JPS5919541A - Gradually desorbing method by adsorbent - Google Patents

Abstract

PURPOSE:To make it possible to show excellent biocompatibility and to perform the gradual desorption of a substance to be adsorbed for a long period of time, by using a three-dimensional crosslinked polymer containing a recurring structural unit shown by formula in a specific ratio as an adsorbent. CONSTITUTION:A three-dimensional crosslinked polymer containing 55-99% recurring structural unit shown by formula (wherein R1 and R2 are 1-5C straight chain or branched alkyl group) is used as an adsorbent. There is not special limit with respect to a substance to be adsorbed by the adsorbent and to be gradually desorbed but one having both hydrophobic properties is pref. For example, as a hydrophobic functional group, there are a phenyl skeleton and an alkyl chain and, as a hydrophilic functional group, an amino group, a substituted amino group, a carboxyl group or a salt thereof or the like are mentioned and, further concretely, methyl orange, methyl dopa or chlornizine are designated. In order to perform the gradual desorption of the substance from the adsorbent, for example, said adsorbent is immersed in a proper liquid.

Description

[Detailed description of the invention] The present invention relates to a sustained release method using a new adsorbent.

Attempts to release chemical substances in a sustained manner have commonly been made using polymers in the form of capsules, especially as used in fertilizers. However, if we try to apply these drugs in vivo, there are problems with their biocompatibility, and furthermore, when they are administered orally, there is a problem with their retention time in the body, so it is not satisfactory. I'm not getting anything.

From this point of view, the present inventors have conducted repeated studies, and as a result, have discovered a method for maintaining excellent biocompatibility over a long period of time, and have completed the present invention.

Drugs are administered to living organisms orally or by injection, but
When administered orally, the absorbed substance enters the circulation and is subsequently eliminated. On the other hand, things that are not digested and absorbed remain in the body until they are excreted as feces, which lasts 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 entire effect can be maintained over a long period of time with only one administration.

The adsorbent in the present invention is a six-dimensional crosslinked body containing repeating structural units represented by the structural formula (Il).

(In the formula, R1 and R2 represent hydrogen or a linear or branched alkyl group having 1 to 5 carbon atoms.) The positions of the two substituents on the benzene nucleus may be ortho, meta, or para; is most preferred. Although R1 and R2 are hydrogen and a straight chain or branched alkyl group having 1 to 5 carbon atoms, specific examples of preferred embodiments include:
N-methylaminoethyl, N,N-dimethylamineethyl, aminoethyl, N-ethylaminoethyl, N,N-
These include diethylaminoethyl, N-isopropylamineethyl, N-n-butylaminoethyl, and the like.

The adsorbent is synthesized by adding a suitable 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.

The adsorbent in the present invention only needs to contain the repeating structural unit represented by the structural formula (I), and there is no problem in containing a sixth component in addition. Composition weight % of the substance represented by the structural formula (Il) based on the entire adsorbent
Although there is no particular restriction on the amount, it is preferably 5 to 99 inches, more preferably 20 to 95 inches. Although there are no particular restrictions on the shape of the adsorbent, those with a particle size of 11u11 or less are preferred.

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. For example, examples of hydrophobic functional groups include phenyl skeletons, alkyl chains, etc., and examples of hydrophilic functional groups include amine groups, substituted amino groups, ) groups, carboxyl groups or salts thereof, and sulfone groups or salts thereof. More specific examples include methyl orange, methyldopa, clonidine, and the like.

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 a living body, it is preferable to perform it under aseptic conditions.

There are no particular restrictions on how to perform sustained release of an adsorbed substance from a sustained release composition, but for example, there is a method of immersing the adsorbed substance in an appropriate 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.

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 constant amount.

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.

Examples of the present invention are shown below, but these are not intended to limit the scope of the present invention.

Reference example (synthesis of adsorbent) p-(2-dimethylamineethyl)styrene 16.22
, divinylbenzene (m/p: 7/3) 6.1
Mix 0.4yi of fx azobisisobutyronitrile with sufficient stirring to uniformly dissolve the mixture. Next, Met-Z■0.27,
This liquid mixture was added to 20Of water in which 22% of common salt had been dissolved, and the mixture was stirred and suspended. Gradually increase the temperature and raise to 90℃ for 6
Allowed time to react. After the reaction, the product was separated and then thoroughly washed with water and acetone. This adsorbent is designated as +1.

In a similar manner, an adsorbent was synthesized using p-(2-diethylamineethyl)styrene and p-(2-isopropylaminoethyl)styrene. These adsorbents are labeled +2 and +6, respectively.

The average particle size of these adsorbents was 100μ.

Comparative Example For comparison, a sustained release experiment of methyl orange was conducted using typical commercially available hydrogen adsorbents Sephadex (■) and Biogel (■).

After thoroughly drying both Sephadex G-25■ and Biogel P-2■, accurately weigh out 17 pieces each.
Next, the mixture was sufficiently swollen with water and then separated. 1 for this,
A 16 mmot/t methyl orange aqueous solution of 7-gold was added, and the mixture was shaken in a constant temperature bath at 57'C for 3 days to completely adsorb the methyl orange. The amount of methyl orange adsorbed was determined by determining the ultraviolet absorption spectrum 't611 of the solution before and after adsorption.
,7 X 10-'mot/S', biogel p-
2, it was 8.4 x 10-7 mol/g.

After P was removed from the methyl orange solution, the adsorbent was freeze-dried. Weigh out 100 ~ of the adsorbent that has adsorbed the methyl orange prepared in this way, and add 55% of the purified water to this.
rn1. Added all. 2 minutes, 7 minutes, while stirring thoroughly.
The concentration of methyl orange in the supernatant after 15 minutes, 60 minutes, 180 minutes, and 24 hours was determined by iUV.
As shown in the figure.

The results showed that with these adsorbents, the release of methyl orange was completed in just a few minutes.

Example 1 After the adsorbents of So1, +2 and +3 synthesized in Reference Example were made into free forms and sufficiently dried, a total of 9 of 12 were taken out, and methanol was added to each to sufficiently swell them. This was gradually replaced with water and then filtered. 1 mIn for this
An aqueous methyl orange solution of 7 ol/l was added in several portions, and the supernatant was adsorbed while being measured using an ultraviolet spectrum.
10-' mat/100m9. After separating the adsorbent from the methyl orange solution, it was freeze-dried. + o o mg of each of the thus prepared adhesive containing methyl orange was weighed and added to 5-mg of methanol, and the state of sustained release of methyl orange was measured by ultraviolet absorption spectroscopy. The results are shown in FIG.

Figure 2 As you can see, the adsorbents from 1 to 2 are 12
Sustained release over 0 days was observed.

Example 2 The same experiment as in Example 1 was conducted using 1-gropanol, 2-gropanol, 1-butanol, imbutyl alcohol, acetonitrile, and methyl ethyl ketone instead of methanol in Example 1.
As with the case in methanol, sustained release was observed for all of the adsorbents No. 3 over 50 days or more, and methyl orange was released in the same sequence.

Example 3 Using the same method as in Example 1, the adsorption amount of any of the adsorbents Nos. 1 to 3 was 6.7 x 10-'rno
Drill the hole so that it is t/100rn9. 100 ml of this sufficiently dried sustained release composition was poured into 5 ml. The mixture was mixed in 50 μg of bovine serum, and its sustained release curve was completely measured. The results are shown in Figure 3.

As can be seen from FIG. 5, the adsorbents +1 to +6 exhibited good sustained release properties over 10 days or more for 50-day bovine serum.

The 50% bovine serum used here was replaced every day to prevent corrosion. -! In addition, 6.5 μl of sodium azide was added as a preservative per 5 ml of serum.

Example 4 +1. After thoroughly drying the adsorbents in Nos. 2 and 6, 12 pieces each were weighed. Ethanol was added to this, and after the mixture was sufficiently swollen overnight, the ethanol was replaced with purified water. After distributing these adsorbents from house to house in a desired oxygen stream, o, 11m
5mj of ol/l methyldone aqueous solution! Add iζ,
The mixture was shaken for 5 days in a constant temperature bath kept at 37°C under a nitrogen atmosphere.

By measuring the ultraviolet absorption spectrum of the supernatant after adsorption, the amount of adsorbed methyl chloride was +1, +2, +
6, each 1. I x 10-4.0.7 x 10
-4 and 1,5 X 10-' mo7/r. After these adsorbents are distributed to each house, -8
Freeze-drying was performed at 0°C. Weigh 10 Omq of the adsorbent ff containing methyldopa prepared as described above, add 50% bovine serum 5-' (11-), and measure the ultraviolet spectrum of the supernatant at predetermined intervals. The sustained release of methyldopa was measured using the following method.The results are shown in FIG.

As can be seen from FIG. 4, the adsorbents of +1 to +5 exhibited sustained release over 4 days or more.

In addition, in order to prevent corrosion of bovine serum, serum should be sire exchanged every day.
Sodium azide f6.5mq/serum 5d=i as preservative
added. -! In addition, when quantifying methyldopa using ultraviolet absorption spectroscopy, double the amount of methyldopa was added to the sample.
After adding all of the IJ and centrifuging, the ultraviolet spectrum of Kanakura was measured in comparison with a reference under the same conditions.

Example 5 Clonidine was added to the adsorbents Nos. 1 to 6 in the same manner as in Example 4, except that an ethanol solution of clonidine (0.1 mol/l) was used instead of the aqueous solution of methyldopa. A sample was prepared.

The sustained release properties of the sample thus obtained in bovine blood grooves were measured using the same method as in Example 4, and the results are shown in Figure 5.

Sustained release over 6 days was observed.

Example 6 The following animal experiment was conducted using the +1 adsorbent 4001Q (5 HR) containing methyldopa prepared in Example 4 as a total sample of 5 HR (rats). Rats were anesthetized by injecting Nemptal into their peritoneal cavities. After that, the hair on the back was trimmed and disinfected with alcohol, and then the entire skin was incised for 2 to 3 crn, and the above-mentioned adsorbent was sprayed aseptically.The entire incision was sutured, and the lower limbs were treated with iodine tincture, and Ventrex was applied to the lower legs. was injected intramuscularly.This Ventrex injection was performed once a day for 2 to 3 days after the surgery.

Blood pressure was measured daily while comparing rats that underwent surgery in this way with rats that received no treatment at all. The result is shown in Figure 6.

The drug's efficacy was observed in rats fully loaded with the adsorbent.

Example 7 A swamp absorbing agent of +1 to 3 containing clonidine was prepared in the same manner as in Example 5.

An animal experiment using SHR was conducted using the same method as in Example 6, and as a result, drug efficacy was observed for 20 days or more.

(See Figure 7) On the other hand, when the body weights of the rats were also measured, better results were obtained compared to rats that were not given drugs.

(See Figure 8)

[Brief explanation of the drawing]

Figure 1 is a graph showing the release results of methyl orange into purified water using a commercially available adsorbent. Section 2 is a graph showing the results of measuring the sustained release of methyl orange into methanol in Example 1. Figure 6 4 is a graph showing the results of measuring the sustained release of methyl orange into the bovine blood groove in Example 3, and FIG. 4 shows the results of measuring the sustained release of methyldopa into the bovine blood groove in Example 4. 5 is a graph showing the results of all measurements of sustained release of clonidine into the bovine blood groove in Example 5, and FIG.
Figure 7 is a graph showing the effect of methyldopa as a blood pressure lowering agent using the adsorbent, Figure 7 is a graph showing the sustained release effect (blood pressure) of clonidine in Example 7, and Figure 8 is the same (sustained release of clonidine in Example 7). It is a graph showing the effect (body weight). Figure 1 Time direction (minutes) Figure 2 0 20 40 60 80 100 12
0 day 1'ail (Sun) Figure 3 B order 1'1 day) Figure 4 0 1 2 3 4 target 1 day) Figure 5 1 2 3 clear m (Sun)

Claims (1)

[Scope of Claims] (1) The following structural formula (■) (In the formula, R1 and R2?''ii hydrogen or carbon number 1 to 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 on the benzene nucleus of structural formula (I) are different. (3) Claim 1 in which R1 and R2 of structural formula m are hydrogen, methyl group, ethyl group, or isopropyl group
The sustained release method according to paragraphs 1 to 2. (4) The substance to be adsorbed has a phenyl skeleton or an alkyl chain, and has one or more of an amine group, a substituted amine group, a carboxyl group or a salt thereof, a sulfone group or a salt thereof. The sustained release method according to paragraphs 1 to 6. (5) The sustained release method according to any one of claims 1 to 4, wherein the substance to be sustainedly released is methyl orange, methyldopa, or clonidine. (6) The sustained release method according to any one of claims 1 to 5, wherein the sustained release is performed in a liquid. 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) In vivo Claim 1 for sustained release
The sustained release method according to paragraphs 5 to 5. 10. The sustained release method according to claims 1 to 9, wherein the OQ adsorbent is spherical and has a size of 1 mM or less.