JPH027695B2 - - Google Patents
Info
- Publication number
- JPH027695B2 JPH027695B2 JP57127614A JP12761482A JPH027695B2 JP H027695 B2 JPH027695 B2 JP H027695B2 JP 57127614 A JP57127614 A JP 57127614A JP 12761482 A JP12761482 A JP 12761482A JP H027695 B2 JPH027695 B2 JP H027695B2
- Authority
- JP
- Japan
- Prior art keywords
- sustained release
- release method
- adsorbent
- group
- substance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000003463 adsorbent Substances 0.000 claims description 41
- 238000013268 sustained release Methods 0.000 claims description 40
- 239000012730 sustained-release form Substances 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 18
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 claims description 17
- 229940012189 methyl orange Drugs 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 16
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 claims description 10
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 claims description 10
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 9
- 229960002896 clonidine Drugs 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 210000002966 serum Anatomy 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000001174 sulfone group Chemical group 0.000 claims description 2
- 230000002459 sustained effect Effects 0.000 claims description 2
- 229920006037 cross link polymer Polymers 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 12
- 239000012888 bovine serum Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- -1 N-methylaminoethyl Chemical group 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 238000002211 ultraviolet spectrum Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000003337 fertilizer Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- STZCRXQWRGQSJD-UHFFFAOYSA-M sodium;4-[[4-(dimethylamino)phenyl]diazenyl]benzenesulfonate Chemical compound [Na+].C1=CC(N(C)C)=CC=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-UHFFFAOYSA-M 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- BIOCRZSYHQYVSG-UHFFFAOYSA-N 2-(4-ethenylphenyl)-n,n-diethylethanamine Chemical compound CCN(CC)CCC1=CC=C(C=C)C=C1 BIOCRZSYHQYVSG-UHFFFAOYSA-N 0.000 description 1
- OHDSHGBRKMRPHC-UHFFFAOYSA-N 2-(4-ethenylphenyl)-n,n-dimethylethanamine Chemical compound CN(C)CCC1=CC=C(C=C)C=C1 OHDSHGBRKMRPHC-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000004847 absorption spectroscopy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940035429 isobutyl alcohol Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- WKEHOEOBHHJZPS-UHFFFAOYSA-N n-[2-(4-ethenylphenyl)ethyl]propan-2-amine Chemical compound CC(C)NCCC1=CC=C(C=C)C=C1 WKEHOEOBHHJZPS-UHFFFAOYSA-N 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Fertilizers (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Description
【発明の詳細な説明】
本発明は、新しい吸着剤による徐放法に関す
る。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new adsorbent-based sustained release method.
化学物質を除放しようとする試みは、殊に肥料
などで用いられているように、ポリマーを用いて
カプセル状にしたものが汎用されている。しか
し、これらのものを生体内に応用しようとすれ
ば、生体適合性に問題があつたり、さらに、経口
的にこれを投与する場合には、体内滞留時間が問
題となつたりするので、満足のいくものが得られ
ていない。 In attempts to release chemical substances in a controlled manner, capsules made of polymers have been widely used, especially in fertilizers. However, if we try to apply these drugs in vivo, there are problems with their biocompatibility, and furthermore, when we administer them orally, we have problems with their retention time in the body. I'm not getting anything.
このような見地から、本発明者らは検討を重ね
てきた結果、優れた生体適合性を有し、しかも、
長期に亘り維持する方法を発見し、本発明を完成
するに至つた。 From this point of view, the inventors have conducted repeated studies and found that it has excellent biocompatibility, and
We have discovered a method to maintain it for a long period of time, and have completed the present invention.
薬物等は経口および注射等により生体に投与さ
れるが、経口的に投与された場合、吸収されたの
は循環液中に入り、一次過程で消失されてしま
う。一方、消化吸収されなかつたものは、ふん便
として排出されるまでは体内に滞つているも
のゝ、その間ですらわずか数日である。したがつ
て、必要一定量の血中濃度を保つためには、一定
時間ごとに何らかの形で投薬しなければならない
のである。このような見地から、わずか１回の投
与で、その効果を長期に持続できることが要請さ
れることゝなる。 Drugs and the like are administered orally or by injection to living organisms, but when administered orally, the absorbed substances enter the circulating fluid and are eliminated in the primary process. On the other hand, food that is not digested and absorbed remains in the body until it is excreted as feces, and even that time is only a few days. Therefore, in order to maintain the necessary constant blood concentration, some form of medication must be administered at regular intervals. From this point of view, it is required that the effect can be maintained for a long period of time with just one administration.
本願発明における吸着剤は、構造式（）で示
されるくり返し構造単位を含む３次元架橋体であ
る。 The adsorbent in the present invention is a three-dimensional crosslinked body containing repeating structural units represented by the structural formula ().
（式中、R1およびR2は水素あるいは炭素数１〜
５のの直鎖または分枝のアルキル基を表わす。）
ベンゼン核に関する二つの置換基の位置はオル
ト、メタ、パラのいづれでもよいが、バラが最も
好ましい。R1およびR2は水素および炭素数１〜
５の直鎖または分枝のアルキル基であるが、好ま
しい態様の例を具体的に述べるならば、Ｎ−メチ
ルアミノエチル、Ｎ，Ｎ−ジメチルアミノエチ
ル、アミノエチル、Ｎ−エチルアミノエチル、
Ｎ，Ｎ−ジエチルアミノエチル、Ｎ−イソプロピ
ルアミノエチル、Ｎ−ｎ−ブチルアミノエチル等
である。 (In the formula, R 1 and R 2 are hydrogen or have 1 to 1 carbon atoms.
5 represents a straight chain or branched alkyl group. ) The positions of the two substituents with respect to the benzene nucleus may be any of ortho, meta, and para, but are most preferably disposed. R 1 and R 2 are hydrogen and carbon number 1-
5 is a straight chain or branched alkyl group, and specific examples of preferred embodiments include N-methylaminoethyl, N,N-dimethylaminoethyl, aminoethyl, N-ethylaminoethyl,
N,N-diethylaminoethyl, N-isopropylaminoethyl, N-n-butylaminoethyl, and the like.
吸着剤を合成する方法は、相当するアミノ基を
有するモノマーと架橋剤を適当量の溶媒を加えた
のち、懸濁重合することによつて得られる。用い
る架橋剤に制限はないが、ジビニルベンゼンは好
ましい態様の例である。 The adsorbent is synthesized by adding a suitable amount of a solvent to a monomer having a corresponding amino group and a crosslinking agent, and then subjecting the mixture to suspension polymerization. Although there are no restrictions on the crosslinking agent used, divinylbenzene is an example of a preferred embodiment.
本発明における吸着剤は、構造式（）で示さ
れるくり返し構造単位を含有しておればよいので
あつて、他に第３成分が含有されることは何らさ
しつかえない。構造式（）で示される物質の吸
着剤全体に対する組成重量％に特に制限はない
が、好ましくは５〜99％、さらに好ましくは20〜
95％である。吸着剤の形状には特に制限はない
が、粒径１mm以下のものが好ましい。 It is sufficient that the adsorbent in the present invention contains a repeating structural unit represented by the structural formula (), and there is no problem in containing a third component in addition to the repeating structural unit. There is no particular restriction on the composition weight % of the substance represented by the structural formula () relative to the entire adsorbent, but it is preferably 5 to 99%, more preferably 20 to 99%.
It is 95%. There are no particular restrictions on the shape of the adsorbent, but one with a particle size of 1 mm or less is preferred.
吸着剤に吸着させ、徐放させる物質に特に制限
はないが、疎水性と親水性の双方の性質を有する
如きものが好ましい。例えば疎水性官能基として
は、フエニル骨格、アルキル鎖などであり、親水
性官能基としては、アミノ基、置換アミノ基、カ
ルボキシル基またはその塩、スルホン基またはそ
の塩などが考えられる。さらに具体的にその例を
述べるならば、メチルオレンジ、メチルドーパ、
クロニジン等である。 Although there are no particular restrictions on the substance to be adsorbed onto the adsorbent and released in a sustained manner, it is preferable to use a substance that has both hydrophobic and hydrophilic properties. Examples of hydrophobic functional groups include phenyl skeletons and alkyl chains, and examples of hydrophilic functional groups include amino groups, substituted amino groups, carboxyl groups or salts thereof, and sulfone groups or salts thereof. More specific examples include methyl orange, methyldopa,
Clonidine, etc.
徐放させようとする物質を吸着剤に吸着させる
方法は従来から知られた方法をとることができ
る。例えば、被吸着物質を溶媒に溶解させてお
き、これに吸着剤を加えて吸着させる方法などで
ある。吸着させる量は、被吸着物質の濃度等によ
り任意の値を取らせることが可能である。吸着剤
はあらかじめ所定の溶媒で膨潤させておくことは
好ましい態様の例である。このようにしてつくら
れた徐放性組成物は、その使用目的に応じてその
まゝ用いてもよいし、乾燥などの処置等も行うこ
とができる。ことに生体に適用する場合は、無菌
状態で行うことが好ましい。 Conventionally known methods can be used to adsorb the substance to be released in an adsorbent manner. For example, there is a method in which the substance to be adsorbed is dissolved in a solvent, and an adsorbent is added to the solution to adsorb the substance. The amount to be adsorbed can be set to any value depending on the concentration of the substance to be adsorbed. A preferred embodiment is to swell the adsorbent with a predetermined solvent in advance. The sustained-release composition thus prepared may be used as is or may be subjected to treatments such as drying, depending on its intended use. In particular, when it is applied to living organisms, it is preferable to carry out the treatment under aseptic conditions.
徐放性組成物から被吸着物質の徐放を行うにあ
たつては特に制限はないが、例えば、適当な液体
中へ浸漬させる手法がある。液体としては水、生
理食塩水、リン酸緩衝液、有機溶媒、血清などが
その例としてあげられる。徐放性組成物をそのま
ま生体内に埋めこみ、生体内において徐放させる
のは好ましい態様例である。 There are no particular restrictions on the sustained release of the adsorbed substance from the sustained release composition, but for example, there is a method of immersing the adsorbed substance in a suitable liquid. Examples of the liquid include water, physiological saline, phosphate buffer, organic solvent, and serum. A preferred embodiment is to implant the sustained-release composition into a living body as it is to allow sustained release in the living body.
本発明における吸着剤を用いた徐放性組成物を
用いれば、驚くべきことに長期に亘つて被吸着物
質の徐放を行うことができる。徐放時間は数日か
ら数ケ月に及び、この間ほゞ一定の量で被吸着物
質の徐放が行われる。 Surprisingly, by using the sustained release composition using the adsorbent of the present invention, it is possible to sustainably release the adsorbed substance over a long period of time. The sustained release time ranges from several days to several months, and during this period, the adsorbed substance is sustainedly released in a substantially constant amount.
本発明における徐放性組成物は、医薬品、遅効
性肥料などとして用いることができ、生体に対し
すぐれた適合性を示した。 The sustained-release composition of the present invention can be used as a medicine, slow-release fertilizer, etc., and exhibits excellent compatibility with living organisms.
以下に本発明の実施例を示すが、これらは本発
明の範囲を制限するものではない。 Examples of the present invention are shown below, but these are not intended to limit the scope of the present invention.
参考例
（吸着剤の合成）
ｐ−（２−ジメチルアミノエチル）スチレン
16.2ｇ、ジビニルベンゼン（ｍ／ｐ：７／３）
6.1ｇ、アゾビスイソブチロニトリル0.4ｇを充分
撹拌混合し、均一に相溶させる。次にメトローズ
0.2ｇ、食塩２ｇを溶解させた水200ｇの中に、
この調合液を入れ、撹拌懸濁させた。温度を徐々
にあげ、90℃で６時間反応させた。反応後、生成
物は別し、続いて水およびアセトンにて充分洗
浄した。この吸着剤を＃１とする。Reference example (synthesis of adsorbent) p-(2-dimethylaminoethyl)styrene
16.2g, divinylbenzene (m/p: 7/3)
6.1 g of azobisisobutyronitrile and 0.4 g of azobisisobutyronitrile are thoroughly stirred and mixed to uniformly dissolve them. Next is Metrose
In 200g of water in which 0.2g and 2g of salt were dissolved,
This mixture was added and stirred to suspend. The temperature was gradually raised and the reaction was carried out at 90°C for 6 hours. After the reaction, the product was separated and then thoroughly washed with water and acetone. This adsorbent is designated as #1.
同様の手法にて、ｐ−（２−ジエチルアミノエ
チル）スチレンおよびｐ−（２−イソプロピルア
ミノエチル）スチレンを用い吸着剤を合成した。
これらの吸着剤を各々、＃２および＃３とする。 In a similar manner, an adsorbent was synthesized using p-(2-diethylaminoethyl)styrene and p-(2-isopropylaminoethyl)styrene.
These adsorbents are designated #2 and #3, respectively.
これらの吸着剤の平均粒径はいずれも100μで
あつた。 The average particle size of these adsorbents was 100μ.
比較例
代表的な市販の水素吸着剤であるセフアデツク
ス
およびバイオゲル
について、比較のために
メチルオレンジの徐放実験を行つた。Comparative Example For comparison, a sustained release experiment of methyl orange was conducted using Cephadex and Biogel, which are typical commercially available hydrogen adsorbents.
セフアデツクスＧ−25
およびバイオゲルＰ−
２
を各々充分乾燥させたのち、１ｇずつを正確
に計りとり、次に水で充分膨潤させたのち、別
した。これに1.16ｍmol／のメチルオレンジ水
溶液７mlを加え、３日間37℃の恒温槽で振とうさ
せ、メチルオレンジを吸着させた。吸着前後の溶
液の紫外吸収スペクトルを測定することにより、
メチルオレンジの吸着量を求めたところ、セフア
デツクスＧ−25では2.7×10-6mol／ｇ、バイオゲ
ルｐ−２では8.4×10-7mol／ｇであつた。 Cephadex G-25 and Biogel P-
After sufficiently drying each sample, 1 g of each sample was accurately weighed out, swelled sufficiently with water, and then separated. To this was added 7 ml of a 1.16 mmol/aqueous solution of methyl orange, and the mixture was shaken in a constant temperature bath at 37° C. for 3 days to adsorb methyl orange. By measuring the ultraviolet absorption spectra of the solution before and after adsorption,
When the amount of methyl orange adsorbed was determined, it was 2.7×10 −6 mol/g for Cephadex G-25 and 8.4×10 −7 mol/g for Biogel p-2.
吸着剤はメチルオレンジ溶液から別したの
ち、凍結乾燥を行つた。このようにして調製され
たメチルオレンジを吸着した吸着剤100mgを計り
とり、これに精製水５mlを加えた。充分に撹拌を
しながら２分、７分、15分、60分、180分、およ
び24時間後の上澄液中のメチルオレンジの濃度を
UVで測定した結果を第１図に示す。 The adsorbent was separated from the methyl orange solution and then freeze-dried. 100 mg of the adsorbent adsorbing methyl orange thus prepared was weighed out, and 5 ml of purified water was added thereto. While stirring thoroughly, measure the concentration of methyl orange in the supernatant after 2 minutes, 7 minutes, 15 minutes, 60 minutes, 180 minutes, and 24 hours.
Figure 1 shows the results of UV measurements.
この結果、これらの吸着剤では、わずか数分に
てメチルオレンジの放出が完了することがわかつ
た。 The results showed that with these adsorbents, the release of methyl orange was completed in just a few minutes.
実施例 １
参考例で合成した＃１、＃２および＃３の吸着
剤をフリー型にして充分乾燥させたのち、１PH正
確に計りとり、各々にメタノールを加えて充分膨
潤させた。これを徐々に水に置換したのち、過
した。これに１ｍmol／のメチルオレンジ水溶
液を７mlずつ数回に分けて加え、上澄液を紫外ス
ペクトルで測定しながら吸着させ、＃１〜３のい
ずれの吸着剤の吸着量も1.67×10-6mol／100mgと
した。吸着剤はメチルオレンジ溶液から別後、
凍結乾燥を行つた。このようにして調整したメチ
ルオレンジを含む吸着剤を各々100mg秤量し、こ
れに５mlずつのメタノールを加えてメチルオレン
ジの徐放状況を紫外吸収スペクトルによつて測定
した。この結果を第２図に示す。Example 1 The adsorbents #1, #2, and #3 synthesized in Reference Example were made into free forms and sufficiently dried, then weighed to an accuracy of 1 PH, and methanol was added to each to sufficiently swell. This was gradually replaced with water and then filtered. Add 7 ml of 1 mmol/ml aqueous solution of methyl orange to this in several portions, adsorb the supernatant liquid while measuring it with an ultraviolet spectrum, and the adsorption amount of all adsorbents #1 to 3 was 1.67×10 -6 mol. /100mg. After separating the adsorbent from the methyl orange solution,
Lyophilization was performed. 100 mg of each of the methyl orange-containing adsorbents prepared in this way was weighed out, 5 ml of methanol was added to each, and the state of sustained release of methyl orange was measured by ultraviolet absorption spectroscopy. The results are shown in FIG.
第２図からわかるように、＃１〜３の吸着剤
は、120日以上に亘る徐放性が見られた。 As can be seen from FIG. 2, adsorbents #1 to #3 exhibited sustained release over 120 days or more.
実施例 ２
実施例１におけるメタノールのかわりに、１−
プロパノール、２−プロパノール、１−ブタノー
ル、イソブチルアルコール、アセトニトリル、メ
チルエチルケトンを用いて、各々実施例１と同様
の実験をしたところ、＃１〜３のいずれの吸着剤
についても、メタノール中の場合と同様に、50日
以上に亘つて徐放性が見られ、同様なパターンで
メチルオレンジを放出した。Example 2 Instead of methanol in Example 1, 1-
Experiments similar to those in Example 1 were conducted using propanol, 2-propanol, 1-butanol, isobutyl alcohol, acetonitrile, and methyl ethyl ketone, and it was found that all adsorbents #1 to #3 were similar to those in methanol. The drug released methyl orange in a similar pattern, with sustained release over 50 days.
実施例 ３
実施例１と同様の手法にて、＃１〜３のいずれ
の吸着剤においても、その吸着量が6.7×
10-6mol／100mgとなるようにした。充分乾燥さ
せたこの徐放組成物100mgを５mlの50％牛血清中
に混合し、その徐放曲線を測定した。その結果を
第３図に示す。Example 3 Using the same method as in Example 1, the adsorption amount of any adsorbent #1 to #3 was 6.7×
The amount was adjusted to 10 -6 mol/100mg. 100 mg of this sufficiently dried sustained release composition was mixed in 5 ml of 50% bovine serum, and its sustained release curve was measured. The results are shown in FIG.
第３図からわかるように、＃１〜３の吸着剤
は、50％牛血清に対し、10日以上に亘る良好な徐
放性を示した。 As can be seen from FIG. 3, adsorbents #1 to #3 exhibited good sustained release over 10 days with respect to 50% bovine serum.
なお、ここで用いた50％牛血清は、腐食を防ぐ
ために毎日とりかえた。また、防腐剤としてアジ
化ソーダを、血清５mlに対し6.5mg加えた。 The 50% bovine serum used here was replaced every day to prevent corrosion. In addition, 6.5 mg of sodium azide was added as a preservative per 5 ml of serum.
実施例 ４
＃１、＃２および＃３の吸着剤をを充分乾燥さ
せた後、各々１ｇを秤量した。これにエタノール
を加え、１晩充分に膨潤させたのち、エタノール
を精製水に置換した。これらの吸着剤を窒素気流
中で別したのち、0.11mol／のメチルドーパ
水溶液５mlずつを加え、窒素雰囲気下で37℃に保
つた恒温槽で５日間振とうさせた。Example 4 After thoroughly drying the adsorbents #1, #2 and #3, 1 g of each was weighed. Ethanol was added to this, and after the mixture was sufficiently swollen overnight, the ethanol was replaced with purified water. After these adsorbents were separated in a nitrogen stream, 5 ml of a 0.11 mol/ml aqueous solution of methyldopa was added, and the mixture was shaken for 5 days in a constant temperature bath kept at 37° C. under a nitrogen atmosphere.
吸着後の上澄液の紫外吸収スペクトルを測定す
ることにより吸着されたメチルドーパの量は、
＃１、＃２、＃３について、各々1.1×10-4、0.7
×10-4および1.5×10-4mol／ｇであることがわか
つた。これらの吸着剤は各々別した後、−80℃
にて凍結乾燥を行つた。以上のようにして調製し
たメチルドーパを含む吸着剤を100秤量し、これ
に50％牛血清５mlを加えて、所定時間ごとに上澄
液の紫外スペクトルを測定することにより、メチ
ルドーパの徐放性を測定した。この結果を第４図
に示す。 The amount of methyldopa adsorbed was determined by measuring the ultraviolet absorption spectrum of the supernatant after adsorption.
1.1×10 -4 and 0.7 for #1, #2, and #3, respectively
×10 −4 and 1.5×10 −4 mol/g. These adsorbents were separated and heated to -80°C.
Freeze-drying was performed at Weighed 100 pieces of the adsorbent containing methyldopa prepared as described above, added 5 ml of 50% bovine serum, and measured the ultraviolet spectrum of the supernatant at predetermined intervals to determine the sustained release of methyldopa. It was measured. The results are shown in FIG.
第４図からわかるように、＃１〜３の吸着剤は
４日以上に亘つて徐放性を示した。 As can be seen from FIG. 4, adsorbents #1 to 3 exhibited sustained release over 4 days or more.
なお、牛血清の腐食を防ぐために、血清は毎日
交換し、防腐剤としてアジ化ソーダを6.5mg／血
清５mlを加えた。また、紫外吸収スペクトルでメ
チルドーパを定量するに当つては、サンプルに２
倍量のアセトニトリルを加え、遠心分離したのち
に、同条件のレフアランスとの比較を含め紫外ス
ペクトルの測定を行つた。 In order to prevent corrosion of the bovine serum, the serum was replaced every day, and 6.5 mg of sodium azide/5 ml of serum was added as a preservative. In addition, when quantifying methyldopa using ultraviolet absorption spectra, it is necessary to
After adding twice the amount of acetonitrile and centrifuging, ultraviolet spectra were measured, including comparison with re-evalance under the same conditions.
実施例 ５
メチルドーパの水溶液のかわりに、クロニジン
のエタノール溶液（0.1mol／）を用いた他は、
実施例４と同様の手法にて、＃１〜＃３の吸着剤
にクロニジンを含有させたサンプルを調製した。
このようにして得られたサンプルを実施例４と同
様の手法にて、牛血清中での徐放性を測定した結
果を第５図に示す。Example 5 An ethanol solution of clonidine (0.1 mol/) was used instead of an aqueous solution of methyldopa.
Samples containing clonidine in adsorbents #1 to #3 were prepared in the same manner as in Example 4.
The sustained release properties of the thus obtained sample in bovine serum were measured using the same method as in Example 4, and the results are shown in FIG.
３日以上に亘る徐放性が見られた。 Sustained release over 3 days was observed.
実施例 ６
実施例４において調製したメチルドーパを含む
＃１の吸着剤400mgを用い、SHR（ラツト）を検
体として、次のような動物実験を行つた。ラツト
の腹腔のネンブタールを注射して麻酔した後、背
中の毛を刈取り、アルコールで消毒した後、皮膚
を２〜３cm切開し、無菌的に計りとつた上記吸着
剤を散布した。切開部を縫合し、ヨードチンキで
消毒後、下肢にペントレツクスを筋注した。この
ペントレツクス注射は術後２〜３日、１回／日の
割で行つた。Example 6 Using 400 mg of #1 adsorbent containing methyldopa prepared in Example 4, the following animal experiment was conducted using SHR (rat) as a specimen. After the rats were anesthetized by injecting Nembutal into their abdominal cavities, the hair on their backs was clipped and disinfected with alcohol.The skin was then incised by 2 to 3 cm, and the measured amount of the adsorbent was sprayed in an aseptic manner. After the incision was sutured and disinfected with iodine tincture, Pentrex was injected intramuscularly into the lower leg. This Pentrex injection was performed once a day for 2 to 3 days after the surgery.
このようにして手術を処したラツトと全く処置
をしないラツトとを比較しながら、血圧の測定を
日々行つた。この結果を第６図に示す。 Blood pressure was measured daily while comparing rats that underwent surgery in this manner with rats that received no treatment at all. The results are shown in FIG.
吸着剤を与えたラツトに薬効が認められた。 Medicinal efficacy was observed in rats given the adsorbent.
実施例 ７
実施例５と同様の手法にてクロニジンを含む
＃１〜３の吸着剤を合成した。Example 7 Adsorbents #1 to #3 containing clonidine were synthesized in the same manner as in Example 5.
実施例６と同様の手法にて、SHRを用いた動
物実験を行つた結果、20日以上の薬効が見られ
た。（第７図参照）
一方、ラツトの体重についても追跡測定したと
ころ、薬品を与えないラツトに比し良好な結果が
得られた。（第８図参照） An animal experiment using SHR was conducted in the same manner as in Example 6, and as a result, efficacy was observed for 20 days or more. (See Figure 7) On the other hand, when the rats' body weights were also tracked and measured, better results were obtained compared to rats that were not given the drug. (See Figure 8)
第１図は市販吸着剤によるメチルオレンジの精
製水への放出結果を示すグラフ、第２図は実施例
１におけるメタノール中へのメチルオレンジの徐
放状況を測定した結果を示すグラフ、第３図は実
施例３における牛血清中へのメチルオレンジの徐
放状況を測定した結果を示すグラフ、第４図は実
施例４における牛血清中へのメチルドーパの徐放
状況を測定した結果を示すグラフ、第５図は実施
例５における牛血清中へのクロニジンの徐放状況
を測定した結果を示すグラフ、第６図は実施例６
における＃１の吸着剤によるメチルドーパの血圧
降下剤としての効果を示すグラフ、第７図は実施
例７におけるクロニジンの徐放効果（血圧）を示
すグラフ、第８図は同じく実施例７におけるクロ
ニジン徐放効果（体重）を示すグラフである。
Figure 1 is a graph showing the release results of methyl orange into purified water using a commercially available adsorbent, Figure 2 is a graph showing the results of measuring the sustained release of methyl orange into methanol in Example 1, and Figure 3 is a graph showing the results of measuring the sustained release of methyl orange into methanol in Example 1. is a graph showing the results of measuring the sustained release status of methyl orange into bovine serum in Example 3, FIG. 4 is a graph showing the results of measuring the sustained release status of methyldopa into bovine serum in Example 4, FIG. 5 is a graph showing the results of measuring the sustained release status of clonidine into bovine serum in Example 5, and FIG. 6 is a graph showing the results of measuring the sustained release status of clonidine into bovine serum in Example 5.
Figure 7 is a graph showing the effect of clonidine sustained release (blood pressure) in Example 7, and Figure 8 is a graph showing the effect of clonidine sustained release (blood pressure) in Example 7. It is a graph showing the release effect (body weight).
Claims (1)
５の直鎖または分枝のアルキル基を表わす。）で
示される繰り返し構造単位を５〜99％含む三次元
架橋ポリマーを吸着剤として使用することを特徴
とする被吸着物質の徐放法。 ２ 構造式（）のベンゼン核に関する二つ置換
基の位置がパラである特許請求の範囲第１項記載
の徐放法。 ３ 構造式（）のR1およびR2が水素、メチル
基、エチル基またはイソプロピル基である特許請
求の範囲第１項ないし第２項記載の徐放法。 ４ 被吸着物質がフエニル骨格またはアルキル鎖
を有し、かつアミノ基、置換アミノ基、カルボキ
シル基またはその塩、スルホン基またはその塩の
うち一つ以上を有する物質である特許請求の範囲
第１項ないし第３項記載の徐放法。 ５ 徐放される物質がメチルオレンジ、メチルド
ーパ、クロニジンである特許請求の範囲第１項な
いし第４項記載の徐放法。 ６ 液体中を徐放するようにした特許請求の範囲
第１項ないし第５項記載の徐放法。 ７ 液体が水または血清である特許請求の範囲第
６項記載の徐放法。 ８ 液体が有機溶媒である特許請求の範囲第６項
記載の徐放法。 ９ 生体内で徐放するようにした特許請求の範囲
第１項ないし第５項記載の徐放法。 １０ 吸着剤が１mm以下の球形である特許請求の
範囲第１項ないし第９項記載の徐放法。[Claims] 1 The following structural formula () (In the formula, R 1 and R 2 are hydrogen or have 1 to 1 carbon atoms.
5 represents a straight chain or branched alkyl group. ) A method for sustained release of an adsorbed substance, characterized in that a three-dimensionally crosslinked polymer containing 5 to 99% of repeating structural units represented by the following formula is used as an adsorbent. 2. The sustained release method according to claim 1, wherein the positions of the two substituents with respect to the benzene nucleus in structural formula () are para. 3. The sustained release method according to claims 1 and 2 , wherein R 1 and R 2 in structural formula () are hydrogen, methyl group, ethyl group, or isopropyl group. 4. Claim 1, wherein the substance to be adsorbed has a phenyl skeleton or an alkyl chain, and has one or more of an amino group, a substituted amino group, a carboxyl group or a salt thereof, a sulfone group or a salt thereof. to the sustained release method described in paragraph 3. 5. The sustained release method according to claims 1 to 4, wherein the substance to be sustained released is methyl orange, methyldopa, or clonidine. 6. The sustained release method according to claims 1 to 5, which allows sustained release in a liquid. 7. The sustained release method according to claim 6, wherein the liquid is water or serum. 8. The sustained release method according to claim 6, wherein the liquid is an organic solvent. 9. The sustained release method according to claims 1 to 5, which allows sustained release in vivo. 10. The sustained release method according to claims 1 to 9, wherein the adsorbent has a spherical shape of 1 mm or less.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57127614A JPS5919541A (en) | 1982-07-23 | 1982-07-23 | Gradually desorbing method by adsorbent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57127614A JPS5919541A (en) | 1982-07-23 | 1982-07-23 | Gradually desorbing method by adsorbent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5919541A JPS5919541A (en) | 1984-02-01 |
| JPH027695B2 true JPH027695B2 (en) | 1990-02-20 |
Family
ID=14964441
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57127614A Granted JPS5919541A (en) | 1982-07-23 | 1982-07-23 | Gradually desorbing method by adsorbent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5919541A (en) |
-
1982
- 1982-07-23 JP JP57127614A patent/JPS5919541A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5919541A (en) | 1984-02-01 |
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