Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
2001-02-07
2002-11-05
Woodward, Ana (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S408000, C525S411000, C525S413000, C528S301000, C528S354000
Reexamination Certificate
active
06476156
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to polyethyleneglycol/polylactide(or polyglycolide or polycaprolactone)/polyethyleneglycol triblock copolymers with an enhanced reactivity, and a process for their preparation.
Specifically, the present invention is directed to a triblock copolymers that are obtained by the process comprising the step to synthesize a polylactide(or polyglycolide or polycaprolactone) having hydroxy groups at both ends, and the step of coupling said polylactide with polyethyleneglycol having acylhalide group of a high reactivity at one of its ends, and the process for preparing the same.
2. Description of the Prior Art
Among the different applications of degradable polymer materials, it is most actively investigated in the field of medicine. A general medical polymer is used as a permanent material with replacement of parts for a living body, whereas a biodegradable polymer is used as a transient material to help healing of the body and disappears through the body's metabolism after completing its function. Due to these properties of the biodegradable polymer, an additional surgical operation to remove the polymer is not necessary after the body has healed. Also, as the body gradually heals, the polymer gradually degrades so that it can help newly developed tissue to function sufficiently.
Since the biodegradable polymer essentially has to have biocompatibility, only limited materials as polylactide, polyglycolide, polycaprolactone and polyethyleneglycol have been used to form the polymer. Many biodegradable polymers comprising polylactide and polyethyleneglycol have been studied in the form of block copolymers. Such polymers are comprised of hydrophobic polylactide and hydrophilic polyethyleneglycol and take the form of micelle in a solution. Also, since said polymers can make the hydrophobic polylactide hydrophilic, they can be applied widely as a bio-materials to be used as a matrix for the slow release of drugs, in tissue engineering, etc.
It was reported that block copolymer consisting of polylactide and polyethyleneglycol forms hydrogel in water and can be in a form of gel or sol by parameters of a temperature, pH, etc. so that it shows a behavior that can be used as slow releasing matrix of drug (Macromol. Chem. Phys. 198, 3385-3395 (1997)).
Most of such block copolymers, however, are in the form of a double block or triblock that is produced by a ring-open polymerization of lactide by polyethyleneglycol. Most triblocks are copolymers with a structural configuration of polylactide/polyethyleneglycol/polylactide, wherein hydrophilic polyethyleneglycol is present in the center and the hydrophobic polylactide is located at both ends.
In comparison to a block copolymer having the aforesaid configuration, a copolymer having a structural configuration of polyethyleneglycol/polylactide/polyethyleneglycol has the advantage to form harder micelle in a physical configuration when it is used as hydrogel. Furthermore, since hydrophilic polyethyleneglycol is present at both ends, its hydrophilizing effect is very great and it is expected to show a superior effect in the compatibility between hydrophobic material and hydrophilic material, and surface hydrophilization of hydrophobic material.
Because of these advantages, many efforts have been made to synthesize triblock copolymers to have a structural configuration of polyethyleneglycol/polylactide/polyethyleneglycol.
To synthesize the triblock copolymer, a method is used to couple the end groups of the synthesized polymer. In this case, the functional groups which are present at the ends of the polymer should have a very high reactivity so as to make the coupling reaction proceed quantitatively and, thus, to prepare block copolymers of the desired structure.
A generally used method is to couple the hydroxy group and the carboxyl group that are present at both ends of the polymer by use of a coupling agent such as diethyl azodicarboxylate (DEAD), triphenylphosphine (TPP), 1,3-dicyclohexylcarbodiimide (DCC) or 4-dimethylaminopyridine (DMAP). This method is generally used in coupling an organic compound. However, if it is used in the coupling reaction of the end groups in polymers, the reactivity is not high and, thus, the yield of block copolymer is very low and the catalysts used in the reaction are not easily removed.
Recently, a method is prevalently used to obtain a high reaction rate by use of a diisocyanate functional group having a high reactivity (J. Polym. Sci., Part A: Polym. Chem. 37, 751-760 (1999)). However, the block copolymer prepared by this method has the disadvantage that diusocyanate functional group with a strong toxicity remains in it.
Therefore, in preparing the block copolymer, it is very important to maintain the high reactivity of the functional groups and to connect the resulting copolymer only by non-toxic ester binding.
SUMMARY OF THE INVENTION
The present invention relates to polyethyleneglycol/polylactide(or polyglycolide or polycaprolactone)/polyethyleneglycol triblock copolymers with an enhanced reactivity, and the process for their preparation.
The present invention is specifically directed to triblock copolymers that are obtained by a process comprising the step of synthesizing a polylactide(or polyglycolide or polycaprolactone) having hydroxy groups at both ends and the step of coupling it with a polyethyleneglycol having an acylhalide group of a high reactivity at one of its ends, and a process for preparing the same.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a non-toxic biodegradable triblock copolymer having an ester structure and a method for preparing the same with a high yield by using a starting material having functional groups of high reactivity.
The inventors have carried out a study to achieve the object and found that triblock copolymers having an ester structure can be prepared with high yield by coupling polyethyleneglycol, having an acylhalide group of a high reactivity at one of its ends, with polylactide (or polyglycolide or polycaprolactone), having a hydroxy group at both ends.
Therefore, the invention relates to a polyethyleneglycol/polylactide (or polyglycolide or polycaprolactone)/polyethyleneglycol copolymer with a structural configuration of hydrophilicity/hydrophobicity/hydrophilicity, and a method for preparing the same.
The copolymer according to the present invention can be prepared by coupling polyethyleneglycol having acylhalide of a high reactivity at one of its ends with polylactide (or polyglycolide or polycaprolactone) having a hydroxy group at both ends in the presence of pyridine.
Specifically, the present invention provides a biodegradable triblock copolymer selected from the group consisting of copolymer of formula (1) to (4) as follows:
PEG-COO-PL-OCO-PEG <formula 1>
PEG-COO-PG-OCO-PEG <formula 2>
PEG-COO-(PL/PG)-OCO-PEG <formula 3>
PEG-COO-PCL-OCO-PEG <formula 4>
In the formulas,
PEG is polyethyleneglycol,
PL is polylactide,
PG is polyglycolide,
PCL is polycaprolactone.
According to the present invention, polylactide having a hydroxy group at both ends is first synthesized by ring-open polymerization of lactide monomer in the presence of secondary alcohol. The ring-open polymerization is carried out under reduced pressure with heating by using a conventional catalyst such as stannous octotate. If &agr;,&ohgr;-alkanediol such as ethylene glycol, 1,3-propanediol, 1,4-butanediol, and 1,6-hexanediol, which is a secondary alcohol, is used as a polymerization initiator, the resulting polylactide has hydroxyl groups at both ends (see scheme 1). At this time, the molecular weight of the polymer can be variously controlled depending on the added amount of the initiator and monomer. Polyglycolide and polycaprolactone can be prepared in the same manner as in the preparation of polylactide.
Polyethyleneglycol having acylhalide group at one of its ends can be synthesized in a two-step reaction. The first
Kim Soo Hyun
Kim Young Ha
Lee Soo-Hong
Park Ki Dong
Korea Institute of Science and Technology
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Woodward Ana
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