer and its preparation method and application for long-acting slow-release preparation | |
| US20250206872A1 (en) | Biodegradable thermoplastic poly(ortho ester) based multiblock copolymers | |
| Sinha et al. | Current polyesteric systems for advanced drug delivery | |
| DiNunzio et al. | Melt extrusion: pharmaceutical applications | |
| WO2026015019A1 (en) | Biodegradable thermoplastic polyoxazoline based copolymers | |
| Chen et al. | ALZAMER® Depot™ bioerodible polymer technology | |
| Sandor | Intracellular delivery of active proteins and genes via erodible nanospheres | |
| WO2001058428A1 (en) | Method of preparing a sustained release composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20050125 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20080819 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20081009 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20081111 |