JPH0379608A - Acrylamide-acrylic acid ipn - Google Patents

Abstract

PURPOSE:To obtain the subject novel IPN making possible to deliver drug with change of temperature by preparing a gel with reacting a solution containing monomer such as acrylamide and a crosslinking agent on a plate, dipping in a solution containing monomer such as acrylic acid and crosslinking agent and polymerizing. CONSTITUTION:Acrylamide is dissolved in a solvent together with an alkyl (meth)acrylate, crosslinking agent and polymerization initiator and reacted on a plate to obtain polyacrylamide gel as a first gel, then said first gel is dipped in a solution containing acrylic acid, an alkyl (meth)acrylate, crosslinking agent and polymerization initiator, thus polymerized to afford the subject interpenetrating network polymeric structural material (IPN) composed of three- dimensional copolymer expressed by formula l [X is crosslinking agent; I is expressed by formula II (k and l are expressed by formula III; R1 is H or CH3, R2 is 1-20C alkyl); p is 10<17>-10<21> to 1g polymer gel] and three-dimensional copolymer expressed by formula IV [II is expressed by formula V (m and n are expressed by formula VI); I and II are stabilized with hydrogen bonding below transition temperature].

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel alternating infiltration network polymer structure that enables drug delivery through temperature changes.

[Conventional technology]

The next generation of drugs will be able to maintain effective drug concentrations in the blood over long periods of time, or drugs that act only on target tissues, i.e., in the right amount, when the right time, and the right amount. This is a drug that can be applied to specific locations, and there are great expectations for its realization. A systemized formulation containing any of these concepts can be used as a drug delivery system (d
rug delivery system, D D
In general, in this DDS, the former two are called controlled-release preparations, and the latter are called controlled-release preparations (contr.S).

Research is being conducted from the perspective of 11ed release and targeting, but a systemized preparation that realizes all of these concepts is the ideal DS, and will be used to develop artificial metabolic organs, future models, etc. It is intended to realize a therapeutic organ.

Stimulus-responsive DO8 is divided into chemical stimulus-responsive D''DS and physical stimulus-responsive DDS, but physical stimulus-responsive DDS
Among these, drug release systems that respond to temperature have also been studied. It has been reported that polyacrylamide gel partially hydrolyzed with alkali shows a gel phase transition phenomenon in aqueous acetone system [Tanaka (T.
ka) Physical Review Letters (Phys, Re
v. Letters) 40(12), 820 (1978
)) Since then, it has been reported that alkyl-substituted amides exhibit extremely large swelling changes with temperature changes in water.

The present inventors previously found that alkyl-substituted amide gels have low mechanical strength, so they used two methods to improve the mechanical strength while maintaining the temperature sensitivity of the gels, thereby creating membranes and monolithic devices. One is a random copolymer of alkyl-substituted acrylamide and a hydrophobic comonomer with a low glass transition temperature (for example, butyl methacrylate: BMA), and the other
One is an interpenetrated network (Inter
Penetrate Networks: IPN
) [Surface Science Vol. 10 No. 2 9
0-95 (1989)).

This IPN is produced by radically polymerizing alkyl-substituted acrylamide and at the same time addition-polymerizing oligomers with 5-terminated hydroxyl groups (polyethylene oxide: PEO, polytetramethylene oxide: PTMO) with trifunctional isocyanate to create a structure in which different types of polymer chains are entangled. This was obtained by These conventional alkylamide polymer gels and the like release drugs at low temperatures, but do not release drugs at high temperatures.

(Problems to be Solved by the Invention) Conventionally known thermosensitive polymer gels are of a type that increases swelling at low temperatures, causing drug release, and rapidly decreases swelling at high temperatures, stopping release. However, this polymer gel cannot be used directly to create a new antipyretic system.

It is a well-known fact that when fever occurs due to illness, lowering the fever with antipyretics is an extremely effective treatment. If there were a system for administering antipyretic drugs that only worked when there was a fever, it would be possible to use antipyretic drugs safely in children and the elderly in terms of side effects, by using a polymer gel whose release changes with temperature. It is hoped that a new type of drug will be developed that releases an effective amount of antipyretic only when the patient has a fever, and stops releasing the drug as soon as the fever returns to normal.

[Means to solve the problem]

The present inventors have conducted various studies on thermosensitive polymers that can release an effective amount of antipyretics only when a fever occurs, and stop releasing the drug as soon as the temperature returns to normal. It was discovered that a specific copolymer of AAc) is a low-temperature-shrinking-high-temperature-swelling gel that can achieve the above object, and the present invention has achieved this.

That is, the present invention provides a three-dimensional copolymer of general formula A and general formula B
Alternately infiltrated network polymer structure (IP) with three-dimensional copolymer of
N): + [In the formula, is -CnH, n-1
(n=1-20), about 1017 per gram of remargel
~1021.

circle and its manufacturing method.

The IPN of the present invention is an acrylamide (AAm)-acrylic acid (AAc) IPN. IPN is an Inter Penetrate Network.
Networks: I P N ), which is a structure in which cross-linked polymers are physically entangled, rather than covalently bonded, in an alternately infiltrated network structure.

And for the IPN of the present invention, A A m and A
As shown in formulas I and ■ below the transition temperature, A c is
It is stabilized by a complex structure formed by hydrogen bonds. This complex is a system that can be dissociated by increasing temperature.

Configure. Particularly in water at low temperatures, this complex is stable, but as the temperature rises, this complex is rapidly destroyed. In other words, it shows low swelling in water at low temperatures, but the transition temperature (T, P)
When the temperature exceeds this level, hydrogen bonds are broken and swelling increases rapidly.

What is the transition temperature (T, P)? and (2) can be arbitrarily controlled by the furkyl methacrylate composition.

That is, by increasing the alkyl methacrylate composition, T and P can be controlled between lO<0>C and 50<0>C.

When the molecular weight of I and ■ is expressed as the molecular weight between crosslinking points, it is approximately 500.
~ Approximately 100,000. The molecular weight between crosslinking points can be determined according to the following formula based on the monomer amount and crosslinking agent concentration during synthesis.

■ or molar molecular weight of U - (AAm or AAc molecular weight)
BX) or ■ tens of monomer molecules (BMA molecular weight)
c, BMA content) In the case of the present invention, the crosslinking concentration is o, oos mol% to 10 mol%, so the molecular weight between the crosslinks of ■ and ■ is about 500 to
It varies within a range of about 100,000.

It shows the monomer composition of the chemical composition, and can be calculated from elemental analysis values.

The acrylamide-acrylic acid IPN of the present invention is produced, for example, as follows.

S I P N (Sequential Inter
Penetrating Polymer Netwo
rk) Method 1, acrylamide (AAm), alkyl methacrylate or alkyl acrylate, a crosslinking agent, and a polymerization initiator are dissolved in a solvent, stirred in a nitrogen stream, and reacted on a glass plate. Sulfoxide (D
MSO) and purified water to obtain a polyacrylamide gel.

Examples of crosslinking agents include the following: (1) Diacrylic and methacrylic derivatives 4 R*;-H or -CH□ R*: -H or -CH.

n=1-100 R1-CHs, R*: When H-n=1, rangelicol dimethacrylate (2) diacrylamide derivative ethyl NH-C) I, -NH methylenebisacrylamide (3) divinyl derivative divinylbenzene 4 ) diallyl derivative diallyl phthalate and the like.

The initiator is peroxide, [t-butyl peroxide octoate (B
PO), etc.], diazo compounds (NN'-azobisisobutyronitrile (AIBN), etc.), solvents include dimethyl sulfoxide (DMSO) and mixed solvents of DMSO and water, alcohol, dioxane, dimethylformamide, (DMF), etc. is used.

Alkyl methacrylate or alkyl acrylate is
AAm alone is introduced because its strength is low. This content is used at a mole fraction of 0 to 0.7 with respect to A m. Further, the amount of the crosslinking agent is 0.005 mol % to 10 mol % based on the total monomers.

Reaction temperature is 20-90'C, preferably 60-80'C
One reaction time is 1 to 72 hours, preferably 12 to 48 hours.

2゜Synthesis of Acrylamide-Acrylic Acid IPN - Acrylic acid (AAc), alkyl methacrylate or alkyl acrylate, and a crosslinking agent are impregnated into the gel and polymerized to form AA.
Synthesize m-AAc IPN. This involves soaking the first gel in an AAc aqueous solution.

This can be done by a swelling method. Measure the water content of the first gel before introducing AAc so that the concentration of the AAC aqueous solution is equal to the AAm concentration in the first gel,
The AAm concentration is calculated from the water content in the first gel and the AA weight, and an AAc aqueous solution approximately equal to this concentration is adjusted. A cross-linking agent and an initiator are added to the AAc aqueous solution that is approximately equal to the AAm concentration to prepare a second monomer solution, and the first gel prepared above is immersed in the second monomer solution, and then heated between glass plates. Wash with purified water and synthesize IPN.

The crosslinking agent and its proportions in this synthesis are the same as in the preparation of the first gel. In addition, the initiator is a redox initiator such as ammonium persulfate, a water-soluble diazo initiator such as 2,2'-azobis(2-aminopropane) dihydrochloride, etc., and the amount added is the total volume (monomer 0.001 to 0.1 mol/Q) relative to the solvent.

The immersion time of the first gel in the 27th Zummer solution is 1 to 48 hours, and the heating temperature of the immersed first gel on the glass plate is 20 to 90°C, preferably 30 to 70°C. The time is about 1 hour or more to about 10 days.

[Effect]

AAm-AAcIPN of the present invention is purified in purified water.
It was found that when the temperature changes, it becomes opaque at low temperatures and becomes transparent at high temperatures. This is AAc-AA on the low temperature side.
This indicates that phase separation occurs due to the formation of a polymer complex by hydrogen bonds between m, and on the other hand, when the temperature rises, the hydrogen bonds of the complex are broken, increasing the swelling property of the gel. Low-temperature-shrinking-high-temperature-swelling polymer gels can be used to respond to temperature changes, such as releasing an effective amount of antipyretics only when there is a fever, and stopping the release of the drug as soon as the fever returns to normal. It becomes possible to realize a new type of drug that is capable of ON-OFF control.

〔Example〕

Examples of the present invention are described below, but the present invention is not limited to these Examples.

Precepts.

Acrylamide (AAm), t-butyl methacrylate (BMA), crosslinking agent methylenebisacrylamide (M
B A A m ) with the amount shown in Table 1, 50 m
A total of 20 m of the thoroughly degassed solvent dimethyl sulfoxide (DMSO) was placed in a 1 m measuring cylinder.
11 and dissolve, and add this 7mer solution to 1
After bubbling with nitrogen for 5 minutes, a polymerization initiator, t-butyl peroxide octoate (BPO), was added, stirred, and poured into a glass plate with a spacer.
The reaction was carried out by heating for 4 hours, and the resulting film was thoroughly washed with DMSO and purified water to form an A A m -B M A copolymer gel (
The first gel) was synthesized.

The physical properties of the AAM-BMA copolymer gel are shown in Table 2.

Table 1 Code AAm/BMA-O AAm/BM^-5 Amount of monomer charged in AAM-BMA copolymer gel AAm BMA MBAAm (g) (g) (g) 4.0 0 0.0434 3.8 0.2 0.0423 PO (■1) 0.036 0.036 (1st gel) DMSO otal AAm/BMA-10 AAm/BMA-20 3,60,40,0412 3,20,80,0390 0,036 0, 036 20 Peng α AA■/BMA-30 A, An/BMA-50 2,81,20,03690,036 2,02,00,03250,036 Table 2 AAM-BMA copolymer gel (first gel) Physical properties Ah/B
MA-017,92 (19,72) AAa/BMA-517,35 (18,73) AAa/BMA-1Of6.30 (17,75) AAa/BMA-2014,50 (15,79) AAa/BMA- 3012,29 (13,87) AAa/Open^-Sho 8.70 (9,86) 45.91 7.66 28.51 0 18
．． 24 (51,43) (7,04) (22,54
)47.30 7.99 27.36 0.0425
& 21.26 (51,55) (7,18)
(22,54) 48.44 7.88 27.38
0.1040 17.94 (52,39) (7,
32) (22,33)昶, 58 8.18 26.
740.2105 8.53 (54,08) (
7,61) (22,54)51.51 8.91
27.290.3204 4.83 (55,77)
(7,89) (22,53)57.13 9.
14 25.03 0.5378 2.25 (59
, 15) (8,45) (22,59) (2) Synthesis of acrylamide-acrylic acid IPN An AAC aqueous solution was prepared at the concentration shown in Table 4, and 0.5% of the crosslinking agent was added to this solution.
5mo1% methylenebisacrylamide (MBAAm
) and ammonium persulfate 2.0g/dm as an initiator
was added to prepare a second monomer solution. Add to this the first
The gel was soaked for 24 hours, then sandwiched between glass plates and heated at 50°C for one week. The produced IPN was washed with purified water for one week or more to synthesize acrylamide-acrylic acid IPN.

Table 5 shows the physical properties of the obtained IPN. Note that Table 3 shows the AAm concentration of the first gel, and based on this, the AAC concentration shown in Table 4 was selected to synthesize AAm-AAc IPN.

Table 3 AAm concentration code in the swollen hydrogel (first gel) AAmtll) Water content AA Otori concentration AAm concentration (%) (%) (ic/g) (@ol/
g) XIO-'100 94.95 0.0505
7.10395 95.99 0.0382 5.3
6790 94.66 0;0483 6.7958
0 90.02 0.0815 11.46570 8
3.93 0.1182 16.62950 69.1
7 0.1823 25.640^Am/BNA-O AAm/BMA-5 AAm/BM^-10 AAiI/BNA-20 AA■/BMA-30 ^Am/BMA-50 1) AAm in dry gel Content (wt.

-%) Table 4 AAc and MBAAm concentration in gel 1 (for IPN synthesis) AA+s/BMA-00,058290,060,58
,76AA Garden/BMA-50,044000,060,
58,76AAm/BMA-100,051030,0
60,58,76AAm/BMA-200,09407
0,100,58,76AAs+/DMA-300,1
36500, 140, 58, 76AA Otori/HMA-50
0,2104G 0.22 0.5 8.76 The hydrogen bond between AAm and AAc in the obtained IPN is due to the I of the amide group and carboxyl group, which are hydrogen bond parts.
This can be determined by looking at the change in the R absorption wavelength. Looking at the change in the N-H bending vibration (amide ■ absorption) of acrylamide before and after IPH, it is observed around 16053-1 in the first gel, while it is 1590 cs'' in IPN.
It was recognized around 1.

That is, when IPN is used, the peak shifts to the lower wave number side. This is due to hydrogen bonding between AAnn and A c.

2. Random AAm-BMA-AAc! ” No. 4
For comparison, random AAm-BMA-AAc copolymers were obtained by polymerizing with the amounts of seven polymers shown in Table 6.

Table 6 Crosslinked random AAm-BMA-AAc copolymer gel coat RAcA! -0 RAcAllB-5 RAcAJ-10 RAcAmB-20 RAcAsdl-30 RAcAmlB-50 Supply amount AAc AAm BMA NBAAm
BPODMSO (g) (g)
(g) (g) (Peng04.
055 4.0 0 0.1735 0.0363
．． 852 3.8 0.2 0.1670 0.036
ota1 3.650 3.6 0.4 0.1605 0.03
63.244 3.2 0.8 0.1475 0.0
360m m 2.839 2.8 1.2 0,1345 0.03
62.028 2.0 2.0 0.1084 0.0
Table 7 shows the results of elemental analysis and degree of swelling as physical properties of the copolymer obtained.

3. - The equilibrium swelling degree of the gel and IPN random gel in purified water at each set temperature was measured in terms of the water content per 1 g of polymer (wa/up), and the
Shown in the figure.

In addition, this equilibrium swelling degree was measured as follows. That is, a gel sample (Wpg) that has been accurately weighed in advance is immersed in distilled water at a predetermined temperature, and the weight (W s + W p ) of the swollen gel sample whose weight does not change after 1 hour is measured, and the degree of swelling Q is calculated as follows: According to the formula, p Figure 1 is a graph showing the temperature dependence of the equilibrium swelling degree of the first gel (A Am / HM A gel), and these graphs show that the equilibrium swelling degree does not change depending on the temperature. ing. It should be noted that although the equilibrium swelling degree of the AAc polymer gel increases as the temperature increases, the increase is monotonous, indicating that it is not rapid.

Figure 2 is a graph showing the temperature dependence of the equilibrium swelling degree of the AAm/BMA-AAc/BMA IPN gel.The IPN gel of the present invention has a transition temperature at which the equilibrium swelling degree rapidly increases with changes in temperature. It represents that. This transition temperature can be shifted to a higher temperature side by increasing the hydrophobicity of the copolymer. That is, by increasing the alkyl methacrylate or alkyl acrylate composition ratio, the transition temperature can be raised. Furthermore, in alkyl methacrylate or alkyl acrylate, the transition temperature can be raised by increasing the number of carbon atoms in the alkyl.

Further, the transition temperature can be arbitrarily set and controlled within the range of 10 to 50°C. This IPN swells transparently at high temperatures, and the film becomes cloudy at low temperatures.

Figure 3 is random A A m-B M A-A A c
It is a graph showing the temperature dependence of the equilibrium swelling degree of a copolymer gel. In the case of random copolymer gel, it is the same as AAc copolymer gel (the degree of swelling increases monotonically with temperature rise,
It shows that it is dull.

Figure 4 shows IPN and AAm/BMA-10 and AAm-A
1 is a graph comparing the temperature dependence of the equilibrium swelling degree of Ac random copolymer gels. As is clear from this figure, AAm
/While the swelling degree of BMA gel and AAm-AAc random copolymer gel hardly changes with temperature or increases slowly with temperature rise, the swelling degree of IPN of the present invention changes with temperature rise. In contrast, it shows a sharp increase in the transition temperature. The temperature at which the contracted state changes to the swollen state ranges from 0 to 50°C depending on the hydrophobic composition.
It can be controlled at any temperature within the range of ℃.

4. The time dependence of the temperature sensitivity of IPN was measured. This is temperature A
After transferring the hydrogel sample that has reached an equilibrium swelling state in constant temperature water at temperature B to constant temperature water at temperature B, the weight of the hydrogel sample is measured over time to determine the change in degree of swelling over 1 hour, and further from temperature B to temperature A. The time dependence of the change in degree of swelling was determined in the same way.

The temperature sensitivity of IPN (AA■/B!4A-10) is shown in FIG.

When the temperature was changed from 10°C to 30°C, the swelling change was faster with respect to the temperature change from the 2nd time onwards compared to the first time.

This seems to be because the first temperature change causes rearrangement of the A and B chains, generating a polymer complex through hydrogen bonding at more stable sites. This shows that by temperature-treating the -degree gel in water (raising it to a high temperature), a gel that swells and changes in response to temperature can be produced.

When the HMA content is 10%: The molar ratio of AAm and AAc is approximately 1:1 in the gel, which can be said to be an ideal state for complex formation, and there is a large swelling change with temperature. It shows a fast reversible swelling change, and similar results can be obtained with a BMA content of 20%.

Furthermore, it was found that IPN with a BMA content of 10% becomes opaque at low temperatures and transparent at high temperatures in purified water with respect to temperature changes. This is AAc-AAm on the low temperature side.
This shows that phase separation occurs due to the formation of a polymer complex by hydrogen bonds between the two, and on the other hand, as the temperature increases, the hydrogen bonds in the complex are broken, increasing the swelling properties of the gel. On the other hand, in the absence of a hydrophobic comonomer (such as butyl methacrylate), no reversible swelling change occurs. This is because the AAm and AAc concentrations in the gel become very low, making it difficult to form a complex again. The presence of hydrophobic monomers controls the degree of swelling of the IPN, thereby achieving reversibility of complex formation. Furthermore, by adjusting the amount of this hydrophobic momer, complex formation and transition temperature (dissociation temperature) can be controlled. By using such a low-temperature contraction/high-temperature swelling gel, drug release control can be realized in which an effective amount of the antipyretic agent is released only when the temperature is high, and the release of the drug is stopped when the temperature returns to normal.

[Brief explanation of drawings]

FIG. 1 is a temperature dependence graph of the equilibrium swelling degree of an AAm/BMA gel, and FIG. 2 is a temperature dependence graph of the equilibrium swelling degree of an IPN (AAm/BMA) gel. Figure 3 is a graph of the temperature dependence of the equilibrium swelling degree of random A m -A c copolymer gel, and Figure 4 is a graph of IPN.
(AAm/HMA-10) and AAm/BM
Figure 5 is a temperature dependence graph of the equilibrium swelling degree of A-10 and random AAm-AAc-10 copolymers.
) is a graph showing reversible changes in swelling degree.

Claims (1)

[Claims] (1) An alternating infiltration network polymer structure (IPN) of a three-dimensional copolymer of general formula A and a three-dimensional copolymer of general formula B. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X is a crosslinking agent, I and II are shown in the following formula, and I
and II are stabilized by hydrogen bonding below the transition temperature, R is H or -CH_3, R_2 is -CnH_2
n-1 (n=1-20). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Approximately 10^2^7 to 10^2^ for 1g of polymer gel
It is 1. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (2) The alternating infiltration network polymer structure according to claim 1, wherein the transition temperature is between 10°C and 50°C. (3) Acrylamide (AAm), alkyl methacrylate or alkyl acrylate, a crosslinking agent, and a polymerization initiator are dissolved in a solvent and reacted on a plate to obtain a polyacrylamide gel as a first gel, and the first gel is A three-dimensional copolymer of the general formula A and a three-dimensional copolymer of the general formula B, which are impregnated in a solution containing an acid (AAc), an alkyl methacrylate or an alkyl acrylate, a crosslinking agent, and a polymerization initiator and polymerized. A method for producing an alternately infiltrated network polymer structure (IPN) with ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X is a crosslinking agent, I and II are shown in the following formula, and I
and II are stabilized by hydrogen bonding below the transition temperature, R is H or -CH_3, R_2 is -CnH_2
n-1 (n=1 to 20), ▲There are mathematical formulas, chemical formulas, tables, etc.▼ p is approximately 10^1^7 to 10^2^ for 1 g of polymer gel
It is 1. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (4) Claim 3, wherein the transition temperature is controlled between 10 and 50°C by the alkyl methacrylate composition in I and II.
A method for producing the alternating infiltration network polymer structure described above.