JPH0655876B2 - Acrylamide-acrylic acid IPN - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a polymer complex having a novel alternating intrusion network structure that enables drug delivery by changing temperature.

[Conventional technology]

Next-generation pharmaceuticals are drugs that can maintain effective drug concentrations in blood for a long period of time, or drugs that act only on target tissues, that is, the required amount, when and when needed. It is a formulation that allows drugs to act on places, and there are great expectations for its realization. A drug delivery system (dr
ug delivery system (DDS), commonly referred to as DD
In S, the former two are called controlled release preparations and the latter are targeting preparations.
Research is being conducted from the standpoint of se) and targeting, but a systemized drug that realizes all of these concepts is an ideal DDS.
It is intended to realize metabolic artificial organs and future-type therapeutic organs.

The stimulus responsive DDS is divided into a chemical stimulus responsive DDS and a physical stimulus responsive DDS. Among the physical stimulus responsive DDS, a drug release system that responds to temperature has been conventionally studied. It has been reported that polyacrylamide gel partially hydrolyzed with alkali shows a phase transition phenomenon of gel in water acetone system [T. Tanaka Physical Review Letters (Phys. Rev. Letters) 40 (1
2), 820 (1978)], it has been reported that alkyl-substituted amides show extremely large swelling change in water with temperature change.

Since the alkyl-substituted amide gel has low mechanical strength, the present inventors have improved the mechanical strength while maintaining the temperature sensitivity of the gel by two methods to produce a film or a monolithic device. One is a random copolymer of an alkyl-substituted acrylamide and a hydrophobic comonomer with a low glass transition temperature (eg, butyl methacrylate: BMA), and the other is an inter-penetrate network.
trate Networks: IPN) [Surface Science Vol. 10, No. 2, pp. 90-95 (1989)].

This IPN radically polymerizes alkyl-substituted acrylamide, and at the same time, oligomers of both end hydroxyl groups (polyethylene oxide: PEO, polytetramethylene oxide:
PTMO) was added to the polymer by trifunctional isocyanate to form a structure in which different polymer chains were entangled. These conventional alkylamide polymer gels and the like release drugs at low temperatures and do not release drugs at high temperatures.

[Problems to be Solved by the Invention]

The conventionally known temperature-sensitive polymer gel has a large swelling property at low temperature, causes drug release, and is a type that stops swelling by rapidly reducing swelling on the high temperature side. No new antipyretic system can be created.

It is a well-known fact that when an illness causes fever, lowering the fever with an antipyretic is a very effective treatment. If there is an antipyretic drug administration system that works only when there is a fever, the antipyretic drug can be safely used for children and the elderly because of side effects. By using a polymer gel that changes its release with temperature, a new type of drug is submitted that releases an effective amount of antipyretic drug only in the presence of heat and stops releasing the drug as soon as the drug returns to normal temperature. Is desired.

[Means for Solving the Problems]

The present inventors have conducted various studies on a temperature-sensitive polymer that releases an effective amount of an antipyretic agent only when a fever is generated, and can immediately stop the release of the drug when the drug returns to normal heat. As a result, acrylamide (AAm) and acrylic acid ( The inventors have found that the specific copolymer of AAc) is a low temperature shrinkage-high temperature swelling type gel and can achieve the above-mentioned object, and have achieved the present invention.

That is, the present invention provides an alternating structure of a tertiary group copolymer of the general formula A and a three-dimensional copolymer of the general formula B in which the hydrogen bond is stabilized at a transition temperature or lower, and the hydrogen bond dissociates when the temperature is exceeded. Polymer composite (IPN) having an infiltration network structure and a molecular weight between cross-linking points of 500 to 100,000: [Wherein X is a cross-linking agent, I and II are represented by the following formula, and R ₁
Is H or —CH ₃ , and R ₂ is —C _n H _{2n + 1} (n = 1 to 2)
0), p is about 10 ¹⁷ to 10 ²¹ with respect to 1 g of the polymer gel.

And its manufacturing method.

The IPN of the present invention is acrylamide (AAm) -acrylic acid (AAc) IPN. What is IPN? Inter Penetrate Networks (IP)
N), which is a complex in which the cross-linked polymer is physically entangled in the alternating penetration network structure, not by covalent bond.

Then, in the IPN of the present invention, AAm and AAc are stabilized by a structure in which a complex is formed by a hydrogen bond as shown in Formulas I and II below the transition temperature. Then, this complex constitutes a system that can be dissociated by increasing the temperature. In particular, this complex is stable on the low temperature side in water, but it has the characteristic that this complex is rapidly destroyed by the temperature rise. That is, it shows a low swelling property in the low temperature side in water,
When the temperature exceeds the transition temperature (TP), hydrogen bonds are broken and the swelling is rapidly increased.

The transition temperature (TP) is optionally controlled by the alkylmethacrylate composition in I and II. That is, by increasing the alkyl methacrylate composition, T. P to 10 ℃
It can be controlled between 50 ° C.

When the molecular weights of I and II are indicated by the molecular weight between cross-linking points, it is about 500
It is about 100,000. This inter-crosslinking point molecular weight can be determined according to the following formula based on the amount of monomer and the concentration of the crosslinking agent at the time of synthesis.

Number of monomer molecules forming I Molar molecular weight of I or II = (AAm or AAc molecular weight) x
a × I or II forming monomer molecules + (BMA molecular weight) × b × I forming monomer molecules forming I or II (a and b are AAm or AA in the first gel or the second gel)
c, Content of BMA) In the present invention, since the crosslinking concentration is 0.005 mol% to 10 mol%, the inter-crosslinking molecular weights of I and II vary in the range of about 500 to about 100,000.

or, Represents the composition of monomers forming I and II, and can be calculated from elemental analysis values.

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

SIPN (Sequential Interpenetrating Polymer Netw)
ork) method 1. Acrylamide (AAm), alkyl methacrylate or alkyl acrylate, a cross-linking agent, and a polymerization initiator are dissolved in a solvent, stirred in a nitrogen stream, reacted on a glass plate, and then the resulting film is treated with dimethyl sulfoxide (D).
MSO) and purified water to obtain polyacrylamide gel.

Examples of the cross-linking agent include the following (1) diacryl and methacryl derivatives R ₁ ; -H or -CH ₃ R ₂ ; -H or -CH ₃ n = 1 to 100 R ₁ ; -CH ₃ , R ₂ ; H, when n = 1, ethylene glycol dimethacrylate (2) diacrylamide Derivative Methylenebisacrylamide (3) Divinyl derivative Divinylbenzene 4) diallyl derivative Examples thereof include diallyl phthalate.

The initiator was peroxide, [t-butyl peroxide octanoate (B
PO) etc.], diazo compound [NN′-azobisisobutyronitrile (AIBN) etc.], the solvent is dimethyl sulfoxide (DMSO) and a mixed solvent of DMSO and water, alcohol, dioxane, dimethylformamide, (DMF), etc. Is used.

Alkyl methacrylate or alkyl acrylate is
Since only AAm has low strength, it is introduced. This content is used at 0 to 0.7 mole fraction with respect to AAm. or,
The amount of cross-linking agent is 0.005 mol% to 10 mol% based on the total monomers.

The reaction temperature is 20 to 90 ° C, preferably 60 to 80 ° C, and the reaction time is 1 to 72 hours, preferably 12 to 48 hours.

2. Synthesis of acrylamide-acrylic acid IPN AAm-AAcIPN is synthesized by impregnating and polymerizing acrylic acid (AAc), alkyl methacrylate or alkyl acrylate, and a crosslinking agent in the first gel. This can be performed by immersing the first gel in an AAc aqueous solution and allowing it to swell. The concentration of the AAc aqueous solution is A in the first gel.
The water content of the first gel was measured before introducing AAc so as to be equal to the Am concentration, and the water content and AAm in the first gel were measured.
The AAm concentration is calculated from the amount, and the AA is almost equal to this concentration.
c Adjust the aqueous solution. AA almost equal to this AAm concentration
c A cross-linking agent and an initiator are added to the aqueous solution to prepare a second monomer solution, the first gel prepared above is dipped in the second monomer solution, and then the glass plate is heated with scissors and then washed with purified water, Synthesize IPN.

The cross-linking agent and the proportion thereof in this synthesis are the same as in the case of producing the first gel. Further, the initiator is a redox initiator such as ammonium persulfate and a water-soluble diazo initiator such as 2,2′-azobis (2-aminopropane) dihydrochloride, and the addition amount thereof is the total volume (monomer + monomer It is 0.001 to 0.1 mol /) with respect to the solvent.

The immersion time of the first gel in the second monomer 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., and the heating time is about 1 hour or more and about 10 days.

[Action]

AAm-AAcIPN of the present invention, in purified water,
It was found that it became opaque on the low temperature side and transparent on the high temperature side with respect to temperature changes. This is AAc-AA on the low temperature side.
It is shown that phase separation occurs due to the formation of a polymer complex due to hydrogen bonding between m and the swelling property of the gel is increased because the hydrogen bonding of the complex is broken when the temperature rises. Such a low temperature shrinkage-high temperature swelling polymer gel allows for a change in temperature such that an effective amount of the antipyretic agent is released only in the presence of heat, and the release of the drug is stopped as soon as the drug returns to normal temperature. It is possible to realize a new type of drug that can be turned on and off.

〔Example〕

Examples of the present invention will be described below, but the present invention is not limited to these examples.

1. Synthesis of AAm-AAc IPN (1) Synthesis of AAm-BMA copolymer gel (1st gel) Acrylamide (AAm) with t-butylmethacrylate (BMA) and cross-linking agent methylenebisacrylamide (MB)
AAm) was placed in a 50 ml graduated cylinder in the amount shown in Table 1, and fully degassed solvent dimethyl sulfoxide (DMSO) was added to dissolve it to a total of 20 ml and dissolved, and this monomer solution was added for 15 minutes. After bubbling with nitrogen, a polymerization initiator t-butyl peroxide octanoate (BPO) was added, and the mixture was stirred and poured into a glass plate with a spacer. This is heated and reacted at 80 ° C. for 24 hours,
Thoroughly wash the resulting membrane with DMSO and purified water to obtain AA
An m-BMA copolymer gel (first gel) was synthesized.

The physical properties of the AAm-BMA copolymer gel are shown in Table 2, respectively.

(2) Synthesis of acrylamide-IPN acrylate An AAC aqueous solution was prepared at the concentration shown in Table 4, and 0.5 mol% methylenebisacrylamide (MBAAm) as a crosslinking agent and 2.0 g of ammonium persulfate as an initiator were added to the solution.
/ dm ³ was added to make a second monomer solution. Soak the above first gel in this for 24 hours, and then scissor it with a glass plate.
Heated at ° C for 1 hour. The produced IPN was washed with purified water for 1 week or more to synthesize acrylamide-acrylic acid IPN.

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

The hydrogen bond between AAm and AAc of the obtained IPN can be seen by observing the change in the IR absorption wavelength of the amide group and the carboxyl group, which are hydrogen bonding parts. N-H bending vibration of acrylamide before and after IPN (amide II
Absorption) was observed in the vicinity of 1605 cm ^-1 in the first gel, whereas it was observed in the vicinity of 1590 cm ^-1 in IPN. That is, when the IPN is selected, the peak shifts to the low wave number side. This is because a hydrogen bond was generated between AAm and AAc.

2. Synthesis of Random AAm-BMA-AAc Copolymer For comparison, a random AAm-BMA-AAc copolymer was obtained by polymerizing at the charged amounts of the monomers shown in Table 6.

Table 7 shows the results of elemental analysis and the degree of swelling as the physical properties of the obtained copolymer.

3. Measurement of the temperature dependence of the equilibrium swelling degree of the first gel, IPN, and random polymer gel.
The water content per gram (ws / wp) was measured and is shown in FIGS. 1 to 4, respectively.

The equilibrium swelling degree was measured as follows. That is, a gel sample (Wpg) that has been precisely weighed in advance is immersed in distilled water at a predetermined temperature, the weight (Ws) of the swollen gel sample that does not change in weight over time is measured, and the swelling degree Q is calculated by the following formula. It was

FIG. 1 is a graph showing the temperature dependence of the equilibrium swelling degree of the first gel (AAm / BMA gel), which shows that the equilibrium swelling degree does not change with temperature. In the AAc polymer gel, the equilibrium swelling degree increases with increasing temperature, but the increase is monotonous and not abrupt.

FIG. 2 is a graph showing the temperature dependence of the equilibrium swelling degree of AAm / BMA-AAc / BMA IPN gel. The IPN gel of the present invention has a transition temperature at which the equilibrium swelling degree increases rapidly with changes in temperature. This transition temperature can be shifted to the higher temperature side by increasing the hydrophobicity of the copolymer. That is, the transition temperature can be raised by increasing the composition ratio of alkyl methacrylate or alkyl acrylate. Further, in the alkyl methacrylate or the alkyl acrylate, the transition temperature can be raised by increasing the carbon number of the alkyl. The transition temperature can be arbitrarily set and controlled within the range of 10 to 50 ° C. This IPN swells transparently on the high temperature side, and the film becomes cloudy on the low temperature side.

FIG. 3 is a graph showing the temperature dependence of the equilibrium swelling degree of a random AAm-BMA-AAc copolymer gel. In the case of the random copolymer gel, the increase in the degree of swelling due to the temperature increase is monotonous, which is similar to the case of the AAc copolymer gel, indicating that it is slow.

Figure 4 shows IPN and AAm / BMA-10 and AAm-AA
It is a graph of comparison of the temperature dependence of the equilibrium swelling degree of c random copolymer gel. As is clear from this figure, AAm /
Although the swelling degree of BMA gel or AAm-AAc random copolymer gel hardly changes with temperature, the swelling degree of IPN of the present invention increases with temperature increase, while the swelling degree of IPN of the present invention increases with temperature. It shows a sharp rise in the transition temperature. The temperature at which the contracted state changes to the swollen state can be controlled at any temperature within the range of 0 to 50 ° C. depending on the hydrophobic monomer composition.

4. Time Dependence of Temperature Sensitivity of IPN The time dependency of temperature sensitivity of IPN was measured. This is temperature A
After the hydrous gel sample that has reached the equilibrium swelling state in the constant temperature water is transferred to the constant temperature water at the temperature B, the weight of the hydrous gel sample is measured over time, and the swelling degree change with time is obtained. It was returned to the constant temperature water again and the time dependence of the change in swelling degree was similarly obtained.

The temperature sensitivity of IPN (AAm / BMA-10) is shown in FIG. From 10 ℃
When the temperature was changed to 30 ° C., the swelling change was rapid with respect to the temperature change after the second time as compared with the first time. This causes rearrangement of A chain and B chain by the first temperature change,
This is probably because a polymer complex by hydrogen bonding is generated at a more stable site. This indicates that once the gel is subjected to a temperature treatment (increased in temperature) in water, a gel that swells and changes in response to temperature quickly is formed.

When the BMA content is 10%: Each of them is contained in the gel at a molar ratio of AAm and AAc of about 1: 1, which can be said to be an ideal state of complex formation, and a large swelling change with temperature, It shows a fast reversible swelling change. The same result can be obtained when the BMA content is 20%.

Further, it was found that IPN having a BMA content of 10% became opaque on the low temperature side and became transparent on the high temperature side in the purified water against the temperature change. This is AAc-AAm on the low temperature side
It is shown that phase separation occurs due to the formation of a polymer complex due to hydrogen bonding between the two, and on the other hand, the swelling property of the gel is increased because the hydrogen bonding of the complex is broken when the temperature rises. On the other hand, no reversible swelling change is shown when there is no hydrophobic comonomer (butyl methacrylate etc.). This is because if there is no hydrophobic comonomer, the degree of swelling becomes high, and once the degree of swelling becomes high, the concentration of AAm and AAc in the gel becomes extremely low, and it becomes difficult to form a complex again. . The presence of the hydrophobic monomer controls the degree of swelling of the IPN, thereby realizing the reversibility of complex formation. Furthermore, the complex formation and transition temperature (dissociation temperature) can be controlled by adjusting the amount of this hydrophobic momer. By using such a low temperature shrinkage / high temperature swelling type gel, it is possible to realize drug release control in which an effective amount is released with an antipyretic agent only when there is heat and the release of the drug is stopped when the temperature returns to normal heat.

[Brief description of drawings]

FIG. 1 is a temperature dependence graph of the equilibrium swelling degree of the AAm / BMA gel, FIG. 2 is a temperature dependence graph of the equilibrium swelling degree of the IPN (AAm / BMA) gel, and FIG. 3 is a random AA.
Graph of temperature dependence of equilibrium swelling degree of m-AAc copolymer gel, FIG. 4 shows IPN (AAm / BMA-10) and AA
m / BMA-10 and random AAm-AAc-10 copolymer temperature dependence graph of equilibrium swelling degree, FIG.
IPN (AAm / BMA- in water at ℃ and 30 ℃
It is a graph which shows the reversible change of the swelling degree of 10).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C08F 220/18 MMD 7242-4J 220/56 MNC 7242-4J C08L 33/26 LHV 7921-4J

Claims (4)

[Claims] 1. Alternating infiltration of a three-dimensional copolymer of the general formula A and a three-dimensional copolymer of the general formula B, which is stabilized by hydrogen bonding below the transition temperature and is dissociated above the temperature. A polymer composite (IPN) having a network structure and a molecular weight between crosslinking points of 500 to 100,000. [Wherein X is a cross-linking agent, I and II are represented by the following formula, and R ₁
Is H or —CH ₃ , and R ₂ is —C _n H _{2n + 1} (n = 1 to 2)
0), p is about 10 ¹⁷ to 10 ²¹ with respect to 1 g of the polymer gel. 2. The transition temperature is between 10 ° C. and 50 ° C.
The polymer composite described. 3. Acrylamide (AAm), alkyl methacrylate or alkyl acrylate, a cross-linking agent and a polymerization initiator are dissolved in a solvent and reacted on a plate to obtain a polyacrylamide gel which is a first gel. Is impregnated with a solution containing acrylic acid (AAc), an alkyl methacrylate or an alkyl acrylate, a cross-linking agent and a polymerization initiator, and polymerized to hydrogen bond and stabilize at a transition temperature or lower. The intermolecular molecular weight between cross-linking points having an alternating penetration network structure of the three-dimensional copolymer of the general formula A and the three-dimensional copolymer of the general formula B in which the hydrogen bond is dissociated is 500.
A method for producing a polymer composite (IPN) of 100,000. [Wherein X is a cross-linking agent, I and II are represented by the following formula, and R ₁
Is H or —CH ₃ , R ₂ is —C _n H _{2n + 1} (n = 1 to 20), p is about 10 ¹⁷ to 10 ²¹ with respect to 1 g of the polymer gel. 4. The transition temperature is controlled between 10 and 50 ° C. by the composition of alkyl methacrylate in I and II.
A method for producing the polymer composite described.