WO2006109945A1

WO2006109945A1 - Temperature and ph sensitive block copolymer and polymeric hydrogles using the same

Info

Publication number: WO2006109945A1
Application number: PCT/KR2006/001185
Authority: WO
Inventors: Doo-Sung Lee; Min-Sang Kim; Je-Sun You; Huynh Dai Phu; Bong-Sup Kim; Minh Khanh Nguyen
Original assignee: Sungkyunkwan University Foundation For Corporate Collaboration
Priority date: 2005-04-13
Filing date: 2006-03-31
Publication date: 2006-10-19
Also published as: DE112006000685B4; DE112006000685T5

Abstract

Disclosed is a block copolymer formed by coupling the following components with each other: (a) a copolymer (A) of a polyethylene glycol (PEG) type compound with a biodegradable polymer; and (b) at least one oligomer (B) selected from the group consisting of poly (β-amino ester) and poly(amido amine). A method for preparing the same block copolymer, and a polymeric hydrogel type drug composition comprising the temperature and pH-sensitive block copolymer and a physiologically active substance that can be encapsulated with the block copolymer are also disclosed. The multiblock copolymer is obtained by copolymerization of a pH-sensitive poly (β-amino ester) and/or poly(amido amine) type oligomer, a hydrophilic and temperature-sensitive polyethylene glycol type compound and a hydrophobic and biodegradable polymer. Therefore, the block copolymer can form a polymeric hydrogel structure due to its amphiphilicity resulting from the combination of a hydrophilic group and a hydrophobic group in the copolymer and ionization characteristics depending on pH variations, and thus can be used as a drug carrier for target-directed drug delivery depending on pH variations in the body.

Description

TEMPERATURE AND PH SENSITIVE BLOCK COPOLYMER AND POLYMERIC HYDROGLES USING

THE SAME Technical Field

[1] The present invention relates to a biodegradable block copolymer useful for temperature and pH sensitive drug carriers, a method for preparing the same, and a polymeric hydrogel type drug composition comprising the above block copolymer. More particularly, the present invention relates to a multiblock copolymer derived from a temperature-sensitive block copolymer comprising a polyethylene glycol type compound and a biodegradable polyester polymer compound, and a poly(β-anino ester) compound and/or a poly(arrido amine) compound that shows ionization characteristics depending on pH values. The multiblock copolymer according to the present invention is capable of target-directed drug delivery depending on temperature and pH variations in the body. The present invention also relates to a polymeric hydrogel comprising the above multiblock copolymer. Background Art

[2] Recently, in the field of medical industry and drug delivery system, intensive research and development has been performed to develop a target-directed drug carrier that utilizes a sol-gel transition phenomenon of hydrogel prepared from an amphiphilic polymer having a hydrophobic group as well as a hydrophilic group.

[3] US Patent No. 4,942,035 discloses the use of a copolymer of polyalkylene glycol, as a hydrophilic polymer, with polylactide, polyglycolide or polycaprolactone, as a biodegradable polyester polymer, for improving the problem of non-degradability of a so-called pluronic gel (polyethylene glycol and polyethylene oxide-polypropylene oxide-polyethylene oxide block copolymer) in the body.

[4] Additionally, US Patent No. 5,476,909 discloses an A-B-A type triblock copolymer as a biodegradable polyester polymer, wherein the hydrophobic block (A) is limited to polylactide (PLA), polyglycolide (PGA) and copolymers thereof, and the hydrophilic block (B) is limited to polyethylene glycol (PEQ and derivatives thereof.

[5] Meanwhile, Korean Laid-Open Patent No. 2000-0012970 discloses a pH-sensitive polymer containing a sulfoneanide group and a method for preparing the same. More particularly, the Korean Patent discloses variations in the solubility of a linear polymer formed by random copolymerization of a sulfoneanide monomer with dimethylacryl anide or isopropylacryl anlde, or the swelling degree of the crosslinked polymer thereof.

[6] The aforementioned prior art utilizes a block copolymer of a hydrophobic biodegradable polymer with a hydrophilic polymer, which shows a sol-gel transition phenomenon depending on temperatures. More particularly, when the block copolymer is injected into the body in the form of an aqueous solution present in a sol state, it undergoes a transition into a gel state, so that it can be used as a release-controlled drug carrier that carries a drug stably in the body and releases the drug gradually. However, when such temperature-sensitive block copolymers having sol-gel transition characteristics are used, there is a problem in that the block copolymers may cause gelling before they are injected completely into the body, because injection of the block copolymers into the body generates a thermal equilibrium state between the injection needle temperature and the body temperature due to the body temperature. Additionally, although it is reported that the hydrophobic part comprising PLA, PLGA or PCL shows pH sensitivity, actual pH sensitivity of the hydrophobic part is not so high as to be applied to the pH condition in the body. Therefore, the block copolymers according to the prior art are not suitable to be applied for drug delivery systems. Disclosure of Invention Technical Problem

[7] We have recognized that when a temperature-sensitive block copolymer hydrogel comprising a polyethylene glycol type compound and a biodegradable polyester polymer compound is used alone, there is a problem in that injection of the hydrogel into the body may cause gelling before it is introduced completely into the body due to the heat transfer caused by the body temperature, resulting in occlusion of an injection needle. Under the above recognition, we have made intensive studies to develop a temperature- and pH-sensitive block copolymer via a coupling reaction of the above temperature-sensitive block copolymer with poly(β-anino ester) (PAE), poly(anido anine) (PAA) or a combination (PAEA) thereof, which shows pH-sensitivity through a change in the ionization degree thereof depending on pH values in the body.

[8] Actually, we have found that the block copolymer hydrogel according to the present invention shows sol-gel transition behavior sensitive to pH values as well as temperatures. For example, the hydrogel according to the present invention shows sol-gel transition behavior, wherein it undergoes gelling at a pH range of 7-7.4 similar to pH values in the body, while it is converted into sol at a pH value lower than the above range. Hence, the block copolymer hydrogel according to the present invention forms gel stably with no problem of occlusion of an injection needle, occurring in the conventional temperature-sensitive hydrogel. Also, we have found that the resultant block can be applied as a carrier for use in release-controlled drug delivery, which carries a drug stably at a specific temperature and a specific pH value in the body and releases the drug gradually.

[9] Additionally, we have conducted studies in order to control the biodegradation rate of a pH-sensitive polymer in the human body. Finally, we succeeded in controlling the biodegradation rate as desired in the human body by nϊjdng a suitable amount of a poly(amido amine) having an amide bond instead of an ester bond in its bacϋone and thus showing a relatively slow biodegradation rate with the pH-sensitive poly(β-anino ester) having an ester bond in its bacMxme and thus showing a relatively high biodegradation rate.

[10] Therefore, it is an object of the present invention to provide a novel temperature- and pH-sensitive multiblock copolymer, a method for preparing the same, and a polymeric hydrogel composition comprising the same multiblock copolymer. Technical Solution

[11] According to an aspect of the present invention, there is provided a block copolymer formed by coupling the following components with each other: (a) a copolymer (A) of a polyethylene glycol (PEQ compound with a biodegradable polymer; and (b) at least one oligomer (B) selected from the group consisting of poly(β-anino ester) and poly(anido amine). There is also provided a method for preparing the same block copolymer.

[12] According to another aspect of the present invention, there is provided a polymeric hydrogel type drug composition comprising the above temperature and pH-sensitive block copolymer and a physiologically active substance that can be encapsulated with the block copolymer.

[13] Hereinafter, the present invention will be explained in more detail.

[14] The present invention is characterized in that a temperature-sensitive block copolymer formed by the copolymerization of a polyethylene glycol type compound and a biodegradable polymer compound is coupled with poly(β-arrino ester), poly(amido amine) or a combination (PAEA) thereof, which experiences a change in the ionization degree depending on pH values, to provide a temperature and pH sensitive multiblock copolymer, which is sensitive to pH variations as well as temperature variations in the body, and to provide polymeric hydrogel using the same multiblock copolymer.

[15] The block copolymer according to the present invention having the above characteristics can provide the following effects:

[16] (1) The conventional block copolymer comprising a hydrophilic polymer such as polyethylene glycol and a biodegradable hydrophobic polymer shows sol-gel transition behavior due to a change in the physical properties of the hydrophilic block and the hydrophobic block. However, it was difficult to apply such conventional block copolymers to an actual drug delivery system due to their poor sensitivity to temperature variations and side effects in the body, caused by the thermal equilibrium of a transfer medium.

[17] On the contrary, according to the present invention, the temperature-sensitive block copolymer comprising the hydrophilic polymer and the biodegradable polymer is coupled with a compound such as poly(β-arrino ester) (PAE), poly(arrido amine) (PAA) or a combination (PAEA) thereof, which shows an ionization degree varied with pH values. Therefore, the resultant block copolymer has pH sensitivity as well as temperature sensitivity, and thus can solve the aforementioned problem related to the conventional temperature-sensitive hydrogel and can form more stable hydrogel.

[18] Particularly, the temperature and pH sensitive block copolymer according to the present invention forms a physically and chemically stable hydrogel in a specific pH range, and undergoes a transition into a sol state in the other pH ranges. In brief, the block copolymer according to the present invention can show reversible sol-gel transition behavior. In other words, in a low pH range (e.g. pH < 7.0), the tertiary amine group present in poly(β-anino ester) (PAE) shows an increased ionization degree, so that the whole PAE is converted into a water soluble compound that cannot form hydrogel. On the other hand, in a high pH range (e.g. pH > 7.2), PAE has a decreased ionization degree and shows hydrophobicity, and thus can form hydrogel.

[19] (2) Additionally, the temperature and pH sensitive block copolymer is safe in the human body, and thus can be used as a release-controlled drug carrier in the medical field and in the gene transfer and drug delivery systems, in particular, as a drug carrier and drug releasing substance. Also, the block copolymer can be applied to a carrier for cell transfer, used as an injectable scaffold.

[20] (3) Further, according to the present invention, it is possible to modify the constitutional elements forming the block copolymer and physical properties thereof, for example, the composition, molar ratio, molecular weight and/or functional groups in the blocks, so as to design the reversible sol-gel transition behavior of the block copolymer in various manners. Thus, it is expected that the block copolymer according to the present invention can be used for various applications, including cancer cell mutation, gene mutation and others.

[21] One constitutional element forming the temperature- and pH-sensitive block copolymer according to the present invention is a copolymer (A) of a PEG type compound with a biodegradable compound. The copolymer (A) allows a sol-gel transition depending on temperature variations, because the hydropbilic PEG type compound and the hydrophobic biodegradable polymer are present in the same molecule.

[22] The PEG type compound forming the copolymer (A) is a general PEG compound known to one skilled in the art. Although there is no particular limitation in selection of the PEG compound, it is preferable to use a PEG type compound represented by the following formula 1.

[23] [Formula 1]

[24]

(VH)

[25] wherein R is a hydrogen atom or a C1~C5 alkyl group, and n is a natural number ranging from 11 to 45.

[26] Although there is no particular limitation in the molecular weight (Mn) of the polyethylene glycol type compound, the polyethylene glycol type compound preferably has a molecular weight of 500 to 5000. Particularly, in the case of polyethylene glycol (PEQ, wherein R is a hydrogen atom, the polyethylene glycol preferably has a molecular weight of 1000 to 2000. In the case of methoxy- polyethylene glycol (MPEQ, wherein R is a methyl group, the methoxypolyethylene glycol preferably has a molecular weight of 500 to 5000. When the polyethylene glycol type compound has a molecular weight (Mn) away from the above range (for example, a molecular weight of less than 500 or greater than 5000), it is difficult to form gel. Even if gel is formed from the block copolymer, the resultant gel shows poor gel strength, so that it cannot be used as a carrier for drug delivery.

[27] The biodegradable polymer forming the copolymer (A) is a conventional biodegradable polymer known to one skilled in the art. Preferably, the biodegradable polymer is a biodegradable aliphatic polyester polymer, and non-liniting examples thereof include caprolactone (CL), glycolide (GA), lactide (LA) or a copolymer thereof. In addition to the aforementioned polymers, any biodegradable polymers capable of forming a copolymer with the PEG type compound may be used in the scope of the present invention.

[28] There is no particular limitation in the copolymer (A) formed by the polymerization of the polyethylene type compound and the biodegradable polymer, as long as the copolymer comprises the above components. However, it is preferable that the copolymer has at least one substituent selected from the group consisting of a primary amine group, a secondary amine group and a double bond, which are capable of reacting with a poly(β-anino ester) and/or poly(anido anine) block. Non-liniting examples of the copolymer (A) include polylactide (PLA), polyglycolide (PGA), poly- caprolactone (PCL), poly(caprolactone-lactide) random copolymer (PCLA), poly(caprolactone-glycolide) random copolymer (PCGA), poly(lactide-glycolide) random copolymer (PLGA), or the like.

[29] Although there is no particular limitation in the molecular weight ratio of the PEG type compound to the biodegradable polymer in the copolymer (A), the ratio is preferably 1:1-3. If the ratio is less than 1:1, it is not possible to form gel. If the ratio is greater than 1:3, hydrophobicity increases undesirably, so that the resultant block copolymer may not be dissolved in water.

[30] Additionally, when the biodegradable polymer forming the copolymer is PCLA,

PCGA or PLGA, it is possible to improve the temperature sensitivity and pH sensitivity by controlling the molar ratio thereof.

[31] Another constitutional element forming the temperature- and pH-sensitive block copolymer according to the present invention may be any compound that shows an ionization degree varied with pH values with no particular limitation. Particularly, the compound is an oligomer (B) formed from a poly(β-anino ester) and/or poly(amido anine) type compound having hydrophobicity and pH-sensitivity at the same time.

[32] The poly(β-anino ester)- and poly(anido anine)-based oligomer (PAEA) comprising poly(β-anino ester) (PAEj, poly(arrido anine) (PAA) or a mixture containing them in an adequate ratio have ionization characteristics characterized by water solubility varied with pH values due to the presence of a tertiary anine group ionized at a pH of 7.2 or less. Therefore, the oligomer can show pH sensitivity by forming hydrogel or by maintaining a sol state depending on pH variations in the body.

[33] The above compounds may be prepared by a process known to one skilled in the art. In one embodiment of such processes, a bisacrylate compound and/or a bisacrylanide compound having a double bond is polymerized with an amine compound via the Michael reaction mechanism to produce a poly(β-amino ester) (PAE), poly(aπido anine) (PAA) or a nixed oligomer containing them in an adequate ratio.

[34] The bisacrylate compound used in the above process may be represented by the following formula 2, and non-liniting examples of such bisacrylate compounds include ethylene glycol diacrylate, 1,4-butanediol diacrylate, 1 ,3-butanediol diacrylate, 1,6-hexanediol diacrylate, 1 ,6-hexanediol ethoxylate diacrylate, 1,6-hexanediol propoxylate diacrylate, 3-hydroxy-2,2-dimethylpropyl 3-hydroxy-2,2-dimethylpropionate diacrylate, 1 ,7-heptanediol diacrylate, 1,8-octanediol diacrylate, 1,9-nonanediol diacrylate, 1,10-decanediol diacrylate, diol diacrylate type compounds (CH =CH-COR-COCH=CH ) such as derivatives of the above compounds, and mixtures thereof.

[35] [Formula 2]

[36]

cvm>

[37] wherein R is a C1-C30 alkyl group.

[38] The bisacrylanide compound used in the above process may be represented by the following formula 3, and non-liniting examples of such bisacrylanide compounds include N,N'-methylene bisacrylanide (MDA), N,N'-ethylene bisacrylanide and mixtures thereof. The bisacrylanide compound is allowed to react with an anine compound such as 4-aninomethylpiperidine (AMPD), N-methyl ethylenedianine (MEDA) or l-(2-aninoethyl)piperidine (AEPZ) through a conventional reaction mechanism such as the Michael reaction mechanism.

[39] [Formula 3]

[40]

(K)

[41 ] wherein R is a C 1 ~C20 alkyl group.

[42] To provide the pH-sensitive poly(β-anino ester) and/or poly(anido amine), the bisacrylate compound and/or the bisacrylanide compound may be used alone or in combination. In the case of a mixture containing at least one compound, the weight ratio of the compounds forming the mixture may be controlled freely in a range of 100:0-0:100.

[43] Additionally, there is no particular limitation in selection of the amine compound as long as the amine compound has an amine group. Preferably, a primary amine represented by the following formula 4, a secondary anine-containing diamine compound represented by the following formula 5, or a mixture thereof are used.

[44] [Formula 4]

[45]

H₂N R₁

(X)

[46] [Foπnula 5]

[47]

(XI) [48] wherein each of R and R is a Cl ~C20 alkyl group.

1 2

[49] Non-liniting examples of such primary amine compounds include

3-methyl-4-(3-methylphenyl)piperazine, 4-(ethoxycarbonylmefhyl)piρerazine, 4-(ρhenylmethyl) piperazine, 4-(l-phenylethyl)piperazine,

4-(l,l-dimethoxycarbonyl)piperazine, 4-(2-(bis-(2-propenyl) anino)ethyl)piperazine, methylanine, ethylanine, butylanine, hexylanine, 2-ethylhexylanine, 2-piperidine- 1 -yl-ethylanine, C-aziridine- 1 -yl-ethylanine, l-(2-aninoethyl)piperazine, 4-(anϊnomethyl)piperazine, N-methylethylenedianine, N- ethylethylenedianine, N-hexylethylenedianine, pycolianine, adenine, etc. Non- liniting examples of such secondary anine-containing diamine compounds include piperazine, piperidine, pyrrolidine, 3,3-dimethylpiperidine, 4,4'-trimethylene dip- iperidine, N,N'-dimethyl ethylene diamine, N,N'-diethyl ethylene diamine, ini- dazolidine, diazepine, etc.

[50] When preparing a pH-sensitive poly(β-anino ester) and/or poly(anido anine), the hisacrylate or bisacrylanide compound is allowed to react with the anine compound preferably in a molar ratio of 1 :0.5~2.0. When the molar ratio of the anine compound is less than 0.5 or greater than 2.0, the resultant polymer has a broad molecular weight distribution and shows poor pH sensitivity, and it is difficult to control the length of a block in the resultant block copolymer.

[51] Although there is no particular limitation in the molecular weight of the oligomer formed from at least one compound selected from the group consisting of poly(β-anino ester) and poly(anido anine), the oligomer preferably has a molecular weight of 500-20,000. If the molecular weight is less than 500, the resultant block copolymer cannot show sol-gel transition behavior depending on pH variations. On the other hand, if the molecular weight is greater than 20,000, the block copolymer cannot show temperature sensitivity.

[52] The block copolymer according to the present invention, formed by coupling the copolymer (A) of a PEG type compound and a biodegradable polymer with the poly(β-anino ester) and/or poly(anido anine) oligomer (B) is preferably a tri- or higher block copolymer, and is more preferably a triblock or pentablock copolymer. More particularly, the block copolymer may be represented by any one of the following formulae 6-11 :

[53] [Formula 6]

[54]

(D

[55] [Formula 7] [56]

[57] (H)

[58] [Formula 8]

[59]

m

[60] [Formula 9]

[61]

(IV)

[62] [Formula 10]

[63]

W

12

[64] (V)

[65] [Formula 1 1]

[66]

[67] (VI)

[68] wherein each of x, y, z, n and is a natural number ranging from 1 to 10,000.

[69] The block copolymer represented by any one of the above formulae 6-11 can form hydrogel or can maintain a sol state depending on pH variations due to its amphiphilic property and pH sensitivity. Particularly, the block copolymer according to the present invention can be used satisfactorily in various applications requiring sensitivity depending on pH variations in the body (for example, carriers for release-controlled drug delivery).

[70] Herein, the block copolymer represented by formula 9 has a hydroxy group only at one end of the copolymer (MPEGPGLA) of a PEG type compound and a biodegradable polyester polymer. Therefore, the hydroxy group may be substituted with an acrylate group, and thus the resultant block copolymer has a block structure coupled with a β-amino ester at one side. [71] Although there is no particular limitation in the molecular weight of the block copolymer, it is preferable that the block copolymer has a molecular weight of 5,000 to 30,000. When the block copolymer has a molecular weight away from the above range, it is difficult to form gel due to a failure in hydrophilicity/hydrophobicity balance.

[72] In addition to the above constitutional elements, the temperature- and pH-sensitive block copolymer according to the present invention may further comprise other components or additives, currently used in the art.

[73] To provide the temperature- and pH-sensitive block copolymer according to the present invention by using the copolymer (A) of a PEG type compound and a biodegradable polymer and a poly(β-amino ester) and/or poly(anido amine) type oligomer, it is possible to utilize any one method of the polymerization methods known to one skilled in the art, including Michael reaction, radical polymerization, cationic polymerization, anionic polymerization, polycondensation, or the like.

[74] In one embodiment of the method for preparing the temperature- and pH-sensitive block copolymer according to the present invention, the method comprises the steps of: (a) polymerizing a PEG type compound with a biodegradable polymer to form a copolymer (A); (b) introducing an acrylate group into the copolymer (A) of PEG with the biodegradable polymer; (c) and coupling the resultant copolymer (A) with at least one oligomer selected from the group consisting of poly(β-anino ester) and poly(aiτido amine).

[75] First, a PEG type compound is polymerized with a biodegradable polyester polymer to form a copolymer, and the reaction may be represented by the following Reaction Scheme 1:

[76] [Reaction Scheme 1]

[77]

+ caprolactone

Methoxy polyCethytene

(4) Methoxy polyethylene glycol) ⁺ caprolactone + Lactide

PCU-PEG-PCLA

MPEG-PCL

[78] Copolymerization of a PEG type compound with a biodegradable polyester polymer is preferably carried out via a ring-opening polymerization reaction. Herein, polymerization temperature and time may be controlled in a range known to one skilled in the art, and the polymerization is carried out preferably at a temperature of 130~150°C for 12-48 hours. Additionally, a catalyst may be used for accelerating the reaction, and particular examples of the catalyst that may be used include stannous octoate, stannous chloride, metal oxides (GeO , Sb O , SnO , etc.), aluminum triiso-

2 3 2 2 propoade, CaH , Zn, lithium chloride, tris(2,6-di-tert-butylphenolate), or the like. Further, it is possible to control the molecular weight and type of the biodegradable polymer in order to change the hydrophcbicity.

[79] The step of introducing an acrylate group into the copolymer formed by the ring- opening polymerization of PEG is preferably carried out by way of the reaction between the terminal hydroxy group (-OH) of the polyethylene glycol-biodegradable polyester copolymer and the halogen of an acryloyl chloride. The reaction may be represented by the following Reaction Scheme 2: [80] [Reaction Scheme 2]

[81]

MPEG-PCL aπrylojd chloride

O CH-

,H- H- , || H- I]

HjC -Q —f C -C -CH — fC -fC fecΛ C CH

O flciyiate cl MPEG-PCL

[82] The temperature and pH sensitive multiblock copolymer may be obtained from the copolymer (A) of PEG with the biodegradable polyester polymer, into which an acrylate group is introduced, via the coupling of an amine group (-NH or -NH ) with an acrylate group (-CH=CH ). The coupling reaction may be represented by the following Reaction Scheme 3:

[83] [Reaction Scheme 3]

[84]

D O O D , H- H- , U H- . [J HjC -D-fc -C-OI— f C4 C4-D4— C- C=CH- + HN NH + H-C -C - C-O-I-Crij]- C- C= CH- \ M ⁵ /x H ^" H ^{; er} H ^' aciykted MPEG-PCL piperaziiie l,->-hexane dial diacrjiatB

[85] There is no particular limitation in the reaction temperature and time of the above step, and the block copolymer may be obtained in a conventional manner known to one skilled in the art.

[86] A primary amine compound and a secondary anine-containing diamine compound, used for the preparation of a poly(β-arrino ester) oligomer, as well as a diol diacrylate type compound that reacts with the above amine compound to form a β-anino ester block may be subjected to the same process as described above.

[87] The multiblock copolymer obtained as described above has a combination of a hy- drophilic block, a hydrophobic block and a poly(β-aπϊno ester) and/or poly(arrido amine) oligomer that shows an ionization degree varied with pH values, and thus the multiblock copolymer can show temperature sensitivity and pH sensitivity at the same time.

[88] Actually, it was possible to determine the block copolymer according to the present invention, for example, methoxypolyethylene glycol-polycaprolactone-beta amino ester (MPEGPCL-β-amino ester) for the introduction of each functional group and for the reaction of terminal groups by using FT-IR and H-NMR. It was also possible to determine that the block copolymer according to the present invention has a structure formed by coupling of a copolymer of a PEG type compound and a biodegradable polymer with a β-anino ester oligomer, through an increase in the molecular weight of the block copolymer, as observed by GPC (gel permeation chromatography).

[89] Meanwhile, it was also possible to determine the reaction degree, molecular weight and block length of the methoxypolyethylene glycol-polycaprolactone-anido amine (MPEGPCL-anido amine) block copolymer, which uses poly(amido amine) alone as a pH-sensitive compound instead of poly(β-amino ester), and the nixed block copolymer, i.e., methoxypolyethylene glycol-polycaprolactone-β-amino ester-anido amine (MPEGPCL- β-arrino ester-arrido amine) copolymer, which uses a mixture of poly(β-anino ester) and poly(anido amine) having pH sensitivity and a different biodegradation rate so as to control the biodegradation rate in the human body, by using FT-IR, H-NMR and GPC. Additionally, in order to determine the pH sensitivity of the block copolymer, sol-gel transition characteristics of the block copolymer were measured by varying pH at a certain temperature. After the measurement, it was shown that the multiblock copolymer according to the present invention has pH sensitivity.

[90] According to another aspect of the present invention, there is provided a polymeric hydrogel type drug composition, which comprises: (a) the temperature and pH sensitive block copolymer; and (b) a physiologically active substance that can be encapsulated with the block copolymer.

[91] Any physiologically active substances can be used and can be encapsulated with the polymeric hydrogel type block copolymer according to the present invention with no particular limitation. Non-limiting examples of such active substances include anti- cancer agents, antibacterial agents, steroids, antiphlogistic analgesic agents, sexual hormones, immunosuppressants, antiviral agents, anesthetic agents, antiemetic agents, antihistamine agents, etc. In addition to the above active substances, the drug composition according to the present invention may further comprise conventional additives such as vehicles, stabilizers, pH adjusting agents, antioxidants, preservatives, binders and disintegrating agents. The composition may further comprise other conventional additives, solvents, or the like.

[92] Additionally, the polymeric hydrogel type drug composition may be provided as oral formulation or parenteral formulation. Particularly, the polymeric hydrogel type drug composition may be provided for intravenous, intramuscular or subcutaneous injection.

[93] According to still another aspect of the present invention, there is provided a carrier for drug delivery or medical diagnosis, which comprises the temperature and pH sensitive block copolymer. Herein, any materials are encapsulated with the block copolymer, as long as they are for treatment, prevention or diagnosis of diseases.

[94] According to yet another aspect of the present invention, there is provided use of a copolymer comprising: (a) at least one hydrophilic block; (b) at least one biodegradable block having hydrophobicity varied with temperatures; and (c) at least one unit having an ionization degree varied with pH values, as a carrier for drug delivery or medical diagnosis.

[95] Herein, the unit (c) having an ionization degree varied with pH values may be at least one oligomer (B) selected from the group consisting of poly (β-anino ester) and poly(anido amine), but is not United thereto. Additionally, the hydrophilic block (a) and the biodegradable block (b) having different hydrophobicity depending on temperature variations are the same as defined above. Also, it is possible to use other hydrophilic and/or hydrophobic materials known to one skilled in the art. Brief Description of the Drawings

[96] The foregoing and other objects, features and advantages of the present invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings in which:

[97] FIG. 1 is a graph showing the sol-gel transition behavior of the triblock copolymer according to Example 1, depending on temperature and pH variations, the triblock copolymer comprising a pH-sensitive polyethylene glycol type compound, a biodegradable polycaprolactone compound and a pH-sensitive biodegradable ρoly(β-anino ester) compound; [98] FIG. 2 is a graph showing the sol-gel transition behavior of the pentablock copolymer according to Example 2, depending on temperature and pH variations, the pentablock copolymer comprising a polyethylene glycol type compound, poly- caprolactone compound and polylactic acid compound, and a polyφ-arrino ester) compound;

[99] FIG. 3 is a graph showing the sol-gel transition behavior of the pentablock copolymer according to Example 4, depending on pH variations, the pentablock copolymer comprising a polyethylene glycol type compound, polycaprolactone compound and polylactic acid compound, and poly(β-aπino ester) and poly(anido amine) nixed in a weight ratio of 60:40; and

[100] FIG. 4 is a graph showing variations in the molecular weight of each of the block copolymers as a function of time at pH 7.4 according to Examples 2 to 7. Mode for the Invention

[101] Reference will now be made in detail to the preferred embodiments of the present invention. It is to be understood that the following examples are illustrative only and the present invention is not limited thereto.

[102] [Examples 1~6. Preparation of Temperature and pH Sensitive Block Copolymer!

[103] Example 1. Preparation of Polyethylene glycol-Biodegradable

Polyester Polymer (PoIycaprolactone)-Poly(β-amino ester) Triblock Copolymer (PAE)

[104] First, 1Og of polyethylene glycol methyl ether (MPEG, Mn=2000, 5000) and 0.2g of stannous octoate (catalyst) were introduced into a reactor and the reaction mixture was dried under vacuum at 110⁰C for 4 hours to remove water. After cooling the dried reaction mixture, 6.Og (5.576 ml) of ε-caprolactone as a biodegradable polyester polymer were added thereto under nitrogen atmosphere, and then the resultant reaction mixture was heated gradually to 135°C under nitrogen atmosphere and subjected to polymerization for 24 hours. It was possible to obtain an MPEGPCL block copolymer having a desired molecular weight by controlling the amount of MPEG and the addition amount of ε-caprolactone so as to control the molecular weight. Stannous octoate was used in an amount of 0.5 wt% based on the amount of MPEG. After the completion of the reaction, the reaction mixture was cooled to room temperature, and a small amount of methylene chloride was added thereto to dissolve the reactants. The reaction mixture was added to an excessive amount of ethyl ether and precipitated therein to remove unreacted materials. Then, the product, from which unreacted materials were removed, was dried under vacuum at 40⁰C for 48 hours. By doing so, a block copolymer (MPEGPCL) of polyethylene glycol with ε-caprolactone (biodegradable polyester polymer compound) was obtained with a yield of 85% or more.

[105] Next, 4g of the MPEGPCL block copolymer obtained as described above were introduced into a reactor and was dried at 85°C under vacuum to remove water. After cooling the reaction mixture to room temperature, methylene chloride was added thereto under nitrogen atmosphere to dissolve the block copolymer. Then, triethyl anine was added to the reaction mixture in a molar ratio of 1.5: 1 based on the amount of the MPEGPCL block copolymer in order to remove HCl as a byproduct, and the dissolved product was cooled to 10°C. Then, acryloyl chloride was added dropwise to the cooled product in a molar ratio of 1.5 : 1 to obtain a block copolymer having a double bond. The above reaction was carried out in an ice-bath under nitrogen atmosphere for 24 hours. After the completion of the reaction, the reaction mixture was precipitated in ethyl ether to remove unreacted materials, filtered and dried under vacuum at room temperature to obtain a polyethylene glycol-polycaprolactone-acrylate block copolymer (MPEGPCL-A) having a double bond at its terminal group, with a yield of 80% or more.

[106] The block copolymer (MPEGPCL-A) having a double bond, obtained as described above, was introduced into a reactor at room temperature, and chloroform was added thereto to dissolve the block copolymer. To form a β-anino ester block, piperazine and 1,6-hexanediol diacrylate were added thereto at room temperature and dissolved. Then, the reaction mixture was allowed to react at 50⁰C for 48 hours. While firing the molar ratio of piperazine: 1,6-hexanediol diacrylate to 1:1, equivalent ratio of the MPEGPCL block copolymer, piperazine and 1,6-hexanediol diacrylate was controlled to obtain a triblock copolymer having a desired molecular weight. After the completion of the reaction, the reaction mixture was precipitated in an excessive amount of ethyl ether to remove unreacted materials, and then the product was filtered to obtain an MPEG PCL-poly(β-anino ester) triblock copolymer with a yield of 70% or more.

[107] Example 2. Temperature- and pH-sensitive Pentablock Copolymer

[108] Example 1 was repeated to obtain triblock copolymers (PCLA-PEGPCLA) comprising ε-caprolactone, D,L-lactide and polyethylene glycol and having various molecular weights, except that polyethylene glycol(PEG, Mn=1500, 1750, 2000) was used instead of polyethylene glycol ether and D,L-lactide was further added besides ε- caprolactone. Each product was obtained with a yield of 91% or more.

[ 109] The PCLA-PEGPCLA block copolymer obtained as described above was introduced into a reactor and was dried at 85°C under vacuum to remove water. After cooling the reaction mixture to room temperature, methylene chloride was added thereto under nitrogen atmosphere to dissolve the block copolymer. Then, triethyl aπine was added to the reaction mixture in a molar ratio of 3: 1 based on the amount of the block copolymer in order to remove HCl as a byproduct, and the dissolved product was cooled to 10⁰C. Then, acryloyl chloride was added dropwise to the cooled product in a molar ratio of 3: 1 to obtain a block copolymer having a double bond. The above reaction was carried out in an ice-bath under nitrogen atmosphere for 24 hours. After the completion of the reaction, the reaction mixture was precipitated in ethyl ether to remove unreacted materials, filtered and dried under vacuum at room temperature to obtain poly(ε-caprolactone/D,L-lactide-polyethylene glycol- poly(ε-caprolactone/D,L-lactide acrylate block copolymer (acrylated PCLA- PEGPCLA) having a double bond at its terminal group, with a yield of 80% or more.

[110] The block copolymer (acrylated PCLA-PEGPCLA) having a double bond, obtained as described above, was introduced into a reactor at room temperature, and chloroform was added thereto to dissolve the block copolymer. To form a β-anino ester block, 4,4^/-trimethylene dipiperazine and 1,4-butanediol diacrylate were added thereto at room temperature and dissolved. Then, the reaction mixture was allowed to react at 50⁰C for 48 hours. While fixing the molar ratio of 4,4'-trimethylene dipiperazine to 1,4-butanediol diacrylate to 1: 1, equivalent ratio of the triblock copolymer, 4,4'-trimethylene dipiperazine and 1,4-butanediol diacrylate was controlled to obtain a pentablock copolymer having a desired molecular weight. After the completion of the reaction, the reaction mixture was precipitated in an excessive amount of ethyl ether to remove unreacted materials, and then the product was filtered to obtain a poly(β-anino ester)-PCLA-PEGPCLA-poly(β-anino ester) pentablock copolymer with a yield of 70% or more.

[Ill] Meanwhile, molecular weight of MPEG, molecular weight of the biodegradable polymer (PCLA), molar ratio of MPEG to the biodegradable polymer, and molecular weight of poly(β-anino ester) were varied as shown in the following Table 1 to provide triblock copolymers (PCLA-PEGPCLA) and pentablock copolymers (poly(β-anino ester)-PCLA-PEGPCLA-poly(β-amino ester)) having various molecular weights. Molecular weight of each block copolymer is also shown in Table 1. In Table 1, PDI refers to a polydispersity index as measured by GPC, and is used to determine whether the block copolymer has a uniform molecular distribution or not. As PDI of a block copolymer decreases, the block copolymer has a more uniform molecular weight distribution. On the other hand, as PDI of a block copolymer increases, the block copolymer has a less uniform molecular weight distribution. [112] Table 1

[113] Example 3 [114] Example 2 was repeated to provide a pentablock copolymer of poly(β-aπino ester- aπido aπine)-PCLA-PEGPCLA-poly(β-anino ester-anido anine) having a molecular weight of 6800, except that 1,6-hexanediol diacrylate and N,N'-methylene bisacrylanide were used in a weight ratio of 80:20 instead of 1 ,4-butanediol diacrylate.

[115] Example 4 [116] Example 2 was repeated to provide a pentablock copolymer of poly(β-anino ester- anido amine)-PCLA-PEGPCLA~poly(β-anino ester-anido anine) having a m olecular weight of 6500, except that 1,6-hexanediol diacrylate and N,N'-methylene bisacrylanide were used in a weight ratio of 60:40 instead of 1,4-butanediol diacrylate.

[117] Example 5 [118] Example 2 was repeated to provide a pentablock copolymer of poly(β-anino ester- anido anine)-PCLA-PEGPCLA-poly(β-anino ester-anido anine) having a molecular weight of 6500, except that 1,6-hexanediol diacrylate and N,N'-methylene bisacrylanide were used in a weight ratio of 40:60 instead of 1,4-butanediol diacrylate.

[119] Example 6 [120] Example 2 was repeated to provide a pentablock copolymer of poly(β-anino ester- anido aπine)-PCLA-PEGPCLA-poly(β-anino ester-anido anine) having a molecular weight of 6500, except that 1,6-hexanediol diacrylate and N,N'-methylene bisacrylanide were used in a weight ratio of 20:80 instead of 1,4-butanediol diacrylate. [121] Example 7

[122] Example 2 was repeated to provide a pentablock copolymer of poly(amido anine)-PCLA-PEGPCLA-poly(anido amine) having a molecular weight of 6500, except that 1,6-hexanediol diacrylate and N,N'-methylene hisacrylanide were used in a weight ratio of 0:100 instead of 1 ,4-bitanediol diacrylate.

[123] [Comparative Example 1-31

[124] Comparative Example 1

[125] Example 2 was repeated to provide a pentablock copolymer of poly(anido arrine)-PCLA-PEG-PCLA-poly(amido amine) having a molecular weight of 5000, except that the oligomer formed from poly(anido amine) had a molecular weight of less than 500. However, the copolymer showed no sol-gel transition behavior under the body temperature conditions (37°C, pH 7.4).

[126] Comparative Example 2

[127] Example 2 was repeated to provide a pentablock copolymer of poly(amido arrine)-PCLA-PEG-PCLA-poly(anido amine) having a molecular weight of 25500, except that the oligomer formed from poly(arrido amine) had a molecular weight of 21000. However, the copolymer showed no sol-gel transition behavior under the body temperature conditions (37°C, pH 7.4).

[128] Comparative Example 3

[129] Example 2 was repeated to provide a pentablock copolymer of poly(β-anino ester- airido airine)-PCLA-PEGPCLA-poly(β-anino ester-aπido amine) having a molecular weight of 5000, except that MPEG4000 was used instead of MPEG2000. However, the copolymer showed no sol-gel transition behavior under the body temperature conditions (37°C, pH 7.4).

[130] Comparative Example 4

[131] Example 2 was repeated to provide a pentablock copolymer of poly(β-anino ester- aπido anine)-PCLA-PE&PCLA-poly(β-anino ester-arrido anine) having a molecular weight of 7700, except that MPEG6000 was used instead of MPEG5000. However, it was difficult to form a gel from the copolymer, because the copolymer had unbalanced hydrophilic/hydrophobic blocks and could not allow a sol-gel transition due- to the use of MPEG having a high molecular weight.

[132] Experimental Example 1. Evaluation for Sol-Gel Transition Behavior

Depending on pH Variations (1)

[133] The following experiment was performed to evaluate sol-gel transition behavior of the block copolymer according to the present invention depending on temperature and pH variations.

[134] The triblock copolymer (MPEG-PCL-β-anino ester) according to Example 1, the pentablock copolymer according to Example 2, and the pentablock copolymer according to Example 4 were added to a buffer solution, in an amount of 30 wt%, 20 wt% and 30 wt%, respectively, to dissolve each block copolymer. Then, each block copolymer solution was titrated with NaCH solution to a pH level of 5.5, 6.0, 6.5, 7.0 and 7.5. After each block copolymer solution having a different pH was heated by 2°C so that the solution was in an equilibrium state at a constant temperature for 10 minutes, each solution was tilted to determine sol-gel transition behavior of each block copolymer. FIGs. 1-3 show the sol-gel transition behavior of each block copolymer depending on temperature and pH variations.

[135] After the evaluation, it was shown that the block copolymer according to the present invention allowed reversible sol-gel transition behavior depending on pH variations as well as temperature variations, due to a change in the ionization degree of the poly(β-anino ester) type oligomer depending on pH variations and a change in the hydrophobicity of the biodegradable polymer depending on temperature variations (see FIGs. 1-3). Particularly, the block copolymer according to the present invention shows reversible sol-gel transition behavior under the same conditions as the human body (37°C, pH 7.4). Therefore, it is expected that the block copolymer according to the present invention has industrial applicability as a drug carrier.

[136] Experimental Example 2. Evaluation for Sol-Gel Transition Behavior

Depending on pH Variations (2)

[137] The block copolymer according to the present invention was prepared under various conditions to provide various kinds of block copolymers. Then, the block copolymers were evaluated for their sol-gel transition behavior depending on temperature and pH variations.

[138] The triblock copolymer (MPEGPCL-P AFj according to Example 1 was modified by varying the molecular weight of MPEG and the molar ratio of MPEG to PCL as shown in Table 2 to provide triblock copolymers having various molecular weights. Then, each triblock copolymer was evaluated for its sol-gel transition behavior. The results are shown in the following Table 2.

[139] After the experiment, Al and A4 showed no sol-gel transition behavior. This results from the imbalanced molecular weight ratio of MPEGPCL-PAE. In other words, it is thought that Al still shows a sol state even if the temperature and pH are varied due to the small molecular weight of PCL. On the contrary, it is thought that A4 cannot show sol-gel transition behavior because it has too high molecular weight to be dissolved in water. It can be expected that the temperature dependence and pH dependence of a pH- sensitive block and the molecular weight of a hydrophilic MPEG block should be considered in addition to the molecular weight ratio and the block ratio of MPEGPCL, in order to provide a temperature- and pH-sensitive block copolymer that shows reversible sol-gel transition behavior under the body temperature and pH conditions.

[140] Therefore, it can be seen from the above results that the temperature- and pH- sensitive block copolymer hydrogel according to the present invention can be obtained not by a simple combination of a hydrophilic block, a hydrophobic block and a pH- sensitive block but by controlling the molecular weight of each constitutional element, molar ratio of constitutional elements and molar ratio of blocks to optimal conditions. Additionally, it is possible to design a medical drug carrier that requires various conditions by such controlling technique and to obtain a commercially available drug carrier.

[141] Table 2

[142] Experimental Example 3. Evaluation for Biodegradation Rate of Block copolymers Depending on pH variations [143] The following experiment was carried out to observe variations in the molecular weight of the pH-sensitive block copolymer hydrogel according to the present invention, after its biodegradation at a specific pH value.

[144] The copolymer according to Example 2 using poly(β-anino ester), which has a relatively high biodegradation rate due to ester groups present in the baclώone, and the copolymers according to Examples 3-7 using poly(amido anine), which has a relatively low biodegradation rate due to anide groups present in the baclώone, were measured for their molecular weights with time at pH 7.4. After the measurement, it could be seen that the block copolymer according to Example 2 showed a relatively high biodegradation rate as determined by the molecular weight reduced to 1/2 of the original molecular weight in a short time of 30 hours or less. On the contrary, the block copolymer hydrogels according to Examples 3-7 showed a relatively low biodegradation rate (see FIG. 4).

[145] Additionally, after measuring the molecular weight of each of the block copolymer hydrogels according to Examples 4-6 with time at a specific pH, it could be seen that it was possible to control the biodegradation rate of the hydrogel in the body by controlling the amount of the poly(β-airino ester) and that of the poly(anido amine), forming the block copolymer hydrogel, and the molar ratio thereof (see FIG. 4).

[146] Therefore, it could be seen from the above experimental results that it was possible to design the temperature- and pH-sensitive block copolymer according to the present invention so as to show and continuously maintain a desired biodegradation rate by using, as a kind of poly(β-anino acid), a copolymer with poly(anido amine) that has a relatively low biodegradation rate in the body. Industrial Applicability

[147] As can be seen from the foregoing, the block copolymer according to the present invention shows pH sensitivity as well as temperature sensitivity, and thus can solve the problems occurring in conventional temperature-sensitive block copolymers according to the prior art. Additionally, the block copolymer according to the present invention can form more stable hydrogel at an adequate temperature and pH, and can solve the problem related to the in vivo stability. Therefore, the block copolymer according to the present invention can be used for various applications in the medical field, in particular, as a drug carrier for drug delivery.

[148] While this invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not United to the disclosed embodiment and the drawings. On the contrary, it is intended to cover various modifications and variations within the spirit and scope of the appended claims.

Claims

Claims[1] A block copolymer formed by coupling the following components with each other:(a) a copolymer (A) of a polyethylene glycol type compound with a biodegradable polymer; and(b) at least one oligomer (B) selected from the group consisting of poly (β-anino ester) and poly(anido amine).[2] The block copolymer according to claim 1, which has both temperature sensitivity and pH sensitivity. [3] The block copolymer according to claim 1, which forms hydrogel at a pH ranging from 7.2 to 7.4 and maintains a sol state at a pH ranging from 6.0 to 7.2. [4] The block copolymer according to claim 1, wherein the polyethylene glycol(PEQ type compound is a compound represented by the following formula 1:

[Formula 1]

wherein R is a hydrogen atom or a C1~C5 alkyl group, and n is a natural number ranging from 11 to 45.

[5] The block copolymer according to claim 1, wherein the polyethylene glycol type compound has a molecular weight of 500 to 5,000.

[6] The block copolymer according to claim 1, wherein the biodegradable polymer is a biodegradable aliphatic polyester polymer.

[7] The block copolymer according to claim 1, wherein the biodegradable polymer is at least one polymer selected from the group consisting of polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), poly(caprolactone-lactide) random copolymer (PCLA), poly(caprolactone-glycolide) random copolymer (PCGA), and poly(lactide-glycolide) random copolymer (PLGA).

[8] The block copolymer according to claim 1, wherein the PEG type compound and the biodegradable polymer have a molecular weight ratio of 1 : 1~3.

[9] The block copolymer according to claim 1, wherein the copolymer (A) of the polyethylene glycol type compound with the biodegradable polymer has at least one substituent selected from the group consisting of a primary anine group, a secondary anine group and a double bond, the substituent being capable of reacting with at least one oligomer (B) selected from the group consisting of poly (β-anino ester) and poly(anido amine). [10] The block copolymer according to claim 1, wherein at least one oligomer (B) selected from the group consisting of poly (β-anino ester) and poly(anido amine) contains a tertiary anine group that is ionized at a pH level of 7.2 or less. [11] The block copolymer according to claim 1, wherein at least one oligomer selected from the group consisting of poly (β-anino ester) and poly(anido anine) is formed by polymerization of:

(a) a bisacrylate or bisacrylanide compound; and

(b) an anine compound.

[12] The block copolymer according to claim 11, wherein the bisacrylate compound is at least one compound selected from the group consisting of ethylene glycol diacrylate, 1 ,4-bαtanediol diacrylate, 1,3-butanediol diacrylate, 1,6-hexanediol diacrylate, 1,6-hexanediol ethoxylate diacrylate, 1,6-hexanediol propoxylate diacrylate, 3-hydroxy-2,2-dimethylpropyl 3-hydroxy-2,2-dimethylpropionate diacrylate, 1 ,7-heptanediol diacrylate, 1,8-octanediol diacrylate, 1,9-nonanediol diacrylate and 1,10-decanediol diacrylate; and the bisacrylanide compound is at least one compound selected from the group consisting of N,N'-methylene bisacrylanide and N,N'-ethylene bisacrylamide.

[13] The block copolymer according to claim 11 , wherein the anine compound is a primary anine compound or a secondary amine-containing diamine compound.

[14] The block copolymer according to claim 13, wherein the primary anine compound is at least one compound selected from the group consisting of 3-methyl-4-(3-methylphenyl)piperazine, 3-methylpiperazine, 4-(bis) piperazine, 4- (phenylmethyl)piperazine, 4- ( 1 -phenylethyl)piperazine, 4-(l,l-dimethoxycarbonyl) piperazine, 4-(2-(bis-(2-propenyl)anino)ethyl) piperazine, methylanine, ethylanine, butylanine, hexylanine, 2-ethylhexylanine,

2-piperidine-l-yl-ethylanine, C-aziridine-1-yl-ethylanine, l-(2-aninoethyl)piperazine, 4-(aninomethyl)piperazine, N- methylethylenedianine, N-ethylethylenedianine, N-hexylethylenedianine, py- colianine and adenine; and the secondary anine-containing diamine compound is at least one compound selected from the group consisting of piperazine, piperidine, pyrrolidine, 3,

3-dimethylpiperidine, 4,

4'-trimethylene dipiperidine, N,N'-dimethyl ethylene diamine, N,N'-diethyl ethylene diamine, inidazolidine and diazepine.

[15] The block copolymer according to claim 11 , wherein the bisacrylate or bisacrylamde compound (a) and the aπϊne compound (b) are used in a molar ratio of 1 0.

5-2.0 [ 16] The block copolymer according to claim 1 , wherein at least one oligomer (B) selected from the group consisting of poly (β-amino ester) and poly(arrαdo amine) has a molecular weight of 500-20,000 [17] The block copolymer according to claim 1 1, wherein at least one oligomer (B) selected from the group consisting of poly (β-arrano ester) and poly(amtdo amne) comprises 1,6-hexanediol diacrylate and N.N'-methylene bisacrylamde, mixed in a weight ratio of 100:0-0:100, so as to provide a controllable biodegradation rate in the human body [ 1 S] The block copolymer according to claim 1 , which is a triblock copolymer or a higher block copolymer [19] The block copolymer according to claim 1, which is a tn-block copolymer or a penta-block copolymer. [20] The block copolymer according to claim 1 , which is selected from the compounds represented by the following formulae 6~ 11

[Formula 6]

[Formula 8]

[Formula 9]

[Formula 10]

W 2

30

wherein each of x, y, z, n and is a natural number ranging from 1 to 10,000. [21] A polymeric hydrogel type drug composition, comprising:

(a) a block copolymer as defined in any one of claims 1 to 20; and

(b) a physiologically active substance that can be encapsulated with the block copolymer.

[22] A carrier for drug delivery or diagnosis of diseases, which comprises the block copolymer as defined in any one of claims 1 to 20.

[23] Use of a copolymer, which comprises (a) at least one hydrophilic block, (b) at least one biodegradable block having hydrophobicity varied with temperatures, and (c) at least one unit having an ionization degree varied with pH values, as a carrier for drug delivery or as a carrier for diagnosis of diseases.

[24] The use according to claim 23, wherein the unit (c) having an ionization degree varied with pH values is at least one oligomer (B) selected from the group consisting of poly (β-arrino ester) and poly(amido anine).