PH-sensitive polymer containing sulfonamide and its synthesis method

There are disclosed pH-sensitive polymers containing sulfonamide groups, which can be changed in physical properties, such as swellability and solubility, depending on pH and which can be applied for a drug-delivery system, bio-material, sensor, etc, and a preparation method therefor. The pH-sensitive polymers are prepared by introduction of sulfonamide groups, various in pKa, to hydrophilic groups of polymers either through coupling to the hydrophilic groups, such as acrylamide, N,N-dimethylacrylamide, acrylic acid, N-isopropylacrylamide, etc, of polymers or copolymerization with other polymerizable monomers. These pH-sensitive polymers may have a structure of linear polymer, grafted copolymer, hydrogel or interpenetrating network polymer.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to pH-sensitive polymers which are changeable 
in physical properties, such as swellability and solubility, depending on 
pH and a method for preparing the polymers. 
2. Description of the Prior Art 
Generally, pH-sensitive polymers are water-soluble with ionizable 
functional groups. Their physical properties, such as solubility, 
swellability, etc., are changed depending on pH. Since the report for the 
phase transition of pH-sensitive polymers in Nature, 165, 414 (1950), many 
pH-sensitive polymers have been developed (see, Journal of Controlled 
Release, 15, 141 (1991)), most of which contain functional groups 
sensitive to pH, for example, carboxylic groups of weak acidity or 
tertiary amino groups of weak basicity. 
Monomers of the pH-sensitive polymers developed thus far, include acrylic 
acid, methacrylic acid, sodium styrene sulfonate, sulfoxyethyl 
methacrylate, aminoethyl methacrylate, N,N-diethylaminoethyl methacrylate, 
N,N-dimethyl aminoethyl methacrylate, vinylpyridine, vinylbenzyl 
trimethylammonium chloride, etc. That is, pH-sensitive polymers may be 
prepared by polymerizing any one or combinations of these monomers to 
homopolymers or copolymers. These pH-sensitive polymers may have a 
structure of linear polymer, grafted copolymer, hydrogel or 
interpenetrating network polymer. 
Carboxylic acid-containing polymers, which are most extensively developed, 
show pH sensitivity in a pH range of 4-6 owing to the intrinsic pKa values 
of the carboxylic acid. They, however, are limited in pharmaceutical 
application because the pKa values do not reach the physiological pH 
values of the human body. 
SUMMARY OF THE INVENTION 
Therefore, it is an object of the present invention to overcome the above 
problems encountered in prior arts and to provide polymers containing 
sulfonamide groups, which can be changed in physical properties, such as 
swellability and solubility, depending on pH. 
It is another object of the present invention to provide pH-sensitive 
polymers which can be applied for a drug-delivery system, bio-material, 
sensor, etc. 
In accordance with the present invention, the pH-sensitive polymers can be 
accomplished by introduction of sulfonamide groups in hydrophilic groups 
of polymers. 
In one aspect of the present invention, the pH-sensitive polymers which 
have bio-applicability are prepared by converting sulfonamide derivatives 
into polymerizable monomers and coupling them with hydrophilic groups, 
such as acrylamide, N,N-dimethylacrylamide, acrylic acid, 
N-isopropylacrylamide, etc, of polymers. 
Alternatively, the pH-sensitive polymers are prepared by copolymerizing the 
sulfonamide monomers with other monomers.

DETAILED DESCRIPTION OF THE INVENTION 
The sulfonamides useful in the present invention are the derivatives of 
para-aminobenzene sulfonamide, as represented by the following structural 
formula: 
##STR1## 
Sulfonamides are of weak acidity and have various pKa values depending on 
the substituents R. Commercially available sulfonamides and their pKa 
values are given in the following Table 1. 
TABLE 1 
______________________________________ 
Sulfonamides and their pKa 
Trade names R pKa 
______________________________________ 
,1 Phthalylsulfa- ,1 thiazole 
acid ## 
,1 Sulfa- ,1 methyzole 
##STR3## 5.5 
- ,1 Sulfa- ,1 thoxazole 
##STR4## 5.0 
- ,1 Sulfa- ,1 methazine 
7.4 5## 
- ,1 Sulfa- ,1 thomidine 
7.4 6## 
- Sulfathetamide --COCH.sub.3 5.4 
Sulfanylamide --H 10.5 
- ,1 Sulfa- ,1 phenazole 
6.09 # 
- ,1 Sulfa- ,1 methoxazole 
6.0 8## 
- ,1 Sulfa- ,1 diazine 
6.52 # 
- ,1 Sulfa- ,1 methoxydiazine 
7.0 10## 
- ,1 Sulfa- ,1 methoxypyridazine 
7.2 11## 
- ,1 Sulfa- ,1 dimethoxine 
6.1 12## 
- ,1 Sulfa- ,1 methoxypyrazine 
6.1 13## 
- ,1 Sulfa- ,1 doxine 
6.1R14## 
______________________________________ 
In accordance with the present invention, the pH-sensitive polymers with 
sulfonamide groups can be prepared in two ways: introduction of 
sulfonamide to a polymer by coupling the amine group of the sulfonamide 
with polymer's functional groups, such as --COOH, --COCl, --OH, --NCO, 
etc., and introduction of sulfonamide with such a specific functional 
group so as to enable the sulfonamide to be polymerized. For the latter, 
sulfonamide monomers are formed, which can be polymerized with other 
monomers to give various pH-sensitive copolymers. 
EXAMPLE I 
Synthesis of Sulfonamide Monomers 
In a 1:1 mixture of acetone (15 ml) and an aqueous sodium hydroxide (0.04 
g) solution were dissolved 10 mmol of sulfadimethoxine and sulfamethazine, 
each. 10 mmol of methacryloyl chloride were slowly added in the mixture to 
give white precipitates which were, then, filtered by suction, washed with 
a copious amount of water, and dried at room temperature for 48 hours 
under a reduced pressure. 
The products thus obtained were named sulfadimethoxine monomer (SXM) and 
sulfamethazine monomer (SAM), respectively. They were analyzed by NMR 
spectra and the data are given, below. 
.sup.1 H-NMR (200 MHz, DMSO d6) 
Structure of SXM 
##STR15## 
a:.delta.3.7, b:.delta.5.9, c:.delta.11.1, d.about.e:.delta.7.5.about.7.8, 
f:.delta.10.1, h:.delta.5.8, i:.delta.5.5 
Structure of SAM 
##STR16## 
a:.delta.2.2, b:.delta.6.7, c:.delta.10.0, d.about.e:.delta.7.8.about.7.9, 
f:.delta.10.0, g:.delta.1.9, h:.delta.5.8, i:.delta.5.5 
EXAMPLE II 
Synthesis of Copolymers 
SXM and SAM, obtained in Example I, each was polymerized with N,N-dimethyl 
acrylamide (DMAAm) at various ratios (SXM or SAM: DMMAm=2.5:97.5, 5:95, 
10:90, 20:80, 30:70,40:60, 50:50, 60:40, 70:30, 80:20, 90:10) to yield 
copolymers. For this copolymerization, the reactants were added at an 
amount of 50 w/v % of dimethylsulfoxide as a solvent while 
2.2-azobisisobutyronitrile, acting as an initiator, was used an at amount 
of 0.5 mol % based on the total moles of the monomer. 
After being purged with nitrogen gas for 30 min, the mixtures were reacted 
at 60.degree. C., 1 atm for 20 hours. The products thus obtained were 
precipitated at room temperature, 1 atm for 12 hours in ethanol 10 ml/g. 
The precipitates were dissolved at room temperature for 3 hours in a 
diluted sodium hydroxide solution 1 w/v % and then, subjected to dialysis 
for a week. Freeze-drying at -48.degree. C. produced pure copolymers, 
which were named PXD for the copolymer of SXM and DMAAm and PAD for the 
copolymer of SAM and DMAAm, respectively. 
The changes in solubility against pH of the products were measured and 
depicted in FIGS. 1 and 2 for PXD and PAD, respectively. Also, the 
products were subjected to NMR spectrum analysis and the results are 
given, below. 
.sup.1 H-NMR(200 MHz, DMSO d6) 
##STR17## 
EXAMPLE III 
Synthesis of Hydrogel 
Each of SXM and SAM was reacted with N,N-dimethyl acrylamide (DMAAm) in 
dimethylsulfoxide. The weight ratios of SXM or SAM to DMAAm were 10:90, 
20:80, 30:70, and 40:60 with the total amount being 25 w/v % of the 
solvent, dimethylsulfoxide. Based on the total moles of the monomers used, 
N,N'-methylenebisacrylamide, serving as a crosslinking agent, was added at 
an amount of 1.0 mol % while 2,2'-azobisisobutyronitrile as an initiator 
was added at an amount of 0.2 mol %. 
After being purged with nitrogen gas for 10 min, the mixtures were reacted 
at 60.degree. C. for 20 hours to give hydrogels. 
The hydrogels were punched into discs 6.5 mm in diameter, which were 
allowed to stand in an NaOH solution, pH 8 for 8 days and then, in an HCl 
solution, pH 3 for one day. After being washed with distilled water to 
remove unreacted monomers and the solvent, the hydrogels were dried for 48 
hours at room temperature, 1 atm and then, for 48 hours at room 
temperature, at a reduced pressure. 
The products were named GXD from the reaction of SXM and DMAAm and GAD from 
the reaction of SAM and DMAAm, respectively. The swellability of GXD and 
GAD was plotted against pH and shown in FIG. 3 and FIG. 4, respectively. 
EXAMPLE IV 
Synthesis of Copolymer 
N-Methacrylamido-N'-(6-methoxy-3-pyridazonyl)-sulfonamide (PNSP) 
2 mmol of a sulfamethoxypyridazine monomer (SPM), which was prepared from 
sulfamethoxypyridazine in the same manner as in Example I, and 8 mmol of 
N-isopropylacrylamide were dissolved in 80 ml of dimethyl sulfoxide, 
purged with nitrogen gas for 30 min and reacted at 60.degree. C. for 20 
hours with the initiating action of 2,2'-azobisisobutyronitrile. This 
initiator was added at an amount of 2 mol % based on the total moles of 
the monomers used. 
The resulting product was precipitated in distilled water, filtered by 
suction, and dried at room temperature, 1 atm for 12 hours. The product 
was dissolved in 1 mmol sodium hydroxide solution and dialyzed for a week, 
followed by freeze-drying the dialysate to afford an 
N-methacrylamido-N'-(6-methoxy-3-pyridazonyl)-sulfonamide copolymer 
(PNSP). 
TEST EXAMPLE I 
Solubility Test of SPM 
SPM absorbed uv light at 340 nm. The solubility of SPM was obtained by 
monitoring the absorbance at 340 nm against pH. The solubility change of 
SPM with pH was plotted in FIG. 5. As seen, the solubility of SPM started 
to increase at pH 7.5-8.0, which almost agrees with the fact that SPM 
starts to precipitate at pH 7.8. 
TEST EXAMPLE II 
Evaluation of Monomer Ratios in Synthesized 
N-methacrylamido-N'-(6-methoxy-3-pyridazonyl)sulfonamide Copolymers (PNSP) 
Using various ratios of the sulfamethoxypyridazine monomer (SPM) to 
N-isopropylacrylamide (NiPAAm) (0:100 (PNiPAAm), 5:95 (PNSP5), 10:90 
(PNSP10), 15:85 (PNSP15), 20:80 (PNSP20), 30:70 (PNSP30), 40:60 (PNSP40), 
and 50:50 (PNSP50)), N-methacrylamido-N'-(6-methoxy-3-pyridazonyl) 
sulfonamide copolymers were prepared. The amounts of the monomers 
incorporated in the synthesized copolymers were measured by use of a UV 
beam at 340 nm. 
The ratios of monomers measured to be actually present in the copolymers 
are given in Table 2, below. 
TABLE 2 
______________________________________ 
Compositions of PNSP 
Samples SPM NiPAAm 
______________________________________ 
PNiPAAm 0 100 
PNSP5 6.6 93.4 
PNSP10 12.9 87.1 
PNSP15 16.0 84.0 
PNSP20 22.9 77.1 
PNSP30 33.0 67.0 
PNSP40 40.1 59.9 
PNSP50 45.7 54.3 
______________________________________ 
TEST EXAMPLE III 
Evaluation of PNSP for pH Sensitivity 
0.1 g of each of the 
N-methacrylamido-N'-(6-methoxy-3-pyridazonyl)sulfonamide copolymers 
containing 5 mol %, 10 mol %, 15 mol %, and 20 mol % of 
sulfamethoxypyridazine (SPM) was dissolved in 20 ml of a phosphate buffer 
solution (PBS). These 0.5 w/v % solutions were tested for pH sensitivity 
at temperatures from 10 to 70.degree. C. 
Poly N-isopropylacrylamide was not affected by temperature. As the 
sulfamethoxypyridazine monomer increased in mol %, the sensitivity to pH 
of PNSP increased. As many as or greater than 30 mol % of the 
sulfamethoxypyridazine monomer made the PNSP almost indifferent to 
temperature. The PNSP showed great pH sensitivity. In FIG. 6, the 
transmittancy of the 
N-methacrylamido-N'-(6-methoxy-3-pyridazonyl)sulfonamide containing 5 mol 
% of sulfamethoxypyridazine monomer is plotted against pH for temperature. 
TEST EXAMPLE IV 
Evaluation of N-methacrylamido-N'-(6-methoxy-3-pyridazonyl)sulfonamide for 
Temperature Influence 
Transmittancy at 540 nm was measured while raising temperature at a rate of 
1.degree. C./min from 10-70.degree. C. For this measurement, 0.1 g of each 
of the N-methacrylamido-N'-(6-methoxy-3-pyridazonyl)sulfonamides 
containing 5 mol %, 10 mol %, 15 mol %, 20 mol % and 30 mol % of 
sulfamethoxypyridazine monomer (SPM) were dissolved in 20 ml of a PBS. 
In contrast to the homopolymer of N-isopropylacrylamide, the 
N-methacrylamido-N'-(6-methoxy-3-pyridazonyl)sulfonamide copolymers 
containing 5 mol % of the sulfamethoxypyridazine monomer (SPM) prepared in 
Example IV changed in transmittancy against temperature depending on pH, 
as shown in FIG. 7. 
TEST EXAMPLE V 
Synthesis of Sulfamethoxypyridazine monomer (SPM)-containing Hydrogel 
(GNSP) 
In a room between two plates of Teflon film-coated glass, 5 mmol of 
sulfamethoxypyridazine monomer (SPM), 0.5 mmol of N-isopropylacrylamide, 2 
wt % of N,N'-methylenebisacrylamide based on the total weight of the 
monomers, 5 ml of distilled water, and 1 ml of 1 w/v % sodium hydroxide 
solution were placed. The reaction system was added with 18.7 .mu.l of an 
N,N,N',N'-tetramethylethylene diamine solution, allowed to stand at 
60.degree. C. for 24 hours, and subjected to polymerization at 5.degree. 
C. for 3 hours in the presence of 2 .mu.l of 10 w/v % ammonium persulfate, 
a redox initiator. 
TEST EXAMPLE VI 
Evaluation of Hydrogel for Sensitivity to pH 
Using sufamethoxypyridazine monomer (SPM), N-isopropylacrylamide at an 
amount of 10 mol %, 20 mol % and 30 mol % and N,N'-methylenebisacrylamide, 
serving as a crosslinking agent, at an amount of 2 mol % based on the 
moles of the sulfamethoxypyridazine monomer, hydrogels were prepared in a 
similar manner to that of Test Example V. 
The three hydrogels thus obtained were tested for equilibrium swellability 
at 25.degree. C. and 37.degree. C. in phosphate buffer solutions ranging, 
in pH, from 4.5 to 9. For the hydrogel containing 10 mol % of 
sulfamethoxypyridazine monomer, a large difference in water swellability 
between the temperatures occurred while no large differences were in the 
hydrogel containing either 20 mol % or 30 mol % of sulfamethoxypyridazine 
monomer. 
FIG. 8 shows the equilibrium swellability of the hydrogel containing 10 mol 
% of sulfamethoxypyridazine monomer against pH for temperatures. 
TEST EXAMPLE VII 
Evaluation of Hydrogel for Temperature Influence 
The same hydrogels as those of Test Example VI were tested for equilibrium 
swellability in 0.1 mol phosphate buffer solutions of pH 6, 7 and 9 over a 
temperature range of 5-30.degree. C. The swellability was smaller at lower 
pHs while being larger at lower temperatures. So, the swellability was 
affected most greatly at pH 9. 
FIG. 9 shows the swellability of the hydrogel containing 10 mol % of 
sulfamethoxypyridazine monomer against temperature for different pH 
conditions. 
As seen in FIG. 1, the PXD copolymers of the present invention abruptly 
change in solubility at specific pH and thus, in transmittancy. The pH 
points at which the solubility was abruptly changed are dependent on the 
composition of the monomers used to prepare the polymers and on the kind 
of the sulfonamide employed. 
The data shown in FIGS. 3 and 4 demonstrate that the swellability of the 
hydrogels, GXD and GAD, increase with pH. As in the solubility, the pH 
points at which the swellability was abruptly changed are dependent on the 
composition of the monomers used to prepare the polymers and on the kind 
of the sulfonamide employed. 
As described hereinbefore, the polymers prepared according to the present 
invention show different physical properties including solubility and 
swellability depending on pH, so that they can be applied for various 
fields such as a drug delivery system, bio material, sensor, etc. The 
present invention has been described in an illustrative manner, and it is 
to be understood the terminology used is intended to be in the nature of 
description rather than of limitation. Many modifications and variations 
of the present invention are possible in light of the above teachings. 
Therefore, it is to be understood that within the scope of the appended 
claims, the invention may be practiced otherwise than as specifically 
described.