KR20110095445A - A preparation method of ph sensitive hydrogel - Google Patents

Abstract

PURPOSE: A method for manufacturing pH-sensitive hydrogel is provided to use the hydrogel as a drug carrier which is disintegrated and released in the small intestine and large intestine. CONSTITUTION: A method for manufacturing pH-sensitive hydrogel comprises: a step of adding polymeric hydrogel and sodium compounds to a reaction solvent and stirring to prepare a porous hydrogel; a step of swelling the porous hydrogel; and a step of coating the porous hydrogel with a intestine-targeting coating solution. The polymeric hydrogel is glycol chitosan-glycidyl (meth)acrylate hydrogel. The coating solution is methacrylic acid copolymers, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, or hydroxypropyl methylcellulose phthalate. A drug delivery system contains the pH-sensitive hydrogel as an drug carrier.

Description

A preparation method of pH sensitive hydrogel

The present invention relates to a method for producing a pH-sensitive hydrogel, where the elasticity is given to be able to withstand the physical environment such as compression, bending, and torsion in the swollen state as well as mechanical properties, where resilience or strong physical properties are needed. It relates to a method for producing a pH-sensitive hydrogel that can be used in various ways.

Hydrogel is a hydrophilic polymer that can swell in water and has a three-dimensional network structure, and is physically or chemically crosslinked, and does not dissolve under aqueous solution and aqueous environment due to the crosslinking structure. This absorbs and swells large amounts of water. The three-dimensional network structure of the hydrogel may be formed by various factors such as covalent bonds, hydrogen bonds, Van der Waals bonds or physical aggregation. In addition, various polymer hydrogels react sensitively to external stimuli such as temperature, pH, solvent composition, ion concentration, electric field, light intensity, chemicals, etc., and exhibit changes in physical properties such as water content continuously or discontinuously.

Meanwhile, in the medical field, drugs or cell delivery carriers, scaffolds for tissue engineering such as artificial skin, artificial cartilage and artificial bone, and all fields of medicine, environment, and cosmetics Although much research has been conducted on hydrogels with a wide variety of uses, there is a need for the development of hydrogels with high yield, activity and efficiency of hydrogel mechanical properties, synthesis time control and bioactive substances immobilized on hydrogels. Is still there.

For example, Korean Patent Publication No. 199595-0000033 discloses a method of preparing gastric-retention-type long-term oral administration tablets using swellable hydrogels prepared by γ-irradiation. Is disclosed.

However, conventionally developed hydrogel formulations have low or no biodegradability or biocompatibility, and are not easy to manufacture because they use γ-irradiation and the like, and are required for the sustained release of the drug and the retention of the hydrogel. Dependent swelling is not possible, or its swelling ratio and swelling behavior are not satisfactory enough for use in practical applications, have poor physical properties and in some cases fail to exhibit the desired drug release rate.

Meanwhile, in recent years, various diseases of the large intestine, such as ulcerative colitis, in which oral administration of drugs can be an effective treatment tool, have been increasing.Therefore, there is a need for a hydrogel capable of releasing active ingredients only in the colon when oral administration of drugs. Is increasing. However, although the oral preparation up to this point assumed the duodenal absorption in many cases, the method of being effectively absorbed from duodenum to the large intestine has not been found so far. Absorption of the drug through the digestive tract is more vigorous in the upper digestive tract close to the stomach, and less absorbed downward. There is also a problem of degradation before the drug is absorbed from the gastrointestinal tract. Conventional oral preparations are hydrolyzed in the stomach or digested by digestive enzymes in the gastrointestinal tract, making it difficult to see the effects of the drug.

The present invention is to solve the problems of the prior art as described above, comprising the steps of: a) preparing a porous hydrogel in which pores are formed by putting a polymer hydrogel and a sodium compound into a reaction solvent and stirring; b) IPN hydrogel can be prepared by a manufacturing method comprising the step of swelling the porous hydrogel, and through this, not only the mechanical properties but also the elasticity can be given to give elasticity even in a physical environment such as compression, bending, and torsion in the swollen state. It is an object of the present invention to provide a method for preparing a pH-sensitive hydrogel that can withstand a variety of places where a resilience or strong physical property is required.

In addition, the present invention c) when the oral administration by including the step of coating the swollen porous hydrogel with a coating solution for enteric target is sensitive to the pH of the body when passed through as it is without affecting the stomach, but when it reaches the small intestine or large intestine It is an object of the present invention to provide a method for preparing a pH-sensitive hydrogel that selectively disintegrates the coating to change its intestinal retention properties or to release the therapeutically active ingredients contained therein.

The present invention has been made in order to achieve the above object, by coating a porous hydrogel formed with a pore with a coating liquid for long targets to give not only mechanical properties but also elasticity in the physical environment such as compression, bending, torsion in the swollen state It can withstand a wide range of applications where resilience or strong physical properties are needed, and when it reaches the small or large intestine, the coating layer is selectively disintegrated to change the intestinal retention properties or to release the therapeutically active ingredients that contain it. It provides a method for preparing a gel.

Hereinafter, the present invention will be described in more detail.

At this time, if there is no other definition in the technical terms used in the present invention, it has a meaning commonly understood by those skilled in the art to which the present invention belongs, and in the following description unnecessarily obscure the subject matter of the present invention. Description of known functions and configurations that may be omitted.

The present invention relates to a method for producing a pH-sensitive hydrogel,

a) preparing a porous hydrogel in which pores are formed by adding a polymer hydrogel and a sodium compound into a reaction solvent;

b) swelling the porous hydrogel; And

c) coating the swollen porous hydrogel with a coating solution for long target to prepare a pH-sensitive hydrogel.

In the present invention, a method for producing a pH-sensitive hydrogel is first a) preparing a porous hydrogel in which pores are formed by putting a polymer hydrogel and a sodium compound into a reaction solvent and stirring.

Reaction solvents that can be used in step a) include saturated hydrocarbons (hexane, pentane, petroleum ether, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), alcohols (methanol, ethanol, benzyl alcohol, etc.), ketones. System (acetone, methyl ethyl ketone, methyl butyl ketone, cyclohexanone, etc.), ester system (methyl acetate, ethyl acetate, etc.), ether system (diethyl ether, isopropyl ether, THR, dioxane, etc.), amide system ( Dimethylformamide, diethylformamide, etc.), sulfoxide-based (dimethylsulfoxide, sulfolane, etc.), organic acids (formic acid, acetic acid, propionic acid, etc.), acetnitriyl or tetralin may be used. It is not.

The hydrophilic polymer can be used as the polymer hydrogel that can be used in step a), and the hydrophilic polymer that can be used as the polymer hydrogel can be divided into natural polymer and synthetic polymer.

Representative natural polymers include collagen, gelatin, fibrin, alginic acid, hyaluronic acid, or chitosan. Examples of synthetic polymers include polyacrylic acid, polyethylene oxide, polyvinyl alcohol, or polyphosphazene, but are not limited thereto. It is not.

Most preferably, glycol chitosan-glycidyl (meth) acrylate hydrogel can be used as the polymer hydrogel in the present invention.

Chitosan has a property of being soluble in water or organic solvents through chemical modification with glycol, a dihydric alcohol. Glycol chitosan is a representative natural polymer obtained through deacetylation of chitin and synthesis of glycol, and has an amine group, which allows easy chemical modification, excellent biocompatibility, and low immunogenicity. In addition, the mechanical properties are good enough to form a hard hydrogel at low concentrations. The structural formulas of the chitin and its derivatives are as shown in the following formula (1) to (3).

[Formula 1]

[Formula 2]

(3)

In addition, the chitin and its derivatives can enhance mechanical properties through blending with other synthetic polymers, and the synthetic polymers that can be used together are glycidyl (meth) acrylates (glycidylmethacrylate, GMA) that share a vinyl group and an epoxy group in a molecule. ) Can be preferably used. The GMA is one of very useful monomers for the synthesis of reactive polymers, and vinyl-based polymers may give various possibilities as modifications of existing polymers. GMA also introduces vinyl groups into chitosan, making it a crosslinking agent.

In addition, in step a), a sodium compound is used to form pores in the hydrogel, and sodium chloride or sodium bicarbonate may be used as the sodium compound.

Thereafter b) swelling the porous hydrogel; proceeds.

The step b) is characterized in that the swelling by putting the hydrogel in the porous alginate solution, it can be prepared through the step b) porous hydrogel with a pore of 10 ~ 300㎛.

The porous hydrogel through step b) has an interpenetrating polymer network (IPN) structure, wherein the IPN structure is at least partially intersected at the molecular scale but is not a covalent bond, and is separated until the chemical bond is broken. Two or more net structures that do not work.

C) coating the swollen porous hydrogel with a coating solution for long target to prepare a pH-sensitive hydrogel.

Specific examples of the coating solution for the long target are methacrylic acid copolymer (EUDRAGIT), shellac (shellac), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methyl One or a mixture of two or more selected from hydroxypropyl methylcellulose phthalate (HPMCP) may be used, but is not limited thereto.

Among them, EUDRAGIT is very stable against hydrolysis, so it has excellent storage properties, and various acrylic acid copolymers used therein are not absorbed or decomposed and thus have no toxicity. EUDRAGIT RL and RS are used as a coating for conditions that require continuous release because they are not permeable through the entire gastrointestinal tract and are only permeable, while EUDRAGIT E is used as a coating to dissolve in the stomach. Among them, EUDRAGIT L and S and L 30D are most preferably used as coating liquids for long targets. EUDRAGIT L 30D is a substance that starts to dissolve from pH 5.5, EUDRAGIT L melts slightly higher than pH 6, EUDRAGIT S is resistant to gastric juice and does not dissolve but in the intestines above pH 7, it melts while forming polymeric salt. Because of its sensitive reactivity, it can be used in the field of intelligent hydrogels requiring sensitive pH dependence to release the drug in the intestine after injecting the drug into the human body.

The long target coating liquid is characterized in that it is selectively disintegrated at pH 5 ~ 8.

Hereinafter, a method of preparing the pH-sensitive hydrogel of the present invention will be described in more detail.

Method for producing a pH-sensitive hydrogel according to the present invention

a) obtaining a precipitate of glycol chitosan-glycidyl group (meth) acrylate by IPN reaction;

b) dissolving the precipitate and the additive in a reaction solvent;

c) putting the mixed solution and sodium compound of step b) into a mold and stirring the gel;

d) removing the sodium compound after desorbing the gel from the mold to form a pore of 10 ~ 300㎛;

e) preparing a porous hydrogel by swelling the gel of step d) in a sodium alginate solution and swelling; And

f) coating the porous hydrogel of step e) with a coating solution for long target to prepare a pH-sensitive hydrogel.

First, a) obtaining a precipitate of glycol chitosan-glycidyl group (meth) acrylate by IPN reaction.

In step a), glycol chitosan and glycidyl (meth) acrylate may be mixed in a weight ratio of 1: 0.073 to 0.44 to obtain a precipitate by IPN reaction.

Scheme of step a) is the same as in Scheme 1.

Scheme 1

Thereafter b) adding the precipitate and the additive to the reaction solvent to dissolve.

Reaction solvents that can be used in step b) include saturated hydrocarbons (hexane, pentane, petroleum ether, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), alcohols (methanol, ethanol, benzyl alcohol, etc.), ketones. System (acetone, methyl ethyl ketone, methyl butyl ketone, cyclohexanone, etc.), ester system (methyl acetate, ethyl acetate, etc.), ether system (diethyl ether, isopropyl ether, THR, dioxane, etc.), amide system ( Dimethylformamide, diethylformamide, etc.), sulfoxide-based (dimethylsulfoxide, sulfolane, etc.), organic acids (formic acid, acetic acid, propionic acid, etc.), acetnitriyl or tetralin may be used. It is not. Most preferably in the present invention, dimethylsulfoxide (dimethylsulfoxide, DMSO) can be used.

In addition, a crosslinking agent, a monomer, an initiator, and the like may be used as the additive of step b).

As a crosslinking agent used in the present invention, glutaraldehyde, N, N'-methylene-bis-acrylamide (N, N'-methylene-bis-acrylamide, BIS), N, N, N ', N' Tetramethyl ethylenediamine (N, N, N ', N'-tetramethyl ethylene diamine) or one or more mixtures selected from ethylene glycol dimethacrylate may be used, but is not limited thereto. no.

Monomers include acrylic acid (AA), HA, alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, and chitosan. , Polylysine, collagen, carboxyethyl chitin, fibrin, dextran, agarose, pullulan, PEG-PLA-PEG, PEG -PLGA-PEG, PEG-PCL-PEG, PLA-PEG-PLA, PHB, P (PEG / PBO) terephthalate, PEG-bis- (PLA-acrylate), PEG-gP (AAm-co-Vamine), PAAm, P (NIPAAm-co-AAc), P (NIPAAm-co-EMA), PVAc / PVA, PNVP, P (MMA-co-HEMA), P (AN-co-ally sulfate), P (bisscrboxy-phenoxy-phosphazene ), P (GEMA-sulfate), P (PEG-co-peptides), alginate-g- (PEO-PPO-PEO), P (PLGA-co-serine), collagen-acrylate, P (HPMA-g-peptide ), P (HEMA / Materigel), HA-g-NIPAAm and the like can be used, but is not limited thereto.

In addition, the initiator may be acetyl peroxide, benzoyl peroxide, diacyl peroxide, cumene hydroxide peroxide, alkyl peroxide, peroxide oxalumium, peroxide ammonium, hydrogen peroxide, azobisisobutyronitrile (AZIBN), azo One or a mixture of two or more selected from biscyclohexanecarbonyl, tetramethylthiuram disulfide, dibenzoyldisulfide, P-toluolsulfinic acid, and alkanesulfinic acid may be used, but is not limited thereto.

C) adding the mixed solution and the sodium compound of step b) to the mold and stirring to gelate.

The sodium compound is used to form voids in the polymer hydrogel, and sodium chloride or sodium bicarbonate may be used, but is not limited thereto.

d) removing the gel from the mold and removing the sodium compound to form a pore of 10 ~ 300㎛; proceed.

In the present invention, the porous hydrogel in which the pores are formed through the steps c) and d) may be prepared.

Porous hydrogels generally maximize the specific surface area by imparting voids to the interior of the hydrogel. Hydrogel can form a variety of pore structure according to the manufacturing method, the swelling speed and the absorbency is different depending on the presence, size, shape of the pores.

Conventional porous hydrogels are very useful because they absorb moisture at a high rate and swell up to several tens of their weight, but are very useful due to their weak mechanical properties in the swollen state. It could not be used in the field.

On the other hand, the hydrogel according to the present invention is a porous hydrogel having a pore of 10 ~ 300㎛ shows an absorption effect by the capillary phenomenon by forming an open channel in which all the pores are connected to each other.

Methods for synthesizing the porous hydrogel include porosigen technique, phase separation technique, salt leaching method, freeze-dry method, gas blowing method, etc. In the present invention, using the salt leaching method in the steps c) and d) To form a porous hydrogel having a pore of 10 ~ 300㎛.

The salt leaching method used in the present invention is to form pores in the polymer hydrogel by removing the salt and the reaction solvent by adding a sodium compound to the mixed solution of step b), polymerization and washing. The salt leaching method can easily adjust the size of the pores according to the size of the salt and can form the pores in the hydrogel in the same principle as described above.

Thereafter e) putting the gel of step d) in a sodium alginate solution, swelling and lyophilizing to prepare a porous hydrogel; And f) coating the hydrogel of step e) with a coating solution for long target to prepare a pH-sensitive hydrogel.

Since the human body has a specific pH for each organ, a polymer having a functional group capable of ionizing in a specific pH range can be used to produce a pH-sensitive hydrogel that can be sensitive to a specific organ. A representative example is a hydrogel containing an enteric drug that does not disintegrate and dissolve in gastric juice, but disintegrate and dissolve in intestinal fluid. This protects the stomach from drugs, while simultaneously protecting it from antibiotics, enzymes, and hormones, and increases the transition to the intestinal site of absorption or activity, resulting in high levels of drug release from the intestine. The drug also reacts with pepsin or peptone to prevent the effects of gastric digestion. The pH of the stomach in the body varies from 1 to 3.5, depending on the presence of food and the contents of the stomach. The pH of the small intestine is 3.8-6.6, and the pH of the large intestine is 7-8. In gels with low pH, the hydrogel is coated with a coating solution for enteric targets that does not disintegrate or elute, but reacts in the small intestine through the small intestine, protecting the stomach from drug effects and protecting the drug from the effects of gastric contents. . The enteric coating should not dissolve below pH 4 because it should avoid disintegration in the stomach, should start to melt above pH 5 and almost melt at pH 7, and other conditions should be resistant to gastric juice, susceptibility to and intestinal fluid. It should be possible to combine most coating liquid components and drug substance and have stability as coating liquid.

Specific examples of the coating solution for the long target are methacrylic acid copolymer (EUDRAGIT), shellac (shellac), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methyl It is characterized in that one or two or more selected from cellulose phthalate (hydroxypropyl methylcellulose phthalate, HPMCP).

The coating liquid for enteric targets used in the present invention is selectively disintegrated at pH 5-8.

The pH-sensitive hydrogel prepared by the preparation method according to the present invention can be used as a drug carrier to orally administer an anti-inflammatory agent, such as a peptide-based drug such as insulin or carcitonin, or 5-aminosalicylic acid or pridonisolone. It can be used as a drug delivery agent and can also be used in medical devices.

The present invention relates to a method for preparing a pH-sensitive hydrogel, wherein the pH-sensitive hydrogel according to the present invention comprises the steps of: a) preparing a porous hydrogel in which a pore is formed by adding a polymer hydrogel and a sodium compound to a reaction solvent and stirring the same. ; b) swelling the porous hydrogel; And c) coating the swollen porous hydrogel with a coating solution for enteric targets to produce a pH-sensitive hydrogel. Compressing, bending, and twisting in a swollen state by providing not only mechanical properties but also elasticity It can withstand the physical environment, such as there is an effect that can be used in a variety of places where resilience or strong physical properties are required.

In addition, the pH-sensitive hydrogel according to the present invention is a fast-swelling (fast water-swelling) porous hydrogel of IPN structure having a pore size of 10 ~ 300㎛, and when administered orally by coating the hydrogel with a coating solution for enteric targets It is sensitive to the pH of the stomach and passes through as it is unaffected, but when it reaches the small intestine or large intestine, the coating layer disintegrates, thereby effectively releasing the therapeutically active ingredients contained therein.

Figure 1 shows the manufacturing process of the SPHs using the salt leaching method, Figure 2 shows the process of forming the IPN in the SPHs, Figure 3 shows the NMR analysis of the pH-sensitive hydrogel according to Example 1 , Figure 4 shows the swelling ratio (swelling ratio) according to the pH and time of the pH-sensitive hydrogel prepared in Example 1, Figure 5 is a pH and time of the pH-sensitive hydrogel prepared in Example 1 It shows the degree of swelling of the hydrogel.

Hereinafter, the present invention can be better understood by the following examples, which are intended to illustrate the present invention and are not intended to limit the protection scope of the present invention.

[reagent]

Glycol Chitosan, Glycidyl Methacrylate (97%), Acrylic Acid (AA, 99%), N, N'-methylene-bis-acrylamide (BIS, 99%), Anhydrous Dimethylsulfoxide (DMSO, 99.9 +% ), Alginic acid sodium salt (viscosity of 2% solution) and sodium chloride were purchased from Sigma-Aldrich. Azobisisobutyronitrile (AIBN) and calcium chloride were purchased from Junsei chemical, and methacrylic acid copolymer (EUDRAGIT S 100) was purchased from Degussa. Sodium chloride was used only for the particle size of 250 or more, AIBN was used once every other, other reagents were used without further purification.

[Test Example]

Hydrogel Characterization

The surface and internal pore structure of the pH sensitive hydrogel prepared in Example 1 were observed by SEM (S-2460N, Hitachi, Tokyo, Japan).

Swelling degree

The hydrogel samples prepared in Example 1 were put in PBS solutions of pH 3, 6, and 7.4, respectively, to measure the degree of swelling. First, the dried sample weight was added to the PBS solution before the sample was added, and the weight was measured at regular time intervals after the addition. The measurement was carried out under a temperature set at 37 ° C. which is the body temperature, and the swelling ratio was calculated by the following equations (1) and (2).

[Equation 1]

Swelling ratio = (W _s -W _d ) / (W _d )

W _s : Weight of swollen pH sensitive hydrogel

W _d : Weight of dried pH sensitive hydrogel

[Equation 2]

% Swelling = (S _t / S _eq ) X 100

S _t : Swelling ratio at a specific time

S _eq : Swelling ratio at equilibrium

When weighing, excess water accumulated on the surface and inside of the swollen hydrogel was removed and measured. The samples were averaged using three of each.

(Each example should be listed as one point, please check the content unit.)

Example 1

Synthesis of Glycol Chitosan-Glycidyl Methacrylate (GC-GMA)

100 mL of water was added to the beaker and stirred for about 1 hour until 1 g of glycol chitosan was dissolved. After confirming that completely dissolved, 0.44 g of glycidyl (meth) acrylate was added thereto and stirred for 48 hours. After stirring for 5 minutes in acetone, the precipitate was settled and filtered through a filter paper. After repeating this process twice, the precipitate filtered through the filter paper was dried in a vacuum oven at −50 ° C. for one day.

Preparation of SPHs Using Salt Leaching Method

6 mL of DMSO was added to a vial bottle, and 0.12 g of GC-GMA prepared in Preparation Example 1 was added thereto, followed by melting with stirring. 0.012 g of the crosslinking agent BIS, 2.823 mL of the monomer AA, and 0.084 g of the initiator AIBN were completely dissolved, 0.23 mL of the mixed solution was added to the mold, and 0.60 g of NaCl was added thereto. The mixture was stirred slowly and flatly using a sylinge needle to dissolve NaCl, and then reacted for 16 hours in a vacuum oven preheated to 65 ° C.

After completion of the reaction, the mixture was cooled sufficiently at room temperature, and then the gel was detached from the mold, and the process of washing with PBS (phosphate buffered saline) solution at pH 3 until no solvent, NaCl removal and DMSO odor remaining in the gel was carried out 3 to 5 times. Repeated times. This process is shown in FIG.

IPN formation on SPHs

The SPHs prepared in Preparation Example 2 were swollen in 3wt% sodium alginate solution for 3 hours and 30 minutes in order to have firm mechanical properties and relatively poorly cracked, and gelled by sufficiently crosslinking in 20wt% calcium chloride solution for 1 hour. . After washing three times for 30 minutes with distilled water and then lyophilized. This process is shown in FIG.

PH sensitivity to SPHs

9 g of EUDRAGIT S (EVONIK Co., Ltd.) was dissolved in 100 mL of ethanol for about 12 hours to prepare a coating solution for long targets of 9 wt%. The hydrogel sample was immersed in and out of the 5 seconds using the tweezers in the coating solution for the long target. This process was repeated twice and dried in a vacuum oven at 30 ℃ to prepare a pH-sensitive hydrogel.

Comparative Example 1

In Example 1, 1 g of N, N'-methylene-bis-acrylamide was added instead of glycol chitosan, and 10 g of acrylic acid was used instead of glycidyl methacrylate. Gels were prepared.

The hydrogel prepared in Comparative Example 1 has a weak physical property and high viscosity, but the gel was not well formed as the shape of the mold. In the present invention, the hydrogel has weak physical properties by introducing glycidyl (meth) acrylate groups into glycol chitosan. To complement the hydrogel was synthesized in the shape of the mold.

3 shows the results of NMR analysis of the pH-sensitive hydrogel according to Example 1, where 12 vinyl groups per 100 glucose units are present as peaks around 6.048 ppm, 5.629 ppm and 3.6 ppm Could confirm.

EUDRAGIT S used as a coating solution for enteric target in the present invention is not dissolved in the gastric fluid due to its resistance to acidic, but in the intestinal pH of 7 or more shows a sensitive dependency depending on the pH of the melting while forming a polymeric salt. The degree of swelling was observed at pH 7.4 of the intestine under the body temperature of 37 ° C., and the swelling degree of the small intestine and stomach was examined at the same temperature conditions at pH 6 and 4, respectively. The swelling behavior of the three hydrogels under each pH condition was calculated as the average value, and the swelling degree was calculated from the weights of the hydrogels coated with EUDRAGIT S at regular time intervals in PBS solutions with different pH. As shown in FIG. 4, Sample A at pH 4 swelled very slowly, and when it reached swelling equilibrium after 53 hours, the degree of swelling was 4.3026. This means that the EUDRAGIT S coating hydrogel is hardly dissolved. Sample B swollen under the condition of pH 6 had a swelling degree of 23.195 when it reached swell equilibrium. In PBS, pH 7.4, the swelling behavior was rapidly increased 11 hours after starting swelling. After swelling and equilibrium, the final swelling value was 33.3209. After the rapid dissolution in the complete dissolution until some time it was confirmed that the hydrogel has a large swelling value.

In addition, Figure 5 shows the swelling degree of the hydrogel according to the pH and time of the pH-sensitive hydrogel prepared in Example 1, the superporous hydrogel containing the drug coated with EUDRAGIT S when injected into the human body In the stomach with a pH of 1 to 3.5, low swelling does not disintegrate the drug encapsulated in the hydrogel to protect the stomach from the drug and at the same time protect the drug from antibiotics, enzymes and hormones. As it passes through the small intestine with a pH of 3.6 to 6.6, EUDRAGIT S dissolves little by little at the distal end of the small intestine, and disintegrates and elutes in the large intestine at pH 7-8, which completely dissolves the coating and causes the hydrogel to swell rapidly. This allows the high concentration of drug encapsulated in the hydrogel to be released. This method can be used to coat hydrogels with EUDRAGIT S, which is sensitive to changes in pH, to make intelligent pH-sensitive hydrogels.

Claims (10)

a) preparing a porous hydrogel in which pores are formed by adding a polymer hydrogel and a sodium compound into a reaction solvent;
b) swelling the porous hydrogel; And
c) coating the swollen porous hydrogel with a coating solution for enteric targets to prepare a pH-sensitive hydrogel;
Method of producing a pH-sensitive hydrogel comprising a. The method of claim 1,
The polymer hydrogel is a glycol chitosan-glycidyl (meth) acrylate hydrogel, characterized in that the production method of pH sensitive hydrogel. The method of claim 1,
The sodium compound is sodium chloride or sodium bicarbonate production method of pH sensitive hydrogel. The method of claim 1,
The porosity of the porous hydrogel is a method of producing a pH-sensitive hydrogel is 10 ~ 300㎛. The method of claim 1,
The step b) is a method of producing a pH-sensitive hydrogel is to swell the porous hydrogel in sodium alginate solution. The method of claim 1,
The long target coating liquid is one or a mixture of two or more selected from methacrylic acid copolymer, cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and the like. Manufacturing method. The method of claim 1,
The coating solution for enteric targets is a pH-sensitive hydrogel manufacturing method characterized in that the disintegration at pH 5. A pH-sensitive hydrogel prepared by the method of any one of claims 1 to 7. A drug delivery agent using a pH-sensitive hydrogel prepared by the method of any one of claims 1 to 7 as a drug carrier. Medical device using a pH-sensitive hydrogel prepared by the method of any one of claims 1 to 7.

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