JPH10507219A - Method for producing polymer sensitive to colon-specific reduction - Google Patents

Abstract

  (57) [Summary] A method comprising the step of copolymerizing an azo and / or disulfide containing α, ω-2 functional reactant with a suitable α, ω-2 functional comonomer by polycondensation or polyaddition reaction, wherein (i) A polymer is produced that is susceptible to specific reduction selected from the group consisting of azo-containing polymers, (ii) disulfide-containing polymers and (iii) azo- and disulfide-containing polymers.

Description

DETAILED DESCRIPTION OF THE INVENTION              Method for producing polymer sensitive to colon-specific reduction   The present invention relates to (i) an azo-containing polymer, (ii) a disulfide-containing polymer, and (III) A specific compound selected from the group consisting of azo and disulfide-containing polymers The present invention relates to a method for producing a naturally sensitive polymer, the method comprising: The disulfide-containing α, ω-2 functional reactant is converted to a suitable α, ω-2 functional comonomer And the step of copolymerizing   The method according to the invention is characterized by the fact that bacteria are used to reduce the length of the medium in the reducing medium in the human colon. After the incubation time, it can be completely degraded or decomposed into monomer units. It is intended to make zo and disulfide containing polymers. The above polymer is a drug To make tablets and capsules for site-specific delivery of It is for.   From International Patent WO 91/11175,       (I) an azo-containing polymer,       (Ii) a disulfide-containing polymer;       (Iii) Azo and disulfide containing polymer For producing a polymer sensitive to colon-specific reduction selected from the group consisting of: Are already known.   The above method involves the formation of an azo and / or disulfide-containing α, ω-2 functional comonomer. Including the step of copolymerizing according to the reaction scheme shown below: However, in this equation     -XH is -NH_Two, -OH,     And     -XX- is -N = N-, -S-S-, And     R₁, R_Two  Is an optionally substituted alkyl, aryl, alkyl Reel-based,     R_Three  Is an optionally substituted alkylidene, arylidene, alkyl Arylidene, polyether, polyester,     Hal is a halogen group, for example, Cl or Br;     that time     And     Z is C = O, CH_Two-CH-OH, SO_TwoAnd And thereby     X and Y are interchangeable in the above formulas.   The process described above allows for greater azo and disulfuration due to changes in the .alpha.,. Omega. Allows the production of sulfide-containing polymers. Final physicochemical and physical properties (parent Aqueous, thermal properties, rheological properties) can vary widely.   The molecular weight of the resulting polymer is advantageously determined by gel permeation chromatography. Can be This determines the type and degree of monomer in the reaction mixture used. It can be changed by adjusting.   The molecular weight of the polymers made by the method of the invention depends on the functional groups that react with each other. It is adjusted by modifying the molar ratio. Reactive for high molecular weight polymers Equivalent amounts of the functional groups should be used.   To avoid absorption in the gastrointestinal tract, the molecular weight of the polymer must be And 10,000,000 polymers for use in the gastrointestinal tract It is well known to those skilled in the art that it can have an average molecular weight of up to US Pat. No. 298,595, column 25, lines 14-33).   These polymers are particularly suited for making specific drug delivery systems. this The latter can be a matrix type system or a reservation type system. Azo in the former case And / or a disulfide-containing polymer is a major part of the drug containment chamber. The latter In part the azo and / or disulfide containing polymer is drug loaded Used to encapsulate the wick. The azo and / or disulfide containing polymer can be Due to their stability in the gastric and upper intestinal fluid fields, the polymers according to the invention It can pass through the mouth, stomach and upper intestine without understanding. In the lower part of the gastrointestinal tract The reduction-sensitive polymer is optionally mediated by an enzyme to reduce its reductive medium. Very slowly dissociated, split and thereby encapsulated by The drug is not completely released at the site of its degradation.   Some segmented disulfide-containing polyamides and reductive cleavage. The hydrophilic group suitable for is 3,3'-dithiobissuccinimidyl propionate and α, ω-amino terminal poly (tetramethylene oxide) or tetraethyleneglycol Prepared by condensation polymerization with ureadiamine (Jeffamine EDR-192). SHIME reactor, a simu that simulates the microbial contents of the human colon lating Human Intestinal Microbial Ecosystem Several polymer films were incubated in the sample.   Also, disulfide and hydrophilic groups to produce certain dry-dose capsules. Some segmented polyurethanes, including Nylmethane diisocyanate (MDI) and α, ω-hydroxy end group Synthesized by reaction of the rimer with a disulfide-containing chain extender. Hid Poly (tetramethylene oxide), poly (butylene) Propylene oxide), poly (caprolactone), poly (ethylene oxide), Li (ethylene oxide / polypropylene oxide) was used.   Similarly, segmented, containing azo-aromatic and hydrophilic groups When the polyurethane is m-xylylene diisocyanate and m, m'-dihydroxya Mixture of zobenzene, poly (ethylene glycol) and 1,2-propanediol It was synthesized by reacting with a product. Polymerization of hydrophilic drug (FOY-305) Or encapsulated in a capsule made of the same or coated with these polymers. these Capsules or coated pellets of SH are used to reproduce the culture of human intestinal flora (Flora) Incubated in the IME reactor. Some trials of reduction sensitive polymers Samples are taken at several measured time intervals. Degradation of the molecular weight was determined for those samples. By performing permeation chromatography on The drug Although released from these pellets, the molecular weight did not decrease substantially. Therefore, there was no decomposition of the azo group in the main chain into an amine group.   A series of azo-containing polyamides is combined with azo-containing diacid chloride and oligomeric α. , Ω-diamine. Reduction of these polymers in vitro Incubated in a selective medium. Some tests show that many azo-containing Limmer incubates in a SHIME reactor simulating human intestinal flora It was shown that the solution became thick and colorless during the treatment. Structural changes¹³C, llama Monitored by analysis with UV, GPC and GPC. Observed for these polymers The bleaching does not necessarily have to be due to the gradation, but the azo hydrazo It is also possible by partial reduction to a type.   Thermodynamic conditions for reductive cleavage of this azopolymer were determined by potentiometry. Decided.   Incubation of hydrophilic azo-containing polyamides in their reducing medium. Has been shown to lead to a reduction of the azo bond with the formation of an amine.   The molecular weight of these azo polymers does not substantially decrease. Azo group to hydrazo group Partial reduction occurs slowly, and the decomposition of azo groups in the main chain to amine groups not exist.   During the incubation, the polymers become viscous and become colorless. During reoxidation the original color reappears, and its molecular weight rises again to its original value .   These experiments show that for polyamides of this type, This indicates that no dating occurs. Changes in color and mechanical properties This is due to the conversion of the zo group to a hydrazo group. Such a discovery is a European patent This is in good agreement with that of Kimura et al. In EP-A-0398472. They are P In a report published in Polymer 33 (1992) 5294-5299, Incubation of Azo-Containing Polyurethane in the Culture of Intestinal Flora The molecular weight does not decrease. From these results he Have no degradation of the azo group to the amine and degraded to the hydrazo group. Concluded that there was only one solution.   The present invention provides for the incubation of the above-described polymers in similar reducing media. The thermodynamic conditions for reductive cleavage of azo or disulfide containing polymers by To try to be good.   In order to achieve this improvement, the invention is defined in the preamble of claim 1. One of the proposed methods is proposed. This method     HX-R_Three-XH is a hydrophilic comonomer,     -XH is -NH_Two, -OH,     -XX- is -N = N-, -S-S-, And     R₁, R_Two  Is an alkyl, aryl, optionally substituted by a methoxy group , An alkylaryl group,     R_Three  Are all substituted or unsubstituted alkylidene, aryl Liden, alkyl arylidene, polyether, polyester,     Hal is a halogen group, for example, Cl or Br;     that time     And     Z is C = O, CH_Two-CH-OH, SO_TwoAnd And thereby     X and Y are interchangeable in each of the above formulas It is characterized by the following.   According to one aspect of the invention, the method comprises dithiobis (succinimidylpropionate). Onert) and a hydrophilic α, ω-2 functional comonomer.   This reduction sensitive polymer is made according to the method described below.Description of starting materials   Jeffamine ED-600 (Mn = 600) (7) is Texaco Chem It is a commercial product purchased from Ical Company (Austin, USA). The polymer is dried by azeotropic removal of water from the toluene solution.   Amine content is determined by titration: Jeffamine ED600: 2.96 m eq / g.   The corresponding azobenzene-4,4'- as described in reference [23]. Azobenzene-4,4'-diacid tallide (5) is converted from dicarboxylic acid (4). Prepared. All other reactants are Janssen Chimica (Belgium, Beerse).   The chloroform is washed with sulfuric acid and water, then dried over calcium hydride Was.   Purification of triethylamine by reaction of tosylamine and ninhydrin, respectively did.   This was finally dried over calcium hydride.Method   Infrared spectra were recorded on a Beckmann IR 4230 instrument. Ultraviolet radiation with a Kontron Uvikon 810 double beam spectrophotometer. The spectrum was measured.   ¹The H-NMR spectrum was measured using a Bruker WH-360 device at 360 MHz. And recorded.   ¹³The C-NMR spectrum was transferred to a Varian Unity-400 spectrophotometer. It was determined using a 5 mm wide probe at 100 MHz.   The molecular weight of each polymer was determined by gel permeation chromatography. PL gel A mixed D (5 μm) column was used with chloroform as eluent. calibration Polystyrene standards were used for   The FT-Raman spectrum comprises a FRT 106 FT Raman module And recorded with a Bruher IFS 66FT infrared spectrophotometer.   The potentiometric measurement uses a Pd electrode as the working electrode and a saturated calorie as the reference electrode. EG & G Princeton Applied using Mel Electrode (SCE) Research Potentiostat / Galvanostat Model 372.   The viscosity was measured using an Ubbelohde viscometer (Haake).   Jeffamine ED-600 and azobenzene-4,4'-diacid chloride The preparation of the polyamide starting from Macromol. Chem 180 (1 979) 2517-1519. By BALASUBRAMANIAN etc. Achieved according to the described method. Dry alcohol-free chloroform 10 g (14.80 mmol) of Jeffamine ED dissolved in 100 ml -600 was placed in a three-necked flask and stirred under a nitrogen atmosphere. In this solution 7 ml (50 mmol) of triethylamine were added. Bring this mixture to -10 ° C And stirred for 15 minutes. Then dry chloroform 10 containing no methanol 4.4 g (13.03 mmol) of azobenzene-4 dissolved in 0 ml 4'-Diacid chloride was added immediately to the reaction mixture. This mixture is After stirring at 10 ° C. for 15 minutes, it was brought to room temperature. Stirring was continued for 24 hours. this The reaction mixture was washed with 0.1M HCl (3 × 150 ml), water, 0.1M NaOH (3 × 150 ml). 150 ml). The chloroform layer was washed with MgSO_FourAnd then filter And evaporated to dryness. The resulting polymer is an orange wax nourishing solid there were.   ¹HNMR spectroscopy (CDCl_Three, 360 MHz): δ = 1.1 pp m (d, CH of PPG ether_Threeγ), δ = 1.35 ppm (d, PPG ether Le CH_Threeβ), δ = 3.65 ppm (m, CH of PEG ether_Twoα), δ = 3 . 8 ppm (m, CHβ of PPG ether), δ = 4.4 ppm (broadened, NH amide) [delta] = 7.95 ppm (m, aromatic protons).   Infrared spectroscopy (film on KBr disk): ν = 3300 cm^-1 NH stretching vibration, ν = 1650cm^-1C = O stretching vibration, ν = 1540cm^-1N- H bending vibration, ν = 1600cm^-1C—H aromatic stretching vibration, ν = 1100 cm^-1 CO stretching vibration.Film forming   Silicone coating of a concentrated solution (about 30%) of azopolyamide in chloroform The glass was poured on a glass plate. After evaporating the solvent in a hot air circulating furnace, Lum was removed from the glass plate.Preparation of reducing medium in vitro   Boil the sodium phosphate buffer (0.25M, pH 6.5) and further add Cooled under Gon atmosphere. Add sodium sulfide and cysteine while stirring. Instead, each was adjusted to a concentration of 50 mM.   The oxidation-reduction potential of this medium was measured at a Pt redox electrode at -430 mV (± 1 0 mV) and kept constant for at least 4 days. Return of this medium Originality was assessed by sulfalazine incubation. The resulting 5-AS A was qualitatively and quantitatively determined by HPLC analysis.Incubation of the film in a chemically reducing medium   About 0.1 g (thickness ± 100 μm) of azopolyamide is changed from 3 hours to 2 days The solution was incubated in 30 ml of a reducing medium solution over a period of time. Regulation Remove the films from the medium at regular time intervals, wash with water and remove Dried in the air and GPC, FT-Raman and¹³According to CNMR measurement, Was analyzed.Incubating a film in a simulated human intestinal medium (SHIME) Option   Approximately 0.05 g (± 100 μm thick azopolyamide was added to the SHIME-reactor medium) Over a period of time varying from 12 hours to 3 days in a 15 ml batch of quality Cubbed. The SHIME reactor uses the ileum (2 containers) and the large intestine (3 containers) It consists of five representative containers. The oxidation-reduction potential of -250 mV (± 50 mV) It was measured daily with a Pt redox electrode. c; o Incubate flask Maintained at 37 ° C. At regular time intervals, remove each film from its medium and add , Dried with vacuum chitomo, and GPC, Raman and¹³By CNMR measurement Analysis.Results and discussion I)Synthesis of disulfide-containing copolyamide   Various disulfide-containing polymers were prepared by using 3,3'-dithiobissuccinimidyl propyl Prepared by polycondensation of onate with a prepolymer of α, ω-amino end group.   3,3'-dithiobissuccinimidyl propionate (DDSP) is Synthesized according to the formula:   5 g (23.778 mmol) of 3,3 'in 125 ml of dry dioxane 250 ml in a solution of dithiobisstacinimidyl propionate (DDSP) 6.25 g (54.3 mmol) of N in a two-neck flask -A solution of hydroxysuccinimide (NHS) was added. The reaction mixture is placed on ice Cool to 0 ° C. in a Seton bath, then add 11.25 g (54.52 mmol) Dicyclohexyl carbonate (DCC) was added. Bring the reaction mixture to 0 ° C. And stirred for 1 hour, and stirring was continued overnight at room temperature. Deposited The dicyclohexylurea (DCU) is filtered off, washed with dry dioxane, and The filtrate was concentrated to 1/3 and kept in the refrigerator overnight.   The precipitated traces of DCU were filtered off and the filtrate was evaporated on a rotary evaporator. Was. The white crude product is treated with a (1: 1) mixture of dry acetone and diethyl ether ( (150 ml) for 1-2 hours under reflux. The DCU Impurities are more soluble in the reflux mixture and pure DDSP is soluble Was found to be less soluble, but the insoluble product was filtered and dried in vacuo. Let dry. This last step was repeated for no DCU in the NMR of the product. It was repeated a few times until it became exhausted. B)DDSP with Jeffamine EDR-192 and PTHF-diamine 750 Copolymerization B-1)1: 1 PTHF-750: EDR-192 2. operation   2.51 g (24.75 meq) EDR in 15 ml dry chloroform -192, 15 ml dry CHCl_Three10.55g (24.75meq) in Chilled solution of PTHF-750 and 13.69 ml of triethylamine (0 ° C.) with 65 ml of CHCl_ThreeSolution of DDSP (49.5 meq) in added. The reaction mixture is stirred at 0 ° C. for 1 hour and the stirring is brought to room temperature. For 36 hours.   The chloroform layer was washed with 0.1M HCl (3 ×), H_TwoO (3x), 0.1M NaOH (3 ×) and finally H_TwoExtracted with O (3x). The CHCl_Threeof Layer MgSO_FourDried over night, then filtered, and the filtrate was rotary evaporated Evaporated on the machine. The product was further dried in vacuum.result   1) Good film formation   2) GPC (NMP): average molecular weight = 21791, dispersity = 2.3   3) Intestinal degradation (see Table 1) II)Degradation of disulfide-containing copolyamide in isolated colon medium.   Incorporate the polymer film in a 15 ml sample taken from the SHIME reactor. Cubbed. This SHIME reactor (simulates human intestinal microbial ecosystem) Is a simulated microbial content of human colon. Each flask Is degassed by flushing with nitrogen and then incubated at 37 ° C. I was vate. At regular times several samples are taken and GPC (dissolution) (Release agent = NMP). Wash sample of undissolved polymer and vacuum And analyzed by GPC. Soluble polymers make the medium Remove by lyophilization and dissolve the residue in NMP and remove the inorganic salts Filtered for removal and analyzed by GPC. III)Mechanical test Tensile test   The tensile strength of each polymer sample was measured using Hounsfield type H10KM. It measured using the tensile tester. Cross-head speed (tensile) of each sample at 25 ° C. (Speed) using a 100N cell at 20 mm / min.Preparation of film   Polymer solution containing 10% (w / w) polymer in chloroform Was poured onto the plate. Cover the plate with a watch glass to delay solvent evaporation and Solidified by air drying. Carefully remove each film from its board Dry at 30 ° C. in vacuo to constant weight. The thickness of the film Using a microscope Forster-Isometer S 2.320 (Belgium) Measured. This film was used to measure tensile strength by Berg & Schmid. The cuts were made using a manual press-cut knife from Model HK500. 1.3Disulfide-containing polyurethane   Some disulfide-containing borourethanes are converted to 4,4'-diphenylmethanediyl A cyanide (MDI), a prepolymer of α, ω-hydroxy end groups, and It is prepared by polycondensation with a disulfide-containing chain extender according to the following reaction formula.   Poly (tetramethylene oxide) as a prepolymer of hydroxy end group, Poly (propylene oxide), poly (caprolactone), poly (ethyleneoxy And poly (ethylene oxide / propylene oxide).Synthesis of azo-containing polyamide   Various azo-containing polymers were used in combination with azobenzene-4,4'-diacid chloride. Chloroform as solvent and proton acceptor with ligomer α, ω-diamine It was synthesized by polycondensation in triethylamine as a product. Azobenzene-4 , 4'-Diacid chloride is the corresponding azobenzene-4,4'-dicarboxylic acid Prepared by reaction with thionyl chloride in toluene as solvent . The selected oligomeric diamines are hydrophilic (Jeffamine ED-600) ( 7), which resulted in a water-soluble (9) polymer:   Characterization of these polymers¹By H-NMR and IR spectroscopy Done. Table 1 shows both the values determined by GPC using polystyrene as a standard. Increase the molecular weight of the azo polymer. Reduction of azo-containing polyamides in chemically reducing media   The degradation of each azopolymer was examined in a reducing medium in vitro. I During the incubation the films became tacky and colorless. That in Each sample is colorless when drying the cubated polymer in air at 50 ° C Showed a rapid color recovery from orange to orange.   Table 3 shows that the hydrophilic azo polymer (9) in a chemically reducing medium was prepared. Before and after incubation by GPC using polystyrene as standard 3 shows the measured molecular weight and viscosity measurement results.   GPC fraction of samples taken at different incubation times (Table 3) The precipitation shows a significant decrease in molecular weight. After 3 hours incubation its molecular weight Apparently decreases by a factor of 10 from the initial value and an additional 48 hours Stay so during the incubation (see Table 3). However, reoxidation The original color appears during and the molecular weight measured by GPC rises to the initial value You. After 6 hours of incubation, the films were placed in the reducing medium. Dissolve completely inSpectroscopic evidence of hydrazo bond formation during azo bond reduction.   Evidence for the formation of hydrazo groups during the reduction of the hydrophobic azopolymer (8)¹³C Obtained by NMR analysis.   Table 4 shows the different chemistry for the oxidized and reduced forms of this hydrophobic azopolymer. Give a shift. The resonance of the aromatic carbon shows that for the oxidized polymer, Y = -N = N-Ph and X = -CON (CH_Three)_TwoAnd the reduced one is Y =- NH-NH_Two  And X = -CON (CH_Three)_TwoAdditive method using the para-X-Ph-Y structure This is based on the rule [25]. Each calculated value is for the oxidized and reduced forms. Well agree with those experimentally determined.   In conclusion, some characteristic carbon resonance lines (eg, C_ThreeAnd C_Five) Have both ports Rimmer type¹³It can be said that they can be easily distinguished from each other by CNMR.   Of reoxidized polymer¹³The CNMR spectrum is in a chemically reducing medium and Obviously after incubation in a SHIME reactor its reduced form and acid It is a chemical mixture. Polymer incubated in chemically reducing medium Redox in air over a period of days, but this still mainly reduces (about 90%) Contains. The polymer incubated in the SHIME reactor is exposed to air at about Reoxidized for two weeks, but mainly containing the oxidized form (about 55%) I have.   FT-Raman spectroscopy is an attractive tool to study azo group reduction It is one of. Aromatic ring vibration in both spectameters is 1613 cm^-1And 1 607cm^-1Appears at 1460cm^-1Typical Raman shift in Can be based on its N = N functionality and exists in its oxidized form ing. This Raman signal is used to distinguish between oxidized and reduced compounds be able to. FT-Raman is therefore a complementary non-destructive technology for this purpose. Can be applied. 1460 cm for reduced polymer^-1Toko The N = N stretch band disappears and is 1298 cm^-1Wide band at Has been replaced by This band is due to the symmetric stretching of NH-NH. You. Reoxidized polymer has 1460 cm characteristic of N = N groups^-1Schiff at the place Including However, the polymer incubated in the SHIME reactor 1460cm^-1The relatively high intensity of the Raman wire at It can be associated with a larger amount of polymer. These results as a whole¹³ It is consistent with CNMR data.Coulometric experiment   The fractionation data [28, 29] indicate that the electrochemical reduction rate of the azo bond is This indicates that the reaction proceeds to the hydrazo group depending on the structure. Reduction over hydrazo derivatives Generally requires more energy than the azo-hydrazo reaction. If energy -If the difference is large enough, the response could be described by two waves (fifth Figure).   However, in some cases, some azo compounds are converted by a four-electron step reaction. It is known that it is reduced to an amine (FIG. 6).   Coulometric measurements using tetrabutylammonium bromide as electrolyte Performed in water. Water-soluble hydrophilic polymer by using water as solvent Only (9) could be examined. From Table 5, we see that the redox potential of (9) Recognized to be -230mV against SCE (+ 6mV against SHE) Can be This is why this polymer is reduced in a chemically reducing medium. This is to explain what is done.   Increases electron density on azo bonds, such as hydroxy, amino, methoxy Groups show a shift towards higher (less negative) redox potentials, and To the amine by 4-electron step reduction (30, 31). Water-soluble azoben Coulometric measurement of the zen-4,4'-dicarboxylic acid (4) shows a methoxy substituted analog It showed a lower half-wave potential than body (10).   There is a 140 mV difference in redox potential between both products. This means that This suggests that the reduction of the xy-substituted diacid is more dominant.   When a hydrophilic azopolymer is incubated in a similar reducing medium, The degradation proceeds with the reduction of the zo group to the amine. Of the reducing medium The solubility of the azopolymer in it is a decisive factor. Coulometric measurements are made for all water soluble Zo compound has a more electropositive reduction potential than its reducing medium Was. These results indicate that the thermodynamic conditions for reductive cleavage of various azo compounds are met. Indicates that it was done.

[Procedure for Amendment] Article 184-8, Paragraph 1 of the Patent Act [Date of Submission] October 9, 1996 [Content of Amendment] Claims 1. In preparing a polymer sensitive to colon-specific reduction selected from the group consisting of: (i) an azo-containing polymer, (ii) a disulfide-containing polymer, and (iii) an azo- and disulfide-containing polymer, azo and / or Alternatively, a disulfide-containing α, ω-2 functional reactant is reacted with a suitable α, ω-2 functional comonomer as follows: [However, -XH is -NH ₂ and -OH, -XX- is -N = N-, -SS-, and R ₁ and R ₂ are an alkyl, aryl, or alkylaryl group optionally substituted with a methoxy group, and R ₃ is all substituted or unsubstituted alkylidene, arylidene, alkylarylidene, poly Hal is a halogen group such as Cl or Br, And Z is C = O, CH ₂ —CH—OH, SO ₂ , and X and Y are interchangeable in each of the above formulas]. A process comprising the step of polymerizing, wherein the α, ω-2 functional comonomer is prepared from ethylene oxide (hydrophilic units) and propylene or butylene oxide (hydrophobic units) in a quantitative ratio such that they have hydrophilic properties. A process for producing a colony-specific reduction-sensitive bolimer, which is a co-reactant containing the prepared block polymer or a mixture of co-reactants. 2. The process according to claim 1, characterized in that it comprises a copolymerization of dithiodi (succinimidylpropionate) with a hydrophilic α, ω-2 functional comonomer. 3. 3. The process according to claim 1, comprising the copolymerization of dithiodi (succinimidylpropionate) with a hydrophilic α, ω-diamine functional comonomer. To a solution of 5 g (47.62 mmol) of 3,3′-dithiopropionic acid in 125 ml of dry dioxane was added 6.25 g (54.3 mmol) of N 2 in a 250 ml two-necked flask under a nitrogen atmosphere. -A solution of hydroxysuccinimide (NHS) was added. The reaction mixture was cooled to 0 ° C. in an ice-acetone bath, and 11.25 g (54.52 mmol) of dicyclohexyl carbonate (DCC) was added. The reaction mixture was stirred at 0 ° C. for 1 hour and stirring continued at room temperature overnight. The precipitated dicyclohexylurea (DCU) was filtered off, washed with dry dioxane, and the filtrate was concentrated to 1/3 and kept in the refrigerator overnight. The precipitated traces of DCU were filtered off and the filtrate was evaporated on a rotary evaporator. The white crude product was recrystallized by refluxing in a (1: 1) mixture of dry acetone and diethyl ether (150 ml) for 1-2 hours. The DCU impurity was more soluble in the refluxing mixture, and pure DDSP was found to be less soluble, but the insoluble product was filtered and dried in vacuo. This last step was repeated a few times until no DCU was observed in the NMR of the product.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C08G 75/24 C08G 75/24 75/30 75/30

Claims (1)

[Claims] 1. In preparing a polymer sensitive to colon-specific reduction selected from the group consisting of: (i) an azo-containing polymer, (ii) a disulfide-containing polymer, and (iii) an azo- and disulfide-containing polymer, azo and / or Alternatively, a disulfide-containing α, ω-2 functional reactant is reacted with a suitable α, ω-2 functional comonomer as follows: HX-R ₃ -XH is a hydrophilic comonomer, wherein -XH is -NH ₂ , -OH, -XX- is -N = N-, -SS-, and R ₁ and R ₂ are an alkyl, aryl, or alkylaryl group optionally substituted by a methoxy group, and R ₃ is all substituted or unsubstituted alkylidene, arylidene, alkylarylidene, polyether Hal is a halogen group such as Cl or Br, And Z is C = O, CH ₂ —CH—OH, SO ₂ , and thereby X and Y are interchangeable in each of the above formulas. For producing polymers sensitive to odor. 2. The process according to claim 1, characterized in that it comprises a copolymerization of dithiobis (succinimidylpropionate) with a hydrophilic α, ω-2 functional comonomer. 3. A process according to claims 1 or 2, characterized in that it comprises the copolymerization of dithiobis (succinimidylpropionate) with a hydrophilic α, ω-diamine functional comonomer.