the novel biodegradable copolymer of the present invention has a core block and a plurality of shell blocks and can be presented by the formula : wherein the number of shell blocks s may be 3 to 10 ( that is , n is an integer between 3 and 10 , and preferably 3 to 6 . each shell block s is linked to the core block c by a covalent bond . thus , the microscopic molecule structure of the copolymer is star shaped ; therefore herein the copolymer is referred to as a “ star copolymer ”. “ biodegradable copolymer ” is defined herein as a copolymer which can chemically break down or degrade within the body to form nontoxic components . the core block c comprises a bioresorbable hydrophobic polyester segment . herein , “ bioresorbable ” means the property which a material has enables the material to be absorbed in an organism . suitable bioresorbable hydrophobic polyester can be , but not limited to , a homopolymer or copolymer synthesized from monomers selected from the group consisting of d , l - lactide , d - lactide , l - lactide , d , l - lactic acid , d - lactic acid , l - lactic acid , glycolide , glycolic acid , ε - caprolactone , ε - hydroxy hexonoic acid , γ - butyrolactone , γ - hydroxy butyric acid , δ - valerolactone , δ - hydroxy valeric acid , hydroxybutyric acids , or malic acid . among them , polycaprolactone is most preferred . the average molecular weight of the bioresorbable hydrophobic polyester is preferably 200 to 10000 , and more preferably 250 to 5000 . the shell block s comprises a hydrophilic polyethylene glycol ( peg ) segment . the average molecular weight of the hydrophilic polyethylene glycol is preferably 200 to 10000 , and more preferably 250 to 7000 . the linkage of the shell block s , hydrophobic polyester , and the core block c , hydrophilic polyethylene glycol , is formed through a urethane linkage . it is noted that a mixture of the biodegradable copolymer of the present invention in water with a solid content of 20 % can undergo a phase transformation with a change in temperature . for example , the mixture , exhibiting a white viscous liquid form of micelle per se at room temperature , turns into a transparent liquid in an ice bath and white precipitates occur upon heating due to the separation of the copolymer and water , and these phenomena are reversible and contrary to the common phenomenon of solubility for a normal substance in a solvent that dissolution occurs upon heating and precipitation occurs at low temperature . the biodegradable copolymer of the present invention presents no cytotoxicity in a physiological environment and exhibits white color in an aqueous medium ( such as water ) which was characterized to be micelles . the critical micelle concentration is low . the micelles are useful as vehicles in a bio - delivery system to encapsulate hydrophobic compounds , for example , drugs ( such as protein complexes , gene drugs , hormone drugs , and anti - cancer drugs ) or bioactive substances and to enable them to have a stable effect . accordingly , in other aspects , the present invention relates to a biodegradable polymeric micelle composition , which comprises : ( a ) a copolymer which is the star - shaped biodegradable copolymer having the formula c s ) n ( wherein n is an integer of 3 to 10 ) of the present invention as described above or the biodegradable linear tri - block copolymer s — c — s . c and s are defined as above , and ( b ) an aqueous medium , such as water , which enables the biodegradable copolymer to disperse therein . the copolymer is dispersed in the aqueous medium . when the concentration of copolymer is higher than the critical micelle concentration , the copolymer forms micelles . the critical micelle concentration is generally between 0 . 001 and 0 . 5 weight percent . the size of the micelle is generally between 20 nm and 800 nm in diameter . as mentioned above , the biodegradable copolymer comprised in the biodegradable polymeric micelle composition can be a linear tri - block copolymer ( s — c — s ) as well as the star - shaped biodegradable copolymer of the present invention . u . s . pat . no . 6 , 201 , 072 discloses an a — b — a - or b — a — b - linear tri - block copolymer containing a biodegradable polyester ( block a ) and peg ( block b ). however , it does not disclose the application of the tri - copolymer in the micelle composition as described in the present invention nor does it mention the micelle structure . in the present invention , the inventors found that the star - shaped biodegradable copolymer , as well as the linear tri - block , can form micelles in a medium . thus the micelle composition of the present invention can be formed from the linear tri - block copolymer or the star - shaped biodegradable copolymer and a medium . the micelle composition of the present invention can encapsulate drugs in the micelles . for example , when the aqueous medium is water , the hydrophilic ends of the copolymer molecules outwardly contact with water molecules and the hydrophobic ends aggregate inwardly , thus forming micelles which encapsulate hydrophobic compounds , drugs , or bioactive substance therein . the biodegradable copolymer of the present invention can be made by the steps as follows . a suitable amount of dbtdl ( dibutyltin dilaurate ) and diisocyanate are added to methoxy - polyethylene glycol dissolved in solution . the mixture is heated and the reaction is performed in a nitrogen atmosphere . then , polyester - diol or - polyol are added and the temperature for reaction is elevated . the product is purified and the structure may be identified using 1 h nmr ( cdcl 3 , 400 mhz ). the copolymer obtained using polyester - diol is s — c — s type tri - copolymer in a linear structure . the novel type star - shaped copolymer of the present invention can be obtained using polyester - polyol , such as polyester - triol and polyester - tetraol . polyester - polyol , such as polyester - triol and - tetraol , can be prepared by referring to the method as described in preparations a and b . the schematic structure of the polyester - triol obtained is shown as follows : the biodegradable copolymer of the present invention shows no cytotoxity determined according to the method described in the astm f895 standard test . the biodegradable polymeric micelle composition can be formed by mixing the copolymer in an aqueous medium in a concentration higher than the critical micelle concentration . the critical micelle concentration can be calculated by means of interpolation in the plotting of the absorbance at uv - vis wavelength versus the concentration of the copolymer in the medium . the application of the biodegradable polymeric micelle composition for the encapsulation of hydrophobic compound can be achieved by the process described as follows . hydrophobic compounds ( such as hydrophobic drugs ) and the copolymer are dissolved in a solvent . the resulting mixture was vacuumed at 60 ° c . by means of rotary evaporation to form a colloid . pure water was added to the colloid at 60 ° c ., forming micelles encapsulating the drug for the application in drug delivery in the present invention . the resultant may be freeze - dried for storage and added water as a medium to form micelles in liquid type before the administration . the administration can be oral , topical , injected , or by another suitable method . 200 g ( 1 . 7522 moles ) of ε - caprolactone monomer ( manufactured by aldrich co .) was placed in a reactor , and 23 . 51 g ( 0 . 175 mole ) of initiator trimethylolpropane and 0 . 567 ml ( 1 . 75 × 10 − 3 mole ) of stannous 2 - ethylhexanoate were added into the reactor . the reaction was performed in a nitrogen atmosphere and the temperature was set at 120 ° c . after 1 . 5 hours of reaction , the reaction was rapidly cooled down to room temperature . the precipitates were purified using ether and then vacuumed to remove solvent , yielding a product characterized by 1 h nmr ( cdcl 3 , 400 mhz ) to be polycaprolactone triol . 200 g ( 1 . 7522 moles ) of ε - caprolactone monomer was placed in a reactor , and 28 . 9 g ( 0 . 175 mole ) of initiator pentaerythritol ( molecular weight = 165 . 15 ) and 0 . 567 ml ( 1 . 75 × 10 − 3 mole ) of stannous 2 - ethylhexanoate were added into the reactor . the reaction was performed in a nitrogen atmosphere and the temperature was set at 120 ° c . after 1 . 5 hours of reaction , the reaction was rapidly cooled down to room temperature . the precipitates were purified using ether and then vacuumed to remove solvent , yielding a product , polycaprolactone tetraol . 45 . 6 g ( 0 . 27 mole ) of hexamethylene diisocyanate and 200 μl of dbtdl were added to 100 g ( 0 . 286 mole ) of methoxy - polyethylene glycol ( molecular weight = 350 ) dissolved in 150 g of toluene . the temperature was set at 60 ° c . and the reaction was performed in a nitrogen atmosphere . after 2 hours of reaction , 81 . 51 g ( 0 . 091 mole ) of pcl - triol ( molecular weight = 900 ) and 100 g of toluene were added , and the reaction was continued for 24 hours . then , the reaction was quenched by dibutylamine ( dba ) to completely consume the nco groups remaining in the reactor . the resultant was precipitated by ether at low temperature , washed repeatedly , and vacuumed until dry , yielding a star copolymer having a formula of c s ) 3 as a powder , herein referred to as “ tri - peg350 - pcl900 ”. the star copolymer obtained from example 1 was dissolved in a 4 μm diphenyl hexatriene ( dph ) ( a hydrophobic fluorescent dye ) aqueous solution to concentrations of 0 . 001 wt %, 0 . 005 wt %, 0 . 01 wt %, 0 . 025 wt %, 0 . 05 wt %, 0 . 1 wt %, 0 . 5 wt %, and 1 wt %, respectively . the absorbance at 412 nm of each resulting mixture was determined using a uv - vis spectrometer . a graph was obtained by plotting absorbance versus concentration , as shown in fig1 . the critical micelle concentration was calculated to be about 0 . 094 wt %, i . e . 4 . 84 × 10 − 4 m , by means of interpolation . 3 . 19 g ( 0 . 019 mole ) of hexamethylene diisocyanate and 200 μl of dbtdl were added to 100 g ( 0 . 02 mole ) of methoxy - polyethylene glycol ( molecular weight = 5000 ) dissolved in 100 g of toluene . the temperature was set at 60 ° c . and the reaction was performed in a nitrogen atmosphere . after 2 hours of reaction , 5 . 7 g ( 0 . 0063 mole ) of pcl - triol ( molecular weight = 900 ) and 6 g of toluene were added , and the reaction was continued for 24 hours . then , the reaction was quenched by dba . the resultant was precipitated by ether at low temperature , washed repeatedly , and vacuumed until dry , yielding a star copolymer having a formula of c s ) 3 as a powder , herein referred to as “ tri - peg5000 - pcl900 ”. the cmc of the product was about 0 . 127 wt %, i . e . 7 . 99 × 10 − 5 m , determined by the method as described in example 1 . 8 g ( 0 . 0475 mole ) of hexamethylene diisocyanate and 200 μl of dbtdl were added to 100 g ( 0 . 05 mole ) of methoxy - polyethylene glycol ( molecular weight = 2000 ) dissolved in 110 g of toluene . the temperature was set at 60 ° c . and the reaction was performed in a nitrogen atmosphere . after 2 hours of reaction , 4 . 75 g ( 0 . 016 mole ) of pcl - triol ( molecular weight = 300 ) and 5 g of toluene were added , and the reaction was continued for 24 hours . then , the reaction was quenched by dba . the resultant was precipitated by ether at low temperature , washed repeatedly , and vacuumed until dry , yielding a star copolymer having a formula of c s ) 3 as a powder , herein referred to as “ tri - peg2000 - pcl300 ”. the cmc of the product was about 0 . 126 wt %, i . e . 2 × 10 − 4 m , determined by the method as described in example 1 . 3 . 2 g ( 0 . 019 mole ) of hexamethylene diisocyanate and 200 μl of dbtdl were added to 100 g ( 0 . 02 mole ) of methoxy - polyethylene glycol ( molecular weight = 5000 ) dissolved in 105 g of toluene . the temperature was set at 60 ° c . and the reaction was performed in a nitrogen atmosphere . after 2 hours of reaction , 1 . 9 g ( 0 . 006 mole ) of pcl - triol ( molecular weight = 300 ) and 2 g of toluene were added , and the reaction was continued for 24 hours . then , the reaction was quenched by dba . the resultant was precipitated by ether at low temperature , washed repeatedly , and vacuumed until dry , yielding a star copolymer having a formula of c s ) 3 as a powder , herein referred to as “ tri - peg5000 - pcl300 ”. the cmc of the product was about 0 . 14 wt %, i . e . 9 . 15 × 10 − m , determined by the method as described in example 1 . 45 . 6 g ( 0 . 27 mole ) of hexamethylene diisocyanate and 200 μl of dbtdl were added to 100 g ( 0 . 286 mole ) of methoxy - polyethylene glycol ( molecular weight = 350 ) dissolved in 150 g of toluene . the temperature was set at 60 ° c . and the reaction was performed in a nitrogen atmosphere . after 2 hours of reaction , 27 g ( 0 . 09 mole ) of pcl - triol ( molecular weight = 300 ) and 30 g of toluene were added , and the reaction was continued for 24 hours . then , the reaction was quenched by dba . the resultant was precipitated by ether at low temperature , washed repeatedly , and vacuumed until dry , yielding a star copolymer having a formula of c s ) 3 as a powder , herein referred to as “ tri - peg350 - pcl300 ”. the cmc of the product was about 0 . 0125 wt % determined by the method as described in example 1 . 8 g ( 0 . 0475 mole ) of hexamethylene diisocyanate and 200 μl of dbtdl were added to 100 g ( 0 . 05 mole ) of methoxy - polyethylene glycol ( molecular weight = 2000 ) dissolved in 150 g of toluene . the temperature was set at 60 ° c . and the reaction was performed in a nitrogen atmosphere . after 2 hours of reaction , 14 . 25 g ( 0 . 016 mole ) of pcl - triol ( molecular weight = 300 ) and 100 g of toluene were added , and the reaction was continued for 24 hours . then , the reaction was quenched by dba . the resultant was precipitated by ether at low temperature , washed repeatedly , and vacuumed until dry , yielding a star copolymer having a formula of c s ) 3 as a powder , herein referred to as “ tri - peg2000 - pcl300 ”. the cmc of the product was about 0 . 0325 wt % determined by the method as described in example 1 . the cytotoxicity response indices of the star copolymers obtained from examples 1 to 6 were determined by the method described in the astm f895 standard test using l929 fibroblast . all of the results showed no cytotoxity . a suitable amount of dbtdl was added to 100 g ( 0 . 05 mole ) of methoxy - polyethylene glycol ( molecular weight = 2000 ) dissolved in 200 ml of dimethylformamide ( dmf ), immediately followed by the addition of 7 . 98 g ( 0 . 0475 mole ) of hexamethylene diisocyanate ( hdi ). the temperature was set at 50 ° c . and the reaction was performed in a nitrogen atmosphere . after 5 hours of reaction , 13 . 25 g ( 0 . 025 mole ) of pcl - diol ( molecular weight = 530 ) was added , the temperature was raised to 100 ° c ., and the reaction was continued overnight . then , the reaction was quenched by dba . after the resultant was cooled down , it was precipitated by 1000 ml of ether , and the resulting precipitates were dissolved in dmf and precipitated from ether . the precipitation process was repeated three times . then the precipitates were vacuumed until dry , yielding a product characterized by 1 h nmr ( cdcl 3 , 400 mhz ) to be a peg2000 - pcl530 - peg2000 tri - block copolymer . the cmc of the product was about 0 . 1367 wt % determined by the method as described in example 1 , as shown in fig2 . suitable amount of dbtdl was added to 200 g ( 0 . 1 mole ) of methoxy - polyethylene glycol ( molecular weight = 2000 ) dissolved in 400 ml of dmf , immediately followed by the addition of 14 . 96 g ( 0 . 095 mole ) of hdi . the temperature was set at 50 ° c . and the reaction was performed in a nitrogen atmosphere . after 5 hours of reaction , 59 . 375 g ( 0 . 0475 mole ) of pcl - diol ( molecular weight = 1250 ) was added , the temperature was raised to 100 ° c ., and the reaction was continued overnight . then , the reaction was quenched by dba . after the resultant was cooled down , it was precipitated by 2000 ml of ether , and the resulting precipitates were dissolved in dmf and precipitated from ether . the precipitation process was repeated three times . then the precipitates were vacuumed until dry , yielding a peg2000 - pcl1250 - peg2000 tri - block copolymer . the cmc of the product was about 0 . 058 wt % determined by the method as described in example 1 . suitable amount of dbtdl was added to 100 g ( 0 . 182 mole ) of methoxy - polyethylene glycol ( molecular weight = 550 ) dissolved in 200 ml of dmf , immediately followed by the addition of 29 g ( 0 . 173 mole ) of hdi . the temperature was set at 50 ° c . and the reaction was performed in a nitrogen atmosphere . after 5 hours of reaction , 172 . 9 g ( 0 . 0865 mole ) of pcl - diol ( molecular weight = 2000 ) was added , the temperature was raised to 100 ° c ., and the reaction was continued overnight . then , the reaction was quenched by dba . after the resultant was cooled down , it was precipitated by 1000 ml of ether , and the resulting precipitates were dissolved in dmf and precipitated from ether . such precipitation process was repeated three times . then the precipitates were vacuumed until dry , yielding a peg530 - pcl2000 - peg530 tri - block copolymer . the cmc of the product was about 0 . 013 wt % determined by the method as described in example 1 . the size of the resulting micelles was determined using a dynamic light scattering instrument ( malvern uk + 44 of malvern instruments company ) to be about 85 nm , as shown in fig3 . suitable amount of dbtdl was added to 100 g ( 0 . 05 mole ) of methoxy - polyethylene glycol ( molecular weight = 2000 ) dissolved in 200 ml of dmf , immediately followed by the addition of 7 . 98 g ( 0 . 0475 mole ) of hdi . the temperature was set at 50 ° c . and the reaction was performed in a nitrogen atmosphere . after 5 hours of reaction , 47 . 5 g ( 0 . 02375 mole ) of pcl - diol ( molecular weight = 2000 ) was added , the temperature was raised to 100 ° c ., and the reaction was continued overnight . then , the reaction was quenched by dba . after the resultant was cooled down , it was precipitated by 1000 ml of ether , and the resulting precipitates were dissolved in dmf and precipitated from ether . such precipitation process was repeated three times . then the precipitates were vacuumed until dry , yielding a peg2000 - pcl2000 - peg2000 tri - block copolymer . the cmc of the product was about 0 . 043 wt % determined by the method as described in example 1 . suitable amount of dbtdl was added to 100 g ( 0 . 022 mole ) of methoxy - polyethylene glycol ( molecular weight = 4600 ) dissolved in 200 ml of dmf , immediately followed by the addition of 3 . 53 g ( 0 . 021 mole ) of hdi . the temperature was set at 50 ° c . and the reaction was performed in a nitrogen atmosphere . after 5 hours of reaction , 22 g ( 0 . 011 mole ) of pcl - diol ( molecular weight = 2000 ) was added , the temperature was raised to 100 ° c ., and the reaction was continued overnight . then , the reaction was quenched by dba . after the resultant was cooled down , it was precipitated by 1000 ml of ether , and the resulting precipitates were dissolved in dmf and precipitated from ether . such precipitation process was repeated three times . then the precipitates were vacuumed until dry , yielding a peg4600 - pcl2000 - peg4600 tri - block copolymer . the cmc of the product was about 0 . 0789 wt % determined by the method as described in example 1 . the size of the resulting micelles was determined using a dynamic light scattering instrument to be about 85 nm . according to the result from the determination of the critical micelle concentration as mentioned above , it is shown that all of the products obtained from examples 1 to 6 and preparations 1 to 5 can form micelles and these micelles are the biodegradable polymeric micelle compositions of the present invention , which were demonstrated to have an ability to encapsulate hydrophobic compounds and can be further employed to encapsulate hydrophobic drugs and bioactive substances . 30 mg of paclitaxel and 150 mg of peg2000 - pcl530 - peg2000 tri - block copolymer were dissolved in 2 ml of acetonitrile . the resulting mixture was vacuumed at 60 ° c . by means of rotary evaporation to form a colloid . pure water was added to the colloid at 60 ° c ., forming micelles encapsulating the drug . the resultant was filtered through 0 . 22 μm filter to remove the impurities in the water and freeze - dried , forming a drug delivery composition . example 8 was performed using the method same as example 7 , provided that 150 mg of peg2000 - pcl2000 - peg2000 tri - block copolymer was used instead of peg2000 - pcl530 - peg2000 tri - block copolymer , forming a drug delivery composition . example 9 was performed using the method same as example 7 , provided that 150 mg of peg530 - pcl2000 - peg530 tri - block copolymer was used instead of peg2000 - pcl530 - peg2000 tri - block copolymer , forming a drug delivery composition . while the invention has been described by way of example and in terms of the preferred embodiments , it is to be understood that the invention is not limited to the disclosed embodiments . to the contrary , it is intended to cover various modifications and similar arrangements ( as would be apparent to those skilled in the art ). therefore , the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such modifications and similar arrangements .
a biodegradable copolymer with a core block comprising bioresorbable hydrophobic polyester segment and from 3 to 10 shell blocks comprising hydrophilic polyethylene glycol segment . the hydrophobic polyester segment and each of the hydrophilic polyethylene glycol segments are linked by a urethane linkage . a polymeric micelle composition containing the copolymer is also provided . the copolymer forms micelles when the concentration of the copolymer in a dispersing medium reaches or exceeds the critical micelle concentration . the micelles possess good drug and bioactive agent delivery characteristics and are suitable for use in drug delivery or cosmetic applications .