JPH0453581B2 - - Google Patents
Info
- Publication number
- JPH0453581B2 JPH0453581B2 JP8406884A JP8406884A JPH0453581B2 JP H0453581 B2 JPH0453581 B2 JP H0453581B2 JP 8406884 A JP8406884 A JP 8406884A JP 8406884 A JP8406884 A JP 8406884A JP H0453581 B2 JPH0453581 B2 JP H0453581B2
- Authority
- JP
- Japan
- Prior art keywords
- nylon
- capsule
- membrane
- compound
- bilayer membrane
- 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
Links
- 239000002775 capsule Substances 0.000 claims description 62
- 239000004677 Nylon Substances 0.000 claims description 52
- 229920001778 nylon Polymers 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 24
- 239000011148 porous material Substances 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 239000012528 membrane Substances 0.000 description 24
- 239000003012 bilayer membrane Substances 0.000 description 22
- 239000000126 substance Substances 0.000 description 14
- 230000035699 permeability Effects 0.000 description 13
- 230000008859 change Effects 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007850 fluorescent dye Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000004985 diamines Chemical class 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000592 Artificial Cell Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 238000012695 Interfacial polymerization Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- -1 chlorocarbonyl Chemical group 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000012262 fermentative production Methods 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000007793 ph indicator Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000035440 response to pH Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
- Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
- Pyridine Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Description
本発明は、ナイロンカプセルに関し、更に詳細
にはPHの微妙な変化に応じて可逆的に膜透過性を
変化させる全く新規な構造を有するナイロンカプ
セルに関する。
外部刺激に応答して膜透過性を可逆的に変化せ
しめる膜を有する小胞体は、生体内の反応モデ
ル、薬物のキヤリアーとして治療、診断、生理、
代謝といつた非常に広い分野において、研究用、
実地用に有用な物質であり、一種の人工細胞とも
いうことができる。また、PHの変化に応じて膜が
開閉して小胞体内に収容しておいた着色液体等が
流出するようにしておけばPHインデイケーターと
しても有効に利用することができ、理工学、生物
学、医学の分野において測定、分析用ツールとし
ても有効に使用することができる。したがつて、
このような物質の新規開発が当業界において強く
望まれていた。
本発明は、このような技術の現状に鑑みてなさ
れたものであつて、従来知られていないきわめて
すぐれたPH応答性を有する小胞体、カプセルを人
工的に且つ生体物質を使用することなく、大量生
産するためになされたものである。
そこでベースとなる物質としては、工業的に大
量生産するには合成高分子物質が、価格的にもま
た品質安定性の面からも、また処理の容易性とい
つた面からも好適であると考え、数多く存在する
合成高分子物質のなかから、各方面からの検討を
加えた結果、ナイロンを選択するに到つた。通常
のプラスチツク技術という面からすると、ナイロ
ンは多孔度が高くて吸湿性の高いものは歓迎され
ないのが現状であるが、本発明においてはこのよ
うな多孔質のナイロンがベースとして好適である
ので、いわゆる低品質ナイロンにも新しい用途を
拓いたものといい得よう。
そしてこのナイロンでカプセルを作つた後、食
塩水を内部に包含せしめた。これを、
で示されるジアルキル化合物（2C12−suc−
COO）のドデカン溶液中に入れたところ、こ
のジアルキル化合物がナイロンカプセルの細孔部
内に充当されたのみでなく、二分子膜構造となる
ことを発見した。次いでこのナイロンカプセルを
PH２の水に入れたところ、全く予期せざること
に、カプセル内に収容しておいた食塩が外部に透
過し、PHを７にしたところ食塩の透過がとまり、
しもこの反応が可逆的なものであるという全く新
規な知見を得た。
即ち、上記ジアルキル化合物が二分子膜（形
成）化合物となり、その結果、これを細孔部内に
充当してなるナイロン膜は一種の生体細胞膜とな
り、このようなナイロン膜を有するカプセルは、
PHの変化に応じて開閉するイオンゲートを備えた
一種の人工細胞ともいうことできるという新知見
を得たのである。
そこで本発明者等は、この新知見を基礎にし
て、ベースとなるナイロンの検討、上記ジアルキ
ル化合物以外の二分子膜化合物のスクリーニング
その他の研究を広く且つ深く行つた結果、遂に本
発明を完成するに到つたのである。
すなわち、本発明は、ナイロンをベースとし、
この細孔部内に特定の二分子膜化合物を充当して
なるナイロン膜で囲まれたナイロンカプセルであ
る。
ナイロンカプセルは、ジアミンと二塩基酸と反
応させたり、またはアミノ酸もしくはラクタムを
重合または重縮合させたりして常法により製造
し、６，６−ナイロン、６，10−ナイロン、２，
12−ナイロンその他が適宜使用される。例えば、
二塩基酸の酸塩化物を水と混ざらない有機溶媒に
溶かしておき、これにジアミンのアルカリ水溶液
を加えて、両液相の界面にナイロンカプセルを瞬
間的に生成せしめるといつた界面重合といつた方
法その他適宜な方法でナイロンカプセルを製造す
る。ジアミンのアルカリ液の液滴の大きさを変え
る等といつた方法でカプセルの大きさも自由に調
節できる。
本発明によれば、このナイロンカプセルは、そ
の中に収容すべき物質の緩衝液といつた溶液類内
で透析して、該物質をカプセルの中空部内に収容
せしめる。これをそのまま、ドデカンといつた有
機溶媒に二分子膜化合物をとかした溶液中に入れ
て放置すれば、ナイロンカプセルの細孔部内に二
分子膜化合物が充当された目的とするナイロンカ
プセルが得られる。
得られたナイロンカプセルは、所定温度のも
と、外部PHが変化することによつてその細孔部内
に充当した二分子膜化合物の構造が可逆的に破壊
されて、カプセルの内包部に収容されていた物質
が外部へと透過するのである。そして外部PHを更
に変化させると二分子膜化合物の構造がまた元に
戻り、物質の透過が停止ないし低下するのであ
る。つまり、本発明にかかるナイロンカプセル
は、PHに応答して開閉するイオンゲートを多数有
するナイロン膜で取り囲まれたカプセル、一種の
小胞体ということができ、この構造は、生体細胞
に極めて類似したものである。イオンゲート開閉
のメカニズムの詳細は今後の研究にまたねばなら
ないが、二分子膜がゲル状態のときには外部PHが
変化しても二分子膜化合物の荷電は変化しないた
めに膜のバリヤー能は高いけれども、液晶相転移
温度（Tc）以上になると、外水相PHが２の場合
には膜化合物は容易にプロトン化して二分子膜構
造が破壊されて膜透過性が急激に増加して、カプ
セル内空部に収容された物質が外水相内へ出て行
き、それぞれ所定の作用を示すものと思料され
る。そして例えば外水相PHが７になると二分子膜
構造へ可逆的に戻つて、バリヤー能の高い膜にな
り、ナイロンカプセルからの物質の透過は停止す
る。この関係を前記した2C12−suc−COOで示
されるアニオン性二分子膜化合物を例にとつて示
せば次のとおりになるものと推定される。
二分子膜（形式）化合物としては次のものが挙
げられる。例えば、
但し式中、ｎ及びｍは９〜19の整数を示し、Ｒ
は、（−CH2−）lCOOH、
（−CH2−）lSO3Ｈ、
から選択されるものである（但し、ｌは１〜５の
整数を示し、R′及びR″はＨ又はCH3を示す。）
このような二分子膜化合物を備えたナイロン膜
で囲まれたナイロンカプセルにおいて、このカプ
セル内には目的に応じて各種の物質を極めて容易
に収容させることができ、それぞれの用途に本発
明カプセルを使用することができる。例えば、食
塩水、
The present invention relates to a nylon capsule, and more particularly to a nylon capsule having a completely novel structure that reversibly changes membrane permeability in response to subtle changes in pH. The endoplasmic reticulum, which has a membrane that reversibly changes membrane permeability in response to external stimuli, is used as an in-vivo reaction model and a drug carrier for treatment, diagnosis, physiology, and treatment.
In a very wide field such as metabolism, for research purposes,
It is a substance that is useful for practical purposes, and can also be called a type of artificial cell. In addition, if the membrane opens and closes in response to changes in pH, allowing colored liquid stored in the endoplasmic reticulum to flow out, it can be effectively used as a pH indicator. It can also be effectively used as a measurement and analysis tool in the fields of science and medicine. Therefore,
New development of such substances has been strongly desired in this industry. The present invention has been made in view of the current state of the technology, and it is possible to create endoplasmic reticulum and capsules that have previously unknown and extremely excellent PH responsiveness, without using any artificial biological materials. This was done for mass production. Therefore, as a base substance, synthetic polymer substances are suitable for industrial mass production in terms of price, quality stability, and ease of processing. After considering many synthetic polymer materials and considering various aspects, we decided on nylon. From the perspective of ordinary plastic technology, nylon with high porosity and high moisture absorption is not welcomed, but in the present invention, such porous nylon is suitable as a base. It can be said that this product has opened up new uses for so-called low-quality nylon. After making capsules out of this nylon, they filled them with saline. this, Dialkyl compound (2C 12 -suc-
When the nylon capsule (COO) was placed in a dodecane solution, the researchers discovered that this dialkyl compound not only filled the pores of the nylon capsule, but also formed a bilayer membrane structure. Next, this nylon capsule
When the capsule was placed in water with a pH of 2, the salt contained in the capsule permeated to the outside, and when the pH was set to 7, the salt permeation stopped.
We obtained a completely new finding that this reaction is reversible. That is, the above-mentioned dialkyl compound becomes a bilayer membrane (forming) compound, and as a result, the nylon membrane formed by filling the pores with this dialkyl compound becomes a kind of biological cell membrane, and a capsule having such a nylon membrane is
They obtained new knowledge that they can be called a type of artificial cell equipped with an ion gate that opens and closes in response to changes in pH. Based on this new knowledge, the inventors of the present invention have conducted extensive and deep research on nylon as a base, screening of bilayer membrane compounds other than the above-mentioned dialkyl compounds, and have finally completed the present invention. It was reached. That is, the present invention is based on nylon,
It is a nylon capsule surrounded by a nylon membrane made by filling the pores with a specific bilayer membrane compound. Nylon capsules are manufactured by a conventional method by reacting diamines with dibasic acids, or by polymerizing or polycondensing amino acids or lactams, and are produced using 6,6-nylon, 6,10-nylon, 2,
12-Nylon and others are used as appropriate. for example,
Interfacial polymerization is a process in which an acid chloride of a dibasic acid is dissolved in an organic solvent that does not mix with water, and an alkaline aqueous solution of a diamine is added to the solution to instantly form a nylon capsule at the interface of both liquid phases. The nylon capsules are manufactured by a suitable method. The size of the capsule can be freely adjusted by changing the size of the droplets of diamine alkaline solution. According to the present invention, the nylon capsule is dialyzed in buffered solutions of the substance to be contained therein to cause the substance to be contained within the cavity of the capsule. If this is placed in a solution of a bilayer membrane compound dissolved in an organic solvent such as dodecane and left to stand, the desired nylon capsule with the bilayer membrane compound filled in the pores of the nylon capsule can be obtained. . The structure of the bilayer membrane compound filled in the pores of the obtained nylon capsule is reversibly destroyed by changing the external pH at a predetermined temperature, and the resulting nylon capsule is housed in the inner capsule of the capsule. The substances that had been in the atmosphere permeate to the outside. When the external pH is further changed, the structure of the bilayer membrane compound returns to its original state, and the permeation of substances stops or decreases. In other words, the nylon capsule according to the present invention can be said to be a type of endoplasmic reticulum, a capsule surrounded by a nylon membrane that has many ion gates that open and close in response to pH, and this structure is extremely similar to that of living cells. It is. The details of the mechanism of opening and closing of the ion gate will have to be studied in the future, but when the bilayer membrane is in a gel state, the charge of the bilayer compound does not change even if the external pH changes, so the barrier ability of the membrane is high. When the temperature exceeds the liquid crystal phase transition temperature (T c ), when the external water phase pH is 2, membrane compounds are easily protonated, the bilayer membrane structure is destroyed, membrane permeability increases rapidly, and the capsule It is thought that the substances accommodated in the inner space go out into the external aqueous phase and exhibit their respective predetermined effects. For example, when the pH of the external aqueous phase reaches 7, it reversibly returns to the bilayer membrane structure, becomes a membrane with high barrier ability, and the permeation of substances from the nylon capsule stops. If this relationship is illustrated using the above-mentioned anionic bilayer membrane compound represented by 2C 12 -suc-COO as an example, it is estimated that it will be as follows. Examples of bilayer membrane (formal) compounds include the following. for example, However, in the formula, n and m represent integers of 9 to 19, and R
is (−CH 2 −) l COOH, (−CH 2 −) l SO 3 H, (However, l represents an integer from 1 to 5, and R' and R'' represent H or CH 3. ) Surrounded by a nylon membrane equipped with such a bilayer membrane compound In the nylon capsule, various substances can be very easily accommodated in the capsule depending on the purpose, and the capsule of the present invention can be used for each purpose.For example, saline solution,
【式】で示される蛍光プロー
ブによる膜透過性の測定；制癌剤その他各種薬剤
によるミサイル療法ないし徐放性マイクロカプセ
ル；酵素または微生物による発酵生産；抗原を用
いる抗体その他免疫物質の生産；組織を用いる生
理学的各種モデルその他、工業的、生物学的、医
学的、農芸化学的、薬学的な用途に対して広範に
適用することができる。
以上詳述したように、本発明に係るナイロンカ
プセルは、ナイロンカプセルの製造、カプセル内
への物質の封入、及びナイロン膜細孔部への二分
子膜形成物質の充当という各工程によつて製造す
るのであるが、これらの工程自体は熟練性をさほ
ど必要とするものではないので、工業化して大量
生産するのに極めてすぐれている。
そのうえ、PHの変化による膜透過性の変化は敏
感且つ可逆的であるうえに、ナイロンカプセルの
寿命が長いので、各種の用途にきわめて長期間使
用することもできる。
以下、本発明を実施例及び測定例について更に
詳しく説明する。
実施例 １
1m molの１，10−ビス（クロルカルボニル）
デカン及び架橋剤として0.03−0.1m molの
trymesoil chlorideを100mlの混合溶媒に溶解し、
その80mlを直径15cmのペトリ皿に入れた。エチレ
ンジアミン（0.38M）及びNaOH（0.8M）を含む
水溶液２mlを、１号ステンレス針のついたガラス
シリンジで前出の酸クロリド溶液に滴下した。こ
の工程期間中、ペトリ皿は常に細かく振動せしめ
ておいた。滴下後、残りの酸クロリド溶液（20
ml）を加え、10分間ペトリ皿をゆらしながら反応
させた。反応後、溶液をデカンテーシヨンしてカ
プセルを混合有機溶媒で３回洗條した。この方法
で、直径２−2.5mm、膜厚５−10μmの粒径のそろ
つたナイロンカプセルを得た。
実施例 ２
実施例１で製造したナイロンカプセルを0.1M
の食塩水溶液中で３日間充分に透析して、カプセ
ル内空部に食塩水をトラツプした。
このようにして食塩水を内部空間部に封入した
ナイロンカプセルを10ケ取り出し、これを、ジア
ルキル化合物
10mgをドデカン１mlに60℃に加熱しながら溶かし
た溶液に加えた。そして室温になるまで放冷し、
その後１時間放置して目的とするナイロンカプセ
ルを得た。
実施例 ３
実施例１で製造したナイロンカプセルを用い
（直径２mm、膜厚1μm）、これを１×10-3Ｍの蛍光
プローブ
を含む0.01Mリン酸バツフアー中で透析し、蛍光
プローブを内空部に封入せしめた。これを、二分
子膜化合物
のドデカン溶液に加えて、目的とするナイロンカ
プセルを得た。
実施例 ４
二分子膜化合物として実施例２で用いたジアル
キル化合物（2C12−suc−COO）を用いたほか
は実施例３と同様の処理をくり返して、蛍光プロ
ーブを内包したPH応答性ナイロンカプセルを得
た。
実施例 ５
実施例２において、ジアルキル化合物の代りに
以下の化合物を用いたほかは実施例２と同様の操
作をくり返して、食塩水を内部に包含し且つ二分
子膜でコートされたナイロンカプセルをそれぞれ
得た。
これらのナイロンカプセルは、後記する測定例
にしたがつて測定した結果、可逆的PH応答性にき
わめてすぐれていることが確認された。
測定例 １
実施例４で製造したナイロンカプセルを石英セ
ル中に入れ、0.1N HCl及び0.1N NaOHを用い
て外水相のPHを２及び７にかえて、蛍光分析によ
り蛍光強度の経時変化を測定し、図面の結果を得
た。
図面は、ナイロンカプセルからの蛍光プローブ
の透過性の可逆的変化を図示したものであり、外
部PHを２と７に変化させた時のカプセル外水相の
けい光強度の経時変化を示したものである。二分
子膜でコートしていないカプセルでは透過も速
く、外部PHの変化によりプローブの膜透過性は変
化しなかつた。2C12−suc−COO二分子膜でコ
ートしたカプセルでは、低温（25℃）、すなわち
Tc以下では透過も遅く、外部PHを２と７と変化
させてもほとんど膜透過性に差がみられなかつ
た。しかし、高温（56℃）では、外部PHが７の時
にはプローブはほとんど透過しないが、外部PHを
２に変化させると膜透過性は９〜10倍も増加し、
再び外部PHを中性に戻すと膜透過性は元の遅い状
態に戻つた。外部PHの変化によるこのような10倍
の膜透過性の変化は二分子膜やカプセル膜にダメ
ージを与えることなく数回繰り返し可能であつ
た。
測定例 ２
実施例２で製造したナイロンカプセルをセル中
に入れ、外水層に0.1M HCl水溶液を極微量加
え、外水層のPHを２に変化させ、その時のカプセ
ル内水層から外水層への膜透過性を、電気伝導度
を測定することによつて追跡した。
その結果、外水層のPHが２になると、NaClが
カプセル外に透過して出ていくことが確認され
た。Measurement of membrane permeability using a fluorescent probe represented by the formula; Missile therapy or sustained release microcapsules using anticancer drugs and other various drugs; Fermentative production using enzymes or microorganisms; Production of antibodies and other immune substances using antigens; Physiology using tissues It can be widely applied to various industrial models, as well as industrial, biological, medical, agricultural chemical, and pharmaceutical applications. As detailed above, the nylon capsule according to the present invention is manufactured through the steps of manufacturing a nylon capsule, encapsulating a substance in the capsule, and applying a bilayer membrane-forming substance to the pores of the nylon membrane. However, since these processes themselves do not require much skill, they are extremely suitable for industrialization and mass production. Furthermore, changes in membrane permeability due to changes in PH are sensitive and reversible, and the nylon capsule has a long lifespan, so it can be used for a very long time in various applications. Hereinafter, the present invention will be explained in more detail with reference to Examples and Measurement Examples. Example 1 1 mmol of 1,10-bis(chlorocarbonyl)
0.03−0.1m mol as decane and crosslinker
Dissolve trymesoil chloride in 100ml of mixed solvent,
The 80 ml was placed in a Petri dish with a diameter of 15 cm. 2 ml of an aqueous solution containing ethylenediamine (0.38M) and NaOH (0.8M) was added dropwise to the above acid chloride solution using a glass syringe equipped with a No. 1 stainless steel needle. During this process, the Petri dish was kept in constant vibration. After dropping, add remaining acid chloride solution (20
ml) and allowed to react for 10 minutes while shaking the Petri dish. After the reaction, the solution was decanted and the capsules were washed three times with mixed organic solvent. By this method, nylon capsules with a uniform particle size of 2-2.5 mm in diameter and 5-10 μm in film thickness were obtained. Example 2 The nylon capsule produced in Example 1 was 0.1M
The capsule was thoroughly dialyzed in a saline solution for 3 days to trap the saline inside the capsule. In this way, 10 nylon capsules with saline sealed in the internal space were taken out, and these were added to the dialkyl compound. 10 mg was added to a solution of 1 ml of dodecane while heating to 60°C. Then let it cool to room temperature,
Thereafter, it was left to stand for 1 hour to obtain the desired nylon capsule. Example 3 Using the nylon capsule manufactured in Example 1 (diameter 2 mm, film thickness 1 μm), it was used as a fluorescent probe of 1×10 -3 M. The tube was dialyzed in a 0.01M phosphate buffer containing 0.01M phosphoric acid to encapsulate the fluorescent probe in the inner cavity. This is a bilayer membrane compound. In addition to the dodecane solution, the desired nylon capsules were obtained. Example 4 The same process as in Example 3 was repeated except that the dialkyl compound (2C 12 -suc-COO) used in Example 2 was used as the bilayer membrane compound to produce a PH-responsive nylon capsule containing a fluorescent probe. I got it. Example 5 A nylon capsule containing saline and coated with a bilayer membrane was prepared by repeating the same procedure as in Example 2 except that the following compound was used instead of the dialkyl compound. I got each. These nylon capsules were measured in accordance with the measurement examples described later, and as a result, it was confirmed that these nylon capsules had extremely excellent reversible PH response. Measurement example 1 The nylon capsule produced in Example 4 was placed in a quartz cell, the pH of the external aqueous phase was changed to 2 and 7 using 0.1N HCl and 0.1N NaOH, and the change in fluorescence intensity over time was measured by fluorescence analysis. Measured and got the results in the drawing. The figure illustrates the reversible change in the permeability of the fluorescent probe from the nylon capsule, and shows the change over time in the fluorescence intensity of the aqueous phase outside the capsule when the external pH was changed from 2 to 7. It is. Permeation was rapid in capsules not coated with a bilayer membrane, and membrane permeability of the probe did not change with changes in external pH. In capsules coated with 2C 12 −suc−COO bilayer, low temperature (25°C), i.e.
Below T c , permeation was slow, and even when the external pH was varied between 2 and 7, there was almost no difference in membrane permeability. However, at high temperatures (56°C), when the external pH is 7, the probe hardly passes through the membrane, but when the external pH is changed to 2, the membrane permeability increases by 9 to 10 times.
When the external pH was returned to neutral again, the membrane permeability returned to its original slow state. Such a 10-fold change in membrane permeability due to a change in external pH could be repeated several times without damaging the bilayer membrane or capsule membrane. Measurement Example 2 The nylon capsule manufactured in Example 2 was placed in a cell, and a very small amount of 0.1M HCl aqueous solution was added to the outer water layer to change the pH of the outer water layer to 2, and the outer water was removed from the capsule inner water layer at that time. Membrane permeability through the layers was followed by measuring electrical conductivity. As a result, it was confirmed that when the pH of the outer water layer reached 2, NaCl permeated out of the capsule.
図面は、ナイロンカプセルからの蛍光プローブ
の透過性の変化を図示したものである。
ａ……二分子膜でコートしないカプセル（56
℃）、ｂ……二分子膜でコートしたカプセル（56
℃、Tc以上）、ｃ……二分子膜でコートしたカプ
セル（25℃、Tc以下）。
The figure illustrates the change in permeability of a fluorescent probe from a nylon capsule. a...Capsule not coated with bilayer membrane (56
°C), b... Capsule coated with bilayer membrane (56
℃, Tc or higher), c... Capsule coated with bilayer membrane (25℃, Tc or lower).
Claims (1)
れる化合物の１種以上を充当してなるPHに応答す
るナイロンカプセル。 〔式中、ｎ及びｍは９〜19の整数を示し、Ｒ
は、−（CH2）l−COOH、 −（CH2）l−SO3Ｈ、 から選ばれるものである。 （但し、ｌは１〜５の整数を示し、R′及び
R″はＨ又はCH3を示す）〕[Scope of Claims] 1. A nylon capsule responsive to pH, which is formed by filling the pores of the nylon capsule with one or more of the compounds represented by formulas (1) to (4). [In the formula, n and m represent integers of 9 to 19, and R
is −(CH 2 ) l −COOH, −(CH 2 ) l −SO 3 H, It is selected from. (However, l represents an integer from 1 to 5, R' and
R″ indicates H or CH 3 )]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8406884A JPS60227827A (en) | 1984-04-27 | 1984-04-27 | Nylon capsule responding to ph |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8406884A JPS60227827A (en) | 1984-04-27 | 1984-04-27 | Nylon capsule responding to ph |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60227827A JPS60227827A (en) | 1985-11-13 |
| JPH0453581B2 true JPH0453581B2 (en) | 1992-08-27 |
Family
ID=13820173
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8406884A Granted JPS60227827A (en) | 1984-04-27 | 1984-04-27 | Nylon capsule responding to ph |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60227827A (en) |
-
1984
- 1984-04-27 JP JP8406884A patent/JPS60227827A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60227827A (en) | 1985-11-13 |
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