KR100964889B1 - pH and temperature sensitive polymers and the hydrogels with biodegradability and method for preparing the same - Google Patents

Abstract

The present invention relates to a method for producing a biodegradable temperature and pH sensitive polymer and a hydrogel thereof, and more particularly, to synthesize a polyamino acid precursor from an amino acid and to use it to contain various functional groups in a repeating unit side chain. And preparing a biocompatible polyasphaltamide copolymer capable of co-sensitivity to pH, and forming biodegradable urethane bonds through chemical crosslinking of the copolymer to simultaneously contain biodegradability and temperature and pH sensitivity. The present invention relates to a polymer that can be used as a drug carrier or a biomaterial and a method for producing the hydrogel thereof.

Biodegradable, temperature and pH sensitive polymers, polyasphaltamides, hydrogels

Description

Temperature and pH sensitive polymers and the hydrogels with biodegradability and method for preparing the same}

The present invention relates to a method for producing a biodegradable temperature and pH sensitive polymer and a hydrogel thereof, and more particularly, to synthesize a polyamino acid precursor from an amino acid and to use it to contain various functional groups in a repeating unit side chain. And preparing a biocompatible polyasphaltamide copolymer capable of co-sensitivity to pH, and forming biodegradable urethane bonds through chemical crosslinking of the copolymer to simultaneously contain biodegradability and temperature and pH sensitivity. The present invention relates to a polymer that can be used as a drug carrier or a biomaterial and a method for producing the hydrogel thereof.

Temperature-sensitive polymers contain water by hydrogen bonds between molecules or water, which form the basic structure at low temperatures, and the hydrophilic groups contained in the polymer are dissolved in water. Out of the chain, the hydrophobic interactions of the molecules increase, leading to phase transitions. This temperature is called the lower critical solution temperature (LCST).

Linear polymers exhibiting this LCST behavior can be crosslinked to form a heat sensitive hydrogel network, which shrinks or expands through volume phase transition in a narrow temperature range upon heating.

Such temperature-sensitive polymers have recently been studied in various ways as biomaterials as well as drug delivery systems.

Temperature-sensitive polymers currently under extensive research include poly N-isopropylacrylamide (PNIPAAm), polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) copolymers, and the like. Can be mentioned. In this temperature sensitive polymer, LCST changes according to the ratio of hydrophilic groups and hydrophobic groups bonded to the polymer main chain or repeating unit. As the hydrophobic group increases, the LCST decreases and the hydrophilic group increases, the LCST increases.

Recently, research on temperature and pH sensitive polymers has been actively conducted by introducing cationic or anionic groups into temperature sensitive polymers.

According to some reports (Lee et al ., Polymer . 2007, vol. 48, 1718; Zhu et al., J. Appl . Polym . Sci . 2006, vol. 100, 3602), ionic group-containing polymers based on poly N-isopropylacrylamide (PNIPAAm) can form temperature and pH sensitive hydrogels through chemical crosslinking reactions. However, the temperature- and pH-sensitive hydrogels have characteristics that are not decomposed in the body.

U.S. Patent No. 6,451,346 proposes block copolymers with polyloctide, polyglycolide, polycaprolactone, hydrophobic polypeptide, polyurethane or polyacetal, but such block copolymers are unexpected in vivo. There is a problem that can be broken down into by-products harmful to the human body through the reaction.

Therefore, there is a need for a temperature and pH sensitive hydrogel that is biodegradable and has good biocompatibility, which is harmless to the human body, which can be used as a drug carrier or a biomaterial.

It is an object of the present invention to provide a polymer capable of simultaneously responding to temperature and pH containing various functional groups in a repeating unit side chain using a polyamino acid precursor, and a method of preparing the same.

Another object of the present invention is to provide a biodegradable polymer and a method for producing a hydrogel thereof through chemical crosslinking of the temperature and pH sensitive polymer.

It is yet another object of the present invention to provide a pharmaceutical use of a biodegradable temperature and pH sensitive polymer and its hydrogels.

In order to achieve the above object, the present invention provides a polymer comprising a repeating unit of the formula (1):

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

n and m each independently represent an integer of 10 to 10,000.

The invention also

Synthesizing a polyamino acid precursor via polycondensation of an amino acid monomer;

Reacting a hydrophobic or amphoteric alkylamine compound with the polyamino acid precursor; And

It provides a method for preparing a polymer comprising a repeating unit of formula 1 comprising the step of grafting a hydrophilic amino alcohol compound to the reaction product obtained from the above step to synthesize a temperature and pH sensitive copolymer:

[Formula 1]

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

n and m each independently represent an integer of 10 to 10,000.

The present invention also provides a hydrogel comprising a repeating unit of formula (2):

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

R ₇ and R ₉ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₈ represents an alkylene group having 1 to 12 carbon atoms or an arylene group having 5 to 14 carbon atoms.

The invention also

Synthesizing a polyamino acid precursor via polycondensation of an amino acid monomer;

Reacting a hydrophobic or amphoteric alkylamine compound with the polyamino acid precursor;

Grafting a hydrophilic amino alcohol compound to the reaction product obtained from the above step to synthesize a temperature and pH sensitive copolymer; And

It provides a method for producing a hydrogel comprising a repeating unit of the formula (2) comprising the step of adding a crosslinking agent to the copolymer to prepare a biodegradable hydrogel:

[Formula 2]

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

R ₇ and R ₉ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₈ represents an alkylene group having 1 to 12 carbon atoms or an arylene group having 5 to 14 carbon atoms.

The present invention also comprises a hydrogel containing a repeating unit of the formula (2); And

Drug delivery agents comprising a pharmaceutically active ingredient are provided:

[Formula 2]

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

R ₇ and R ₉ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₈ represents an alkylene group having 1 to 12 carbon atoms or an arylene group having 5 to 14 carbon atoms.

Hydrogel of the present invention exhibits a volume-phase transition behavior that is sensitive to pH as well as temperature, and unlike the simple temperature-sensitive copolymers, the hydrogel has excellent acidic swelling behavior required for long-term retention in the stomach and is biodegradable. The stability problem in the body can be solved at the same time, and it is expected to be used for various purposes in the medical and drug delivery fields.

EMBODIMENT OF THE INVENTION Hereinafter, the structure of this invention is demonstrated concretely.

The present invention relates to a polymer comprising a repeating unit of Formula 1 below:

[Formula 1]

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

n and m each independently represent an integer of 10 to 10,000.

The terms used in the definition of the substituents of the compounds of the present invention are as follows.

"Alkylene" refers to a divalent saturated hydrocarbon of straight, branched chain or cyclo of 1 to 12 carbon atoms, more preferably 4 to 8 carbon atoms, unless otherwise stated. Examples of alkylene groups include, but are not limited to, ethylene, propylene, butylene, pentylene, hexylene, and the like.

"Alkyl" refers to a monovalent saturated hydrocarbon of straight, branched, or cyclo chain having 1 to 12 carbon atoms unless otherwise specified. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohhexyl, isoheptyl, Isooctyl, isononyl and isodedecyl, but is not limited to these.

"Arylene" refers to a divalent aromatic hydrocarbon having 5 to 14 carbon atoms, more preferably 6 to 13 carbon atoms, unless otherwise specified. The aromatic hydrocarbon may include heteroatoms such as oxygen, nitrogen, or sulfur as ring members.

The alkylene, alkyl, or arylene may each be substituted by one or more substituents selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy, hydroxy, amino, cyano, alkoxycarbonyl and the like.

The polymer including the repeating unit represented by Chemical Formula 1 of the present invention is not particularly limited as long as it is a compound as defined above.

R ₂ and R ₆ each independently represent an alkylene group having 2 to 4 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 4 carbon atoms,

R ₂ and R ₆ each independently represent an alkylene group having 2 or 3 carbon atoms,

More preferably, R ₃ and R ₄ each independently represent an alkyl group having 2 or 3 carbon atoms,

R ₂ and R ₆ each represent an ethylene group,

Most preferably, R ₃ and R ₄ each represent an isopropyl group.

In addition, n and m each independently represent an integer of 10 to 10,000, more preferably 20 to 2000, most preferably.

Polymers including repeat units of Formula 1 of the present invention include, for example, polyasphaltamide derivatives.

The invention also

Synthesizing a polyamino acid precursor via polycondensation of an amino acid monomer;

Reacting a hydrophobic or amphoteric alkylamine compound with the polyamino acid precursor; And

It relates to a method for preparing a polymer comprising a repeating unit of Formula 1 comprising the step of grafting a hydrophilic amino alcohol compound to the reaction product obtained from the above step to synthesize a temperature and pH sensitive copolymer:

[Formula 1]

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

n and m each independently represent an integer of 10 to 10,000.

Hereinafter, each step of the method for preparing a polymer including the repeating unit of Formula 1 according to the present invention will be described in more detail with reference to FIG. 1.

The first step is to synthesize a polyamino acid precursor through polycondensation of an amino acid monomer.

The polyamino acid precursor may be obtained by bulk polymerizing the amino acid monomer and the catalyst mixture for 3 to 8 hours while reducing the pressure from 400 torr to 25 torr at a temperature of 20 to 200 ° C.

The amino acid monomer is not particularly limited, but is preferably aspartic acid.

The catalyst is a catalyst and at the same time serves as a solvent of the amino acid monomer, can be prepared with toluenesulfonic acid (p-toluenesulfonic acid), sulfuric acid (sulfuric acid), but is preferably phosphoric acid (o-phosphoric acid).

The amino acid and catalyst mixture may be prepared in a ratio of 1: 2 to 5: 1, but is preferably mixed in a ratio of 1: 0.5 to 1.5. Within the ratio range, the highest molecular weight can be produced.

The polyamino acid precursor is not particularly limited by changing the number depending on the amino acid monomer, but is preferably polysuccinimide (PSI).

The second step is to react the hydrophobic or amphoteric alkylamine compound with the polyamino acid precursor, the reaction is 20 to 60 by adding 40 to 90 parts by weight of the hydrophobic or amphoteric alkylamine compound with respect to 100 parts by weight of the polyamino acid precursor Ring-opening of the precursor under the temperature condition of ℃.

The hydrophobic or amphoteric alkylamine compound may be diisopropylaminoethylamine (2-diisopropylamino-ethylamine), isopropylethylenediamine (N-isopropylethylenediamine), dimethylaminopropylamine (3-dimethylamino-1-propylamine), or diethyl. Aminopropylamine (3-diethylaminopropylamine) etc. can be used individually or 2 types or more.

The hydrophobic or amphoteric alkylamine compound is preferably included in an amount of 40 to 90 parts by weight based on 100 parts by weight of the polyamino acid precursor. When the hydrophobic or amphoteric alkylamine compound is present within the numerical range, it may exhibit desirable LCST behavior.

The third step is to synthesize the temperature and pH sensitive copolymer by grafting the hydrophilic amino alcohol compound to the side chain of the polyamino acid precursor.

As the hydrophilic amino alcohol compound, aminoethanol, aminopropanol, aminobutanol and the like may be used alone or in combination of two or more.

The hydrophilic amino alcohol compound is preferably included in 10 to 60 parts by weight based on 100 parts by weight of the reaction product. If it is less than 10 parts by weight, the hydrophobic group is increased to be insoluble in water, and if it exceeds 60 parts by weight, the hydrophilic group may be increased to negatively affect the LCST behavior.

Temperature and pH sensitive polymer prepared by the method for producing a polymer comprising a repeating unit of Formula 1 of the present invention may include an amphoteric polyasphaltamide copolymer having both hydrophobicity and hydrophilicity.

The invention also relates to a hydrogel comprising a repeating unit of formula (2):

[Formula 2]

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

R ₇ and R ₉ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₈ represents an alkylene group having 1 to 12 carbon atoms or an arylene group having 5 to 14 carbon atoms.

The hydrogel including the repeating unit of Formula 2 of the present invention may include an amphoteric polyasphaltamide derivative having both hydrophilic and hydrophobic characteristics, and is not particularly limited as long as it is a compound as defined above.

R ₂ and R ₆ each independently represent an alkylene group having 2 to 4 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 4 carbon atoms,

R ₇ and R ₉ each independently represent an alkylene group having 2 to 4 carbon atoms,

R ₈ preferably represents an alkylene group having 4 to 8 carbon atoms or an arylene group having 6 to 13 carbon atoms,

R ₂ and R ₆ each independently represent an alkylene group having 2 or 3 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 2 or 3 carbon atoms,

R ₇ and R ₉ each independently represent an alkylene group having 2 or 3 carbon atoms,

R ₈ more preferably represents an alkylene group having 5 to 7 carbon atoms,

R ₂ and R ₆ each represent an ethylene group,

R ₃ and R ₄ each represent an isopropyl group,

R ₇ and R ₉ each independently represent an ethylene group,

R ₈ most preferably represents a hexamethylene group.

The invention also

Synthesizing a polyamino acid precursor via polycondensation of an amino acid monomer;

Reacting a hydrophobic or amphoteric alkylamine compound with the polyamino acid precursor;

Grafting a hydrophilic amino alcohol compound to the reaction product obtained from the above step to synthesize a temperature and pH sensitive copolymer; And

It relates to a method for preparing a hydrogel comprising a repeating unit of the formula (2) comprising the step of adding a crosslinking agent to the copolymer to prepare a biodegradable hydrogel:

[Formula 2]

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

R ₇ and R ₉ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₈ represents an alkylene group having 1 to 12 carbon atoms or an arylene group having 5 to 14 carbon atoms.

In the method for producing a hydrogel comprising a repeating unit of Formula 2 of the present invention, the first to third steps are to prepare an amphoteric temperature and pH sensitive copolymer, preferably a polyasphaltamide copolymer, The fourth step is a step of preparing a hydrogel containing biodegradability as well as temperature and pH sensitivity by forming a biodegradable urethane bond through a chemical crosslinking reaction between the hydroxyl group and the crosslinking molecule of the copolymer.

The crosslinking agent may be lysine diisocyanate, diisocyanate butane, phenylene diisocyanate, diphenylmethane diisocyanate, or hexamethylene diisocyanate.

The crosslinking agent is preferably included in a 0.4 mol to 1 mol ratio with respect to the moles of the hydroxyl group of the temperature and pH sensitive copolymer. If it is less than 0.4 mol ratio, no crosslinking reaction occurs, and if it exceeds 1 mol ratio, swelling ratio with respect to temperature does not appear.

In the chemical crosslinking reaction, one or more catalysts selected from the group consisting of dibutyltin dilaurate may be further added.

The catalyst is preferably included in an amount of 0.01 to 0.02 parts by weight based on 100 parts by weight of the temperature and pH sensitive copolymer.

As described above, a representative example of a method for preparing a hydrogel including a repeating unit of Formula 2 according to the present invention will be described with reference to FIG. 1.

First, as shown in Scheme 1, asphalt acid and phosphoric acid were selected as an amino acid monomer, and they were uniformly mixed in a ratio of 1: 1 to synthesize polysuccinimide as a polyamino acid precursor through bulk polymerization.

Second, as shown in Scheme 2, the polysuccinimide was gradually added to DIPAEA which shows hydrophobicity in DMF (N, N-dimethylformamide) solvent to ring-open the succinimide ring of the polysuccinimide, and ethanolamine as a hydrophilic group was added. A polyasphaltamide copolymer showing temperature and pH sensitivity was synthesized by grafting to the side chain of polysuccinimide.

Third, as shown in Scheme 3, a polyasphaltamide copolymer showing a temperature and pH sensitivity, a crosslinking agent HMDI, and a catalyst are added to cause a chemical crosslinking reaction, from which biodegradable temperature and pH sensitive polymer (hydrogel) is added. Was synthesized.

The present invention also comprises a hydrogel containing a repeating unit of the formula (2); And

It relates to a drug carrier comprising as a pharmaceutically active ingredient:

[Formula 2]

Where

를 나타내고, R ₁ is

Lt; / RTI >

를 나타내며,R ₅ is

Indicates

R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms,

R ₇ and R ₉ each independently represent an alkylene group having 2 to 6 carbon atoms,

R ₈ represents an alkylene group having 1 to 12 carbon atoms or an arylene group having 5 to 14 carbon atoms.

The hydrogel including the repeating unit of Formula 2 of the present invention may include an amphoteric polyasphaltamide derivative having both hydrophilic and hydrophobic characteristics, and is not particularly limited as long as it is a compound as defined above.

The pharmaceutically active ingredient included in the drug carrier of the present invention is not particularly limited and may include various known pharmaceutically active ingredients without limitation.

The drug carrier of the present invention may further use a pharmaceutically acceptable carrier, the carrier including a carrier and a vehicle commonly used in the medical field, specifically, ion exchange resin, alumina, aluminum stearate, lecithin, serum Proteins (e.g. human serum albumin), buffers (e.g. various phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts or electrolytes (e.g. protamine sulfate, hydrogen phosphate Sodium, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose based substrates, polyethylene glycol, sodium carboxymethylcellulose, polyarylates, waxes, polyethylene glycols or wool Including but not limited to.

In addition to the above components, the drug carrier of the present invention may further include a lubricant, a humectant, an emulsifier, a suspending agent, a preservative, and the like.

The drug carrier of the present invention may be prepared in a parenteral dosage form such as an oral dosage form or an injection.

Examples of formulations for oral administration include tablets, troches, lozenges, water soluble or oily suspensions, prepared powders or granules, emulsions, hard or soft capsules, syrups or elixirs. For formulation into tablets and capsules, lactose, saccharose, sorbitol, mannitol, starch, amylopectin, binders such as cellulose or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch or sweet potato starch, magnesium stearate Lubricating oils, such as calcium stearate, sodium stea fumarate or polyethylene glycol wax. In addition, the capsule formulation may contain a liquid carrier such as fatty oil in addition to the above-mentioned substances.

Formulations for oral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, and lyophilized preparations. Non-aqueous solvents and suspending solvents may be used vegetable oils such as propylene glycol, polyethylene glycol or olive oil, injectable esters such as ethyl oleate.

In one embodiment, the drug carrier according to the present invention may be prepared in an aqueous solution for parenteral administration. Preferably, buffer solutions such as Hanks' solution, Ringer's solution, or physically buffered saline may be used. Aqueous injection suspensions can be added with a substrate that can increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran.

Another preferred embodiment of the drug carrier of the present invention may be in the form of a sterile injectable preparation of an aqueous or oily suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg Tween 80) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions (eg solutions in 1,3-butanediol) in nontoxic parenterally acceptable diluents or solvents. Vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose any non-irritating non-volatile oil can be used including synthetic mono or diglycerides.

Hereinafter, the present invention will be described in more detail through examples according to the present invention, but the scope of the present invention is not limited to the examples given below.

Example 1 Preparation of Temperature and pH Sensitive Polyasphaltamide Copolymer

Asphalt acid (L-aspartic acid), a monomer, and a catalyst and o-phosphoric acid, which acts as a solvent, are uniformly mixed at a ratio of 1: 1, and thus, as shown in Table 1 in a rotary evaporator. The temperature and pressure were gradually adjusted to obtain polysuccinimide through bulk polymerization for 5 hours.

Polysuccinimide (PSI), a precursor of polyamino acid, was dissolved in diisopropylaminoethylamine (2-diisopropylamino-ethylamine, DIPAEA, 0.3-0.9 mol ratio) in a dimethylformamide (N, N-dimethylformamide, DMF) solvent. After quantitatively ring-opening the succinimide ring in the main chain by dropwise dropwise at 40 ° C. for 24 hours under nitrogen stream, ethanolamine (2-ethanolamine, EA, (0.1-0.7 mol ratio) × 1.5) Was added and reacted at 40 ° C. for 24 hours. The reaction solution was terminated in 250 mL of diethyl ether, filtered using a glass filter, washed with 2 L of diethyl ether, and the solvent and unreacted monomer were removed. Then, dried in a vacuum oven for 24 hours. To give an amphoteric polyasphaltamide copolymer having both hydrophobicity and hydrophilicity.

The amphoteric polyasphaltamide copolymer prepared from the above was confirmed the composition of the respective functional groups using ¹ H-NMR and the low critical solution temperature (LCST) for each dilute aqueous solution (Table 2) Could. In addition, in Figure 2, the amphoteric polyasphaltamide derivatives prepared in various compositions were dissolved in distilled water at 1% by weight, respectively, and the temperature controller and thermocouple equipped with a UV-visible spectrophotometer (Biochrom libraS22, UK) were used at a wavelength of 500 nm at 1 nm /. The temperature was raised to min to confirm the LCST of the solution.

As shown in Figure 2, the higher the hydrophobic group diisopropylaminoethylamine composition was confirmed that the lower LCST, which is present in the hydrogen bond between the hydrophilic group of the polymer and water molecules at low temperature dissolved in water However, increasing the temperature results in LCST behavior because the bonding force of the hydrophobic portion of the polymer is superior to the hydrogen bonding force. On the other hand, if the hydrophobic group of the polymer is increased, the LCST is lowered and the LCST can be controlled by changing the composition of the hydrophobic and hydrophilic groups or the alkyl chain.

Figure 3 selects copolymer C of Table 2 to observe LCST in pH 6, 7, 8, 9 and 10 buffer. As a result, it was confirmed that the LCST behavior was low at high pH, but the lower the pH, the higher the LCST. This is expected to be a result of pKa value, which is approximately 6.5 by acid-base titration. Therefore, at low pH (pH> pKa), tertiary amines were ionized in the diisopropylaminoethylamine group, resulting in electrostatic repulsion, and LCST could not be observed. At high pH (pH <pKa), It was observed that LCST was lowered due to hydrophobic interaction.

Example 2 Preparation of Biodegradable Hydrogel

The copolymer D prepared in Example 1 in a thermostat maintained at 60 ° C. was treated with hexamethylene diisocyanate as a crosslinking agent under a dimethylformamide solvent to 0.4, 0.6, 0.8 and 1 mol, respectively, for the hydroxy group concentration of ethanolamine. As a ratio and 0.02 parts by weight of dibutyltin dilaurate was added as a catalyst and reacted for 3 hours. The hydrogel thus obtained was washed in distilled water for 2 days to remove unreacted material and dimethylformamide, and the final temperature and pH sensitive hydrogel was obtained by freeze drying.

4A and 4B are graphs showing the swelling behavior of the hydrogel obtained by crosslinking copolymer D with 40 mol of hexamethylene diisocyanate, which is a crosslinking agent for a hydroxyl group, according to temperature and pH.

Figure 4a shows the swelling ratio with time by repeating the experiment after reaching the swelling equilibrium for 24 hours in distilled water of 10 ℃ and then transferred to distilled water of 50 ℃ to reach the swelling equilibrium for 6 hours. Hydrogel showed relatively rapid swelling at 10 ° C. initially and reached equilibrium within about 24 hours, and when transferred to 50 ° C., hydrogel contracted rapidly and reached equilibrium within about 6 hours. The swelling ratio was 5 to 6 times in distilled water at 10 ° C. and about 2 times in distilled water at 50 ° C. Increasing the temperature increases the mutual attraction between the chain and the chain inside the hydrogel, shrinks the gel and swells again when the temperature is lowered.

Figure 4b in the same manner as above to reach the swelling equilibrium hydrogel in pH 2 buffer solution for 6 hours, and then to the swelling equilibrium for 6 hours to measure the swelling ratio repeatedly after 6 hours. The swelling ratio was 15 to 16 times at pH 2 and 2 times at pH 10. This is because the tertiary amine of the diisopropylaminoethylamine group is ionized at pH 2, so that the electrostatic repulsion force is increased, and the swelling ratio is greatly increased, and at pH 10, the ion is not ionized and moisture escapes from the inside of the hydrogel, causing the hydrogel to shrink. I could confirm it.

5 shows a photograph of the form of the hydrogel prepared by lyophilization using a field emission scanning electron microscope (FE-SEM).

All the hydrogels had regular net porosity as the pores produced by the crosslinking agent were lyophilized, and the pore size changed significantly with temperature and pH.

Figure 6 shows the hydrolysis test results of the hydrogel prepared in 0.4 mol ratio of hexamethylene diisocyanate. The hydrogel was immersed in PBS (phosphate buffered saline: pH 7.4) solution in a fixed temperature bath at 37 ° C, separated by centrifuge (11000rpm) for 10 minutes at 4 ° C, and decomposed polymer and electrolyte remaining in the hydrogel. After washing with distilled water for 1 hour to remove the centrifuged hydrogel under the same conditions, the collected solid was freeze-dried to determine the final weight. % Biodegradability is represented by the following equation (1).

% Biodegradability = (Wr / Ws) × 100

Where Ws is the initial hydrogel weight and Wr is the final hydrogel weight collected by centrifugation.

As shown in Figure 6, depending on the elapsed time, the weight loss of about 75 to 80% on the 1 to 2 days, and after 3 days it can be seen that the rapid loss occurs. This may be due to the cleavage of the bond due to the hydrolysis of the crosslinked urethane group.

Figure 1 schematically shows a synthetic scheme of temperature and pH sensitive polymer containing the biodegradable of the present invention.

Figure 2 shows the phase transition graph according to the composition of the polyasphaltamide copolymer.

Figure 3 shows the phase transition graph of the polyasphaltamide copolymer with pH change.

Figure 4 shows a graph showing the reversible swelling behavior according to the temperature (a) and pH (b) of the polyasphaltamide copolymer hydrogel.

Figure 5 is a cross-sectional photo of the polyasphaltamide copolymer hydrogel swelled differently depending on the temperature and pH.

Figure 6 shows a graph observing the biodegradable behavior of polyasphaltamide copolymer hydrogel over time.

Claims (24)

A polymer comprising a repeating unit of Formula 1 below: [Formula 1]

Where R ₁ is

Lt; / RTI &gt; R ₅ is

Indicates R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms, R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms, n and m each independently represent an integer of 10 to 10,000. The method of claim 1, R ₂ and R ₆ each independently represent an alkylene group having 2 to 4 carbon atoms, R ₃ and R ₄ each independently represent an alkyl group having 1 to 4 carbon atoms. The method of claim 1, R ₂ and R ₆ each independently represent an alkylene group having 2 or 3 carbon atoms, R ₃ and R ₄ each independently represent an alkyl group having 2 or 3 carbon atoms. The method of claim 1, A polymer, which is a polyasphaltamide derivative. Synthesizing a polyamino acid precursor via polycondensation of an amino acid monomer; Reacting a hydrophobic or amphoteric alkylamine compound with the polyamino acid precursor; And Method for preparing a polymer comprising a repeating unit of formula 1 comprising the step of grafting a hydrophilic amino alcohol compound to the reaction product obtained from the above step to synthesize a temperature and pH sensitive copolymer: [Formula 1]

Where R ₁ is

Lt; / RTI &gt; R ₅ is

Indicates R ₂ and R ₆ each independently represent an alkylene group having 2 to 6 carbon atoms, R ₃ and R ₄ each independently represent an alkyl group having 1 to 8 carbon atoms, n and m each independently represent an integer of 10 to 10,000. The method of claim 5, Polyamino acid precursor is a method for producing a polymer, characterized in that obtained by bulk polymerization of the amino acid monomer and catalyst mixture for 3 to 8 hours at a temperature condition of 20 to 200 ℃. The method of claim 6, A method for producing a polymer, characterized in that the mixture of amino acids and catalysts in a ratio of 1: 2 to 5: 1. The method of claim 5, Method for producing a polymer, characterized in that the polyamino acid precursor is polysuccinimide (PSI). The method of claim 5, 40 to 90 parts by weight of a hydrophobic or amphoteric alkylamine compound with respect to 100 parts by weight of a polyamino acid precursor to open the ring of the precursor at a temperature of 20 to 60 ℃. The method of claim 5, The hydrophobic or amphoteric alkylamine compound is diisopropylaminoethylamine (2-diisopropylamino-ethylamine), isopropylethylenediamine (N-isopropylethylenediamine), dimethylaminopropylamine (3-dimethylamino-1-propylamine) and diethylamino Propylamine (3-diethylaminopropylamine) method for producing a polymer, characterized in that it comprises one or more selected from the group consisting of. The method of claim 5, The hydrophilic amino alcohol compound is a method for producing a polymer, characterized in that it comprises one or more selected from the group consisting of aminoethanol, amino propanol, and amino butanol. The method of claim 5, The hydrophilic amino alcohol compound is a method for producing a polymer, characterized in that contained in 10 to 60 parts by weight based on 100 parts by weight of the reaction product. delete delete delete delete delete delete delete delete delete delete delete delete

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