POLYETHER-BASED BLOCK COPOLYMERS HAVING HYDROPHOBIC DOMAINS

Abstract

The invention relates to a polymerization method in which alkyl glycidyl ethers and epoxides, such as ethylene oxide, polypropylene oxide, 1-ethoxyethyl glycidyl ether and gycidol, are copolymerized and block copolymers are synthesized. The inventive methods include an initiator, oligomer blocks of 1 to 40 alkyl glycidyl ether units of type (I), (II) or (III), and 80 to 1000 epoxy units of large polyether blocks, such as polyethylene oxide (PEO), polypropylene oxide (PPO), polyethoxyethylene glycidyl ether (PEEGE), linear and branched polyglycidol (PG, hbPG) or random copolymers of two, three or four different epoxide units, such as ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and/or glycidol.

Claims

1. A process for producing a block copolymer comprising copolymerizing one or more alkyl glycidyl ethers of the type (I), (II), or (III) ##STR00013## with one or more epoxides selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE), glycidol and/or mixtures of two, three or four different epoxides from among these to form blocks composed of polyethylene oxide (PEO), polypropylene oxide (PPO), polyethoxyethylene glycidyl ether (PEEGE), linear or branched polyglycidol (PG, hbPG) and/or random copolymers of the above epoxides; or with one or more polyethers selected from the group consisting of polyethylene oxide (PEO), polypropylene oxide (PPO), polyethoxyethylene glycidyl ether (PEEGE), linear or branched polyglycidol (PG, hbPG), monomethyl polyethylene oxide (mPEO), monomethyl propylene oxide (mPPO), monobutyl propylene oxide (mPBO) or a random copolymer of two, three or four different epoxide units.

2. The process as claimed in claim 1, wherein said process further comprises providing, in a first step S.sub.1, a reaction mixture with an initiator I selected from the group consisting of a deprotonated residual group of an opened alkyl glycidyl ether of the type (I), (II) or (III); a deprotonated residual group of a polyether such as polyethylene oxide (PEO), polypropylene oxide (PPO), polyethoxyethylene glycidyl ether (PEEGE), linear or branched polyglycidol (PG, hbPG), monomethyl polyethylene oxide (mPEO), monomethyl propylene oxide (mPPO), monobutyl propylene oxide (mPBO) or a random copolymer of two, three or four different epoxide units selected from ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and/or glycidol; and a deprotonated residual group of an alcohol.

3. The process as claimed in claim 2 further comprising polymerizing, in a second step S.sub.2, the initiator I provided in step S.sub.1 with from 2 to 40 mol of an alkyl glycidyl ether of (I), (II) or (III), a mixture of two or three alkyl glycidyl ethers of (I), (II), (III) or a mixture of at least one alkyl glycidyl ether (I), (II), (III) with ethylene oxide (EO) and/or 1-ethoxyethyl glycidyl ether (EEGE), based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical oligomer (A.sub.1).sub.0.5I(A.sub.1).sub.0.5 or IA.sub.1.

4. The process as claimed in claim 3 further comprising copolymerizing, in a third step S.sub.3, the symmetrical or unsymmetrical oligomer (A.sub.1).sub.0.5I(A.sub.1).sub.0.5 or IA.sub.1 obtained in step S.sub.2 with from 80 to 1000 mol of an epoxide, based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical block copolymer (B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1).sub.0.5 or IA.sub.1B.sub.1, where the epoxide is selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and glycidol; or, copolymerizing, in a third step S.sub.3, the symmetrical or unsymmetrical oligomer (A.sub.1).sub.0.5I(A.sub.1).sub.0.5 or IA.sub.1 obtained in step S.sub.2 with a mixture of a total of from 80 to 1000 mol of two, three or four different epoxides, based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical block copolymer (B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1).sub.0.5 or IA.sub.1B.sub.1, where the two, three or four epoxides are selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and glycidol; or, copolymerizing, in a third step S.sub.3, the symmetrical or unsymmetrical oligomer (A.sub.1).sub.0.5I(A.sub.1).sub.0.5 or IA.sub.1 obtained in step S.sub.2 with from 80 to 1000 mol of a first epoxide, based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical block copolymer (B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1).sub.0.5 or IA.sub.1B.sub.1 and subsequently polymerizing the block copolymer with from 80 to 1000 mol of a second epoxide, based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical block copolymer (C.sub.1B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1C.sub.1).sub.0.5 or IA.sub.1B.sub.1C.sub.1, where the first and second epoxide are selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and glycidol and said first and second epoxide are different from one another.

5. The process as claimed in claim 2, further comprising copolymerizing, in a second step S.sub.2, the initiator I provided in step with from 80 to 1000 mol of an epoxide, based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical oligomer (B.sub.1).sub.0.5I(B.sub.1).sub.0.5 or IB.sub.1, where the epoxide is selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and glycidol; or, copolymerizing, in a second step S.sub.2, the initiator I provided in step S.sub.1 with a mixture of a total of from 80 to 1000 mol of two, three or four different epoxides, based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical block copolymer (B.sub.1).sub.0.5I(B.sub.1).sub.0.5 or IB.sub.1, where the two, three or four epoxides are selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and glycidol, or, copolymerizing, in a second step S.sub.2, the initiator I provided in step S.sub.1 with from 80 to 1000 mol of a first epoxide, based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical oligomer (B.sub.1).sub.0.5I(B.sub.1).sub.0.5 or IB.sub.1 and subsequently polymerizing the oligomer with from 80 to 1000 mol of a second epoxide, based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical oligomer (C.sub.1B.sub.1).sub.0.5I(B.sub.1C.sub.1).sub.0.5 or IB.sub.1C.sub.1, where the first and second epoxide are selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and glycidol and said first and second epoxide are different from one another.

6. The process as claimed in claim 5, further comprising copolymerizing, in a third step S.sub.3, the symmetrical or unsymmetrical oligomer (B.sub.1).sub.0.5I(B.sub.1).sub.0.5, (C.sub.1B.sub.1).sub.0.5I(B.sub.1C.sub.1).sub.0.5, IB.sub.1 or IB.sub.1C.sub.1 obtained in step S.sub.2 with from 2 to 40 mol of an alkyl glycidyl ether of the type (I), (II) or (III), a mixture of two or three alkyl glycidyl ethers of the type (I), (II), (III) or a mixture of at least one alkyl glycidyl ether (I), (II), (III) with ethylene oxide (EO) and/or 1-ethoxyethyl glycidyl ether (EEGE), based on the molar amount of the initiator I, to give a symmetrical or unsymmetrical block copolymer (A.sub.1B.sub.1).sub.0.5I(B.sub.1A.sub.1).sub.0.5, (A.sub.1C.sub.1B.sub.1).sub.0.5I(B.sub.1C.sub.1A.sub.1).sub.0.5, IB.sub.1A.sub.1 or IB.sub.1C.sub.1A.sub.1.

7. The process as claimed in claim 6 further comprising repeating the steps S.sub.2 and S.sub.3 alternately one or more times using an alkyl glycidyl ether of the type (I), (II) or (III), a mixture of two or three alkyl glycidyl ethers of the type (I), (II), (III) or a mixture of at least one alkyl glycidyl ether (I), (II), (III) with ethylene oxide (EO) and/or 1-ethoxyethyl glycidyl ether (EEGE) or using one or two different first and second epoxides or mixtures of a plurality of epoxides which are selected independently of the preceding steps from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and glycidol.

8. The process as claimed in claim 1, wherein all process steps are carried out in a reaction mixture containing one or more deprotonated bases, where the at least one base comprises a counterion.

9. The process as claimed in claim 8, wherein all process steps are carried out in a reaction mixture containing one or more crown ethers for complexing a counterion.

10. A block copolymer which produced by the process as claimed in claim 1.

11. A block copolymer having the structure
A.sub.1IA.sub.1,
[.sub.i=1.sup.NA.sub.iB.sub.i].sub.0.5I[.sub.i=1.sup.NA.sub.iB.sub.i].sub.0.5,
[.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)].sub.0.5I[.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)].sub.0.5,
I[.sub.i=1.sup.NA.sub.iB.sub.i] and
I[.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)] where N=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, each of the blocks A.sub.i consists independently of a residual group of an oligomer formed by from 1 to 40 alkyl glycidyl ether units (I), (II) or (III) ##STR00014## or a residual group of a random cooligomer having from 2 to 40 units of two or three alkyl glycidyl ethers (I), (II), (III) or having from 2 to 40 units of at least one alkyl glycidyl ether (I), (II), (III) and at least one of the epoxides ethylene oxide (EO) and 1-ethoxyethyl glycidyl ether (EEGE); each of the blocks B.sub.i consists independently of a residual group of a polyether comprising from 80 to 1000 epoxide units, or a random copolymer of two, three or four different epoxide units; each of the blocks C.sub.i consists independently of a residual group of a polyether comprising from 80 to 1000 epoxide units; and I is a residual group of an alkyl glycidyl ether of the type (I), (II) or (III); or I is a residual group of a polyether comprising from 80 to 1000 epoxide units, or a random copolymer of two, three or four different epoxide units; or I is a residual group of an alcohol.

12. The block copolymer as claimed in claim 11, wherein the block copolymer has a polydispersity
M.sub.w/M.sub.n2, M.sub.w/M.sub.n1.6, M.sub.w/M.sub.n1.2 or M.sub.w/M.sub.n1.1.

13. The block copolymer as claimed in claim 11, wherein the block copolymer has a molar mass MW ranging from 4000 g.Math.mol.sup.1MW40 000 g.Math.mol.sup.1.

14. A pharmaceutical retard system, pharmaceutical administration system with controlled release or pharmaceutical formulation with controlled release comprising one or more block copolymers as claimed in claim 11.

15. The process as claimed in claim 1, wherein the epoxide units are ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and/or glycidol.

16. The process as claimed in claim 2, wherein said alcohol is selected from the group consisting of methanol, butanol, benzyl alcohol (BnOH), 2-(benzyloxy)ethanol, pentaerythritol, 1,1,1-trimethylolpropane (TMP), bisphenol A, CH.sub.3(CH.sub.2).sub.tOH and OH(CH.sub.2).sub.tOH where t=1-21.

17. The process as claimed in claim 8, wherein the counterion is selected from the group consisting of potassium, lithium and sodium.

18. The block copolymer as claimed in claim 11, wherein the residual group of the polyether the blocks B.sub.i is a residual of a polyether selected from the group consisting of polyethylene oxide (PEO), polypropylene oxide (PPO), polyethoxyethylene glycidyl ether (PEEGE), linear or branched polyglycidol (PG, hbPG) and the copolymer epoxide units of the blocks B.sub.i are selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and/or glycidol; the residual group of the polyether of the blocks C.sub.i is a residual of a polyether selected from the group consisting of polyethylene oxide (PEO), polypropylene oxide (PPO), polyethoxyethylene glycidyl ether (PEEGE), linear or branched polyglycidol (PG, hbPG); and the residual group of the polyether of I is a residual group of a polyether selected from polyethylene oxide (PEO), polypropylene oxide (PPO), polyethoxyethylene glycidyl ether (PEEGE), linear or branched polyglycidol (PG, hbPG), monomethyl polyethylene oxide (mPEO), monomethyl propylene oxide (mPPO), monobutyl propylene oxide (mPBO), and the copolymer epoxide units of I are selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and glycidol, and the residual group of an alcohol of I is selected from the group consisting of methanol, butanol, benzyl alcohol (BnOH), 2-(benzyloxy)ethanol, pentaerythritol, 1,1,1-trimethylolpropane (TMP), bisphenol A, CH.sub.3(CH.sub.2).sub.tOH or OH(CH.sub.2).sub.tOH where t=1-21.

Description

[0122] The schematic depiction in FIG. 1 illustrates the mechanisms critical for the functionality of the block copolymers of the invention, namely the swelling by means of water or mixtures of water and alcohol and the formation of micellar hydrophobic domains. The formation of micellar hydrophobic domains in water or aqueous mixtures reduces the free energy and brings about aggregation and mutual alignment of the alkyl segments of the alkyl glycidyl ether blocks to form locally crystalline structures. The micellar hydrophobic and partially crystalline domains bind and store organic active substance molecules and are characterized by a high uptake capability (capacity). When the temperature is increased, the partially crystalline domains melt and the organic active substance molecules bound therein are released.

[0123] Owing to their functionality, the block copolymers of the invention are outstandingly suitable for the production of pharmaceutical formulations with controlled release. For this purpose, the block copolymer is dissolved in a water-miscible solvent and mixed with the active substance. Subsequent replacement of the solvent by water or aqueous-alcoholic solutions produces a gel in which the hydrophobic active substance is incorporated into the hydrophobic, micellar domains.

[0124] Accordingly, the invention encompasses pharmaceutical retard systems, pharmaceutical administration systems with controlled release and/or pharmaceutical formulations with controlled release, which comprise one or more of the above-described block copolymers.

[0125] For the purposes of the present invention, indications of amounts like from 2 to 40 mol of an alkyl glycidyl ether . . . based on the molar amount of the initiator and from 80 to 1000 mol of an epoxide . . . based on the molar amount of the initiator refer to ratios of from 20 to 40 alkyl glycidyl ether units per initiator molecule and from 80 to 1000 epoxide units per initiator molecule, respectively.

[0126] For the purposes of the present invention, A.sub.i is, in each case independently of A.sub.j where ji, one of the following residual groups (I), (II), (III)

##STR00009##

[0127] of an oligomer of up to 40 units of an alkyl glycidyl ether of the type (I), (II), (III), a residual group of a random cooligomer of from 2 to 40 units of two or three alkyl glycidyl ethers of the type (I), (II), (III) or a residual group of a random cooligomer of from 2 to 40 units of at least one alkyl glycidyl ether of the type (I), (II), (III) and at least one of the epoxides ethylene oxide (EO) and 1-ethoxyethyl glycidyl ether (EEGE).

##STR00010##

[0128] The number of alkyl glycidyl ether units of the type (I), (II), (III) in the oligomers (I), (II), (III) or units in the random cooligomers containing alkyl glycidyl ether units of the type (I), (II), (III) can assume any value in the range from 1 to 40 or from 2 to 40, respectively, i.e. y=0, y=1, y=2, y=3, y=4, y=5, y=6, y=7, y=8, y=9, y=10, y=11, y=12, y=13, y=14, y=15, y=16, y=17, y=18, y=19, y=20, y=21, y=22, y=23, y=24, y=25, y=26, y=27, y=28, y=29, y=30, y=31, y=32, y=33, y=34, y=35, y=36, y=37, y=38, y=39 or y=40.

[0129] Accordingly, each of the blocks A, comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 units.

[0130] For the purposes of the present invention, B.sub.i and C.sub.i are each, in each case independently of B.sub.j where ji or in each case independently of C.sub.j where ji, respectively, one of the following residual groups of a polyether comprising from 80 to 1000 epoxide units, for example polyethylene oxide (PEO), polypropylene oxide (PPO), polyethoxyethylene glycidyl ether (PEEGE) or linear polyglycidol (PG),

##STR00011##

[0131] Linear polyglycidol (PG) can be produced by polymerization of 1-ethoxyethyl glycidyl ether and subsequent unprotection and hydrolysis by means of a weak acid. Apart from linear polyglycidol (PG), it is possible for the blocks B.sub.i and C.sub.i also to consist of branched polyglycidol (hbPG). Branched polyglycidol (hbPG) is obtained by polymerization of the epoxide glycidol.

[0132] Furthermore, for the purposes of the present invention, B.sub.i is also a residual group of a random copolymer comprising from 80 to 1000 epoxide units or cooligomer of two, three or four different epoxide units selected from the group consisting of ethylene oxide (EO), propylene oxide (PO), 1-ethoxyethyl glycidyl ether (EEGE) and glycidol.

[0133] The structure of block copolymers of the invention is described by the formulae

A.sub.1IA.sub.1,

[.sub.i=1.sup.NA.sub.iB.sub.i].sub.0.5I[.sub.i=1.sup.NA.sub.iB.sub.i].sub.0.5,

[.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)].sub.0.5I[.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)].sub.0.5,

I[.sub.i=1.sup.NA.sub.iB.sub.i] and

I[.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)]

[0134] where N=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

[0135] which represent the structural quantity S, where

[0136] S={A.sub.1IA.sub.1, (B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1).sub.0.5, IA.sub.1B.sub.1, (C.sub.1B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1C.sub.1).sub.0.5, IA.sub.1B.sub.1C.sub.1, (A.sub.2B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1A.sub.2).sub.0.5, IA.sub.1B.sub.1A.sub.2, (A.sub.2C.sub.1B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1C.sub.1A.sub.2).sub.0.5, IA.sub.1B.sub.1C.sub.1A.sub.2, (B.sub.2A.sub.2B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1A.sub.2B.sub.2).sub.0.5, IA.sub.1B.sub.1A.sub.2B.sub.2, (B.sub.2A.sub.2C.sub.1B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1C.sub.1A.sub.2B.sub.2).sub.0.5, IA.sub.1B.sub.1C.sub.1A.sub.2B.sub.2, (C.sub.2B.sub.2A.sub.2B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1A.sub.2B.sub.2C.sub.2).sub.0.5, IA.sub.1B.sub.1A.sub.2B.sub.2C.sub.2, (C.sub.2B.sub.2A.sub.2C.sub.1B.sub.1A.sub.1).sub.0.5I(A.sub.1B.sub.1C.sub.1A.sub.2B.sub.2C.sub.2).sub.0.5, IA.sub.1B.sub.1C.sub.1A.sub.2B.sub.2C.sub.2, . . . }.

[0137] As explained above in connection with the process of the invention, the above structural formulae encompass, depending on the sequence of the process steps, structures in which the sequence of the blocks A.sub.i has been exchanged with the blocks B.sub.i and (B.sub.iC.sub.i).

[0138] According to the invention, the structural formulae [.sub.i=1.sup.NA.sub.iB.sub.i].sub.0.5I[.sub.i=1.sup.NA.sub.iB.sub.i].sub.0.5 and [.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)].sub.0.5I[.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)].sub.0.5 designate symmetrical and pseudo-symmetrical block copolymers in which the blocks A.sub.i, B.sub.i, C.sub.i in the in each case two segments [.sub.i=1.sup.NA.sub.iB.sub.i].sub.0.5 and [.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)].sub.0.5 conjugated with the initiator I consist of the same number of monomers or numbers of monomers which differ by 1. Where the respective number of monomers in the blocks A.sub.i, B.sub.i, C.sub.i in the two segments [.sub.i=1.sup.NA.sub.iB.sub.i].sub.0.5 and [.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)].sub.0.5 conjugated with the initiator I are equal or differ by 1 depends on whether the number of mol used for polymerization of the blocks A.sub.i, B.sub.i, C.sub.i (from 1 to 40 for A.sub.i and from 80 to 1000 for B.sub.i and C.sub.i, in each case based on the initiator) is even or odd.

[0139] For the purposes of the invention, the terms symmetrical and unsymmetrical do not refer to chemical structures having point or mirror symmetry. Rather, the terms symmetrical and unsymmetrical relate to the polymerization sequence which forms the segments [.sub.i=1.sup.NA.sub.iB.sub.i].sub.0.5, [.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)].sub.0.5 and [.sub.i=1.sup.NA.sub.iB.sub.i], [.sub.i=1.sup.NA.sub.i(B.sub.iC.sub.i)] proceeding from the initiator I.

[0140] The epoxides used in the process of the invention and their usual oligomers are shown below:

##STR00012##

Measurement Methods

[0141] All chemicals and solvents were, unless listed separately, procured from commercial suppliers (Acros, Sigma-Aldrich, Fisher Scientific, Fluka, Riedel-de-Han, Roth) and used without further purification. Deuterated solvents were procured from Deutero GmbH (Kastellaun, Germany). All experiments were, unless indicated otherwise, carried out at room temperature (20-25 C.), atmospheric pressure (985-1010 hPa) and typical atmospheric humidity (40-100% rH). (Source: measurement station of Institut fr Physik der Atmosphare, Johannes Gutenberg University, Mainz).

NMR Spectroscopy

[0142] .sup.1H- and .sup.13C-NMR spectra were recorded on an Avance III HD 300 (300 MHz, 5 mm BBFO head with z gradient and ATM from Bruker at a frequency of 300 MHz (.sup.1H) or 75 MHz (.sup.13C). Spectra at 400 MHz (.sup.1H) were recorded on an Avance II 400 (400 MHz, 5 mm BBFO head with z gradient and ATM) from Bruker. The chemical shifts are reported in ppm and are relative to the proton signal of the deuterated solvent.

Gel Permeation Chromatography (GPC)

[0143] The GPC measurements were carried out in accordance with DIN 55672-3 2016-01 using dimethylformamide (DMF) admixed with 1 g/l of lithium bromide as eluent on an Agilent 1100 series instrument with an HEMA 300/100/40 column from MZ-Analysetechnik. Detection of the signals was carried out by means of an RI detector (Agilent G1362A) and UV (254 nm) detector (Agilent G1314A). Recording of the GPC rate and curves was carried out using primarily the signal of the RI detector and optionally the signal of the UV detector. The measurements were carried out at 50 C. and a flow rate of 1.0 ml/min. Calibration was carried out using polyethylene glycol standards 200, 1000, 2000, 6000, 20 000 and 40 000 and polystyrene standards from Polymer Standard Service.

[0144] When using the solvent THF, this is introduced by means of a Waters 717 plus injector into a column of the type MZ-Gel SD plus e5/e3/100. An RI detector model Agilent 2160 Infinity is used for the measurement. The eluent is degassed by means of a degasser model ERC-3315a and a flow rate of 1.0 ml/min is set using a Spectra Series P1000 pump. The measurement is carried out at a temperature of 25 C. A poly(ethylene glycol) standard from Polymer Standard Service was used for calibration. In addition, a toluene standard was used. The injection volume is 100 l. The elution graphs are evaluated by means of the software PSS WinGPC Unity.

[0145] In the context of the present invention, the following abbreviations are used:

[0146] PE . . . petroleum ether

[0147] EA . . . ethyl acetate

[0148] DCM . . . dichloromethane

[0149] CSA . . . DL-camphor-10-sulfonic acid

[0150] DMP . . . 2,2-dimethoxypropane

[0151] THF . . . tetrahydrofuran

[0152] DMF . . . dimethylformamide

[0153] eq . . . equivalents

[0154] EO . . . ethylene oxide

[0155] PO . . . propylene oxide

[0156] EEGE . . . 1-ethoxyethyl glycidyl ether

[0157] D . . . polydispersity

[0158] The invention will be illustrated below with the aid of examples.

PHDGE.SUB.6.-b-PEG.SUB.136.-b-PHDGE.SUB.6

[0159] In a 50 ml Schlenk flask with septum, 1 g (0.20 mmol, 1 eq.) of polyethylene glycol (Mw=6000 g/mol), 30 mg (0.26 mmol, 1.6 eq.) of potassium tert-butoxide and 88 mg (0.33 mmol, 2 eq.) of [18]crown-6 crown ether were dissolved in 10 ml of benzene and 1.5 ml of methanol. A gentle, static vacuum was applied to the flask so that the benzene began to boil and the mixture was subsequently stirred at 60 C. for 30 minutes. The reaction mixture was subsequently dried overnight at 60 C. in a high vacuum. After drying was complete, the reaction flask was flooded with argon, and 0.68 ml (2.00 mmol, 12 eq.) of hexadecyl glycidyl ether (HDGE) was added through the septum by means of a syringe. The reaction mixture was subsequently stirred at 80 C. for 24 hours under an argon atmosphere.

[0160] After the reaction was complete, the reaction mixture was dissolved in 3 ml of dichloromethane at a temperature of 25 C. and subsequently added dropwise to about 40 ml of diethyl ether. After allowing to stand at room temperature for 2 hours, the precipitated polymer was centrifuged and decanted. The remaining solvent was removed at 40 C. under reduced pressure.

M.sub.w(.sup.1H-NMR)=9 580 g/mol M.sub.n(GPC)=8 300 g/mol M.sub.w/M.sub.n(GPC*)=1.06

PDDGE.SUB.7.-b-PEG.SUB.227.-b-PDDGE.SUB.7

[0161] In a 50 ml Schlenk flask with septum, 1 g (0.10 mmol, 1 eq.) of polyethylene glycol (Mw=10 000 g/mol), 18 mg (0.16 mmol, 1.6 eq.) of potassium tert-butoxide and 88 mg (0.20 mmol, 2 eq.) of [18]crown-6 crown ether were dissolved in 10 ml of benzene and 1.5 ml of methanol. A gentle, static vacuum was applied to the flask so that the benzene began to boil and the mixture was subsequently stirred at 60 C. for 30 minutes. The reaction mixture was subsequently dried overnight at 60 C. in a high vacuum. After drying was complete, the reaction flask was flooded with argon, and 0.39 ml (1.4 mmol, 14 eq.) of dodecyl glycidyl ether (DDGE) was added through the septum by means of a syringe. The reaction mixture was subsequently stirred at 80 C. for 24 hours under an argon atmosphere.

[0162] After the reaction was complete, the reaction mixture was dissolved in 3 ml of dichloromethane at a temperature of 25 C. and subsequently added dropwise to about 40 ml of diethyl ether. After allowing to stand for 2 hours at room temperature, the precipitated polymer was centrifuged and decanted. The remaining solvent was removed at 40 C. under reduced pressure.

M.sub.w(.sup.1H-NMR)=13 400 g/mol M.sub.n(GPC)=13 000 g/mol M.sub.w/M.sub.n(GPC*)=1.08

PDDGE.SUB.7.-b-PEG.SUB.454.-b-EDDGE.SUB.7

[0163] In a 50 ml Schlenk flask with septum, 1 g (0.05 mmol, 1 eq.) of polyethylene glycol (Mw=20 000 g/mol), 9 mg (0.08 mmol, 1.6 eq.) of potassium tert-butoxide and 26 mg (0.10 mmol, 2 eq.) of [18]crown-6 crown ether were dissolved in 10 ml of benzene and 1.5 ml of methanol. A gentle, static vacuum was applied to the flask so that the benzene began to boil and the mixture was subsequently stirred at 60 C. for 30 minutes. The reaction mixture was subsequently dried overnight at 60 C. in a high vacuum. After drying was complete, the reaction flask was flooded with argon, and 0.19 ml (0.7 mmol, 14 eq.) of dodecyl glycidyl ether (DDGE) was added through the septum by means of a syringe. The reaction mixture was subsequently stirred at 80 C. for 24 hours under an argon atmosphere.

[0164] After the reaction was complete, the reaction mixture was dissolved in 3 ml of dichloromethane at a temperature of 25 C. and subsequently added dropwise to about 40 ml of diethyl ether. After allowing to stand for 2 hours at room temperature, the precipitated polymer was centrifuged and decanted. The remaining solvent was removed at 40 C. under reduced pressure.

M.sub.w(.sup.1H-NMR)=23 900 g/mol M.sub.n(GPC)=20 800 g/mol M.sub.w/M.sub.n(GPC*)=1.14

PHDGE.SUB.14.-b-PEG.SUB.454.-b-PHDGE.SUB.14

[0165] In a 25 ml Schlenk flask with septum, 2 g (0.1 mmol, 1 eq.) of polyethylene glycol (Mw=20 000 g/mol), 18 mg (0.16 mmol, 1.6 eq.) of potassium tert-butoxide and 53 mg (0.20 mmol, 2 eq.) of [18]crown-6 crown ether were dissolved in 10 ml of benzene and 1.5 ml of methanol. A gentle, static vacuum was applied to the flask so that the benzene began to boil and the mixture was subsequently stirred at 60 C. for 30 minutes. The reaction mixture was subsequently dried overnight at 60 C. in a high vacuum. After drying was complete, the reaction flask was flooded with argon, and 0.95 ml (0.84 mmol, 28 eq.) of hexadecyl glycidyl ether (HDGE) was added through the septum by means of a syringe. The reaction mixture was subsequently stirred at 80 C. for 24 hours under an argon atmosphere.

[0166] After the reaction was complete, the reaction mixture was dissolved in 5 ml of dichloromethane at a temperature of 25 C. and subsequently added dropwise to about 40 ml of diethyl ether. After allowing to stand for 2 hours at room temperature, the precipitated polymer was centrifuged and decanted. The remaining solvent was removed at 40 C. under reduced pressure.

M.sub.w(.sup.1H-NMR)=28 300 g/mol M.sub.n(GPC)=22 000 g/mol M.sub.w/M.sub.n(GPC*)=1.28

Setting of the Melting Point by Copolymerization of HDGE and DDGE in a Prescribed Ratio

BnO-PHDGE.SUB.9.-co-PDDGE.SUB.3

[0167] In a 25 ml Schlenk flask with septum, 30 mg (0.2 mmol, 1 eq.) of benzyloxyethanol (BnO), 18 mg (0.018 mmol, 0.8 eq.) of potassium tert-butoxide and 104 mg (0.4 mmol, 2 eq.) of [18]crown-6 crown ether were dissolved in 5 ml of benzene and 1 ml of methanol. A gentle, static vacuum was applied to the flask so that the benzene began to boil and the mixture was subsequently stirred at 60 C. for 30 minutes. The reaction mixture was subsequently dried overnight at 40 C. in a high vacuum. After drying was complete, the reaction flask was flooded with argon, and 0.765 ml of a mixture of 530 mg (1.8 mmol, 9 eq.) of hexadecyl glycidyl ether (HDGE) and 143 mg (0.6 mmol, 3 eq.) of dodecyl glycidyl ether (DDGE) was added through the septum by means of a syringe. The reaction mixture was subsequently stirred at 80 C. for 24 hours under an argon atmosphere.

[0168] After the reaction was complete, the reaction mixture was dissolved in 3 ml of dichloromethane at a temperature of 25 C. and subsequently added dropwise to about 40 ml of methanol. The mixture was subsequently stored at 20 C. for 12 hours. The precipitated polymer was centrifuged and decanted. The remaining solvent was removed at 40 C. under reduced pressure.

M.sub.w(.sup.1H-NMR)=3410 g/mol M.sub.n(GPC)=3000 g/mol M.sub.w/M.sub.n(GPC**)=1.09

BnO-PDDGE.SUB.18.-b-PEEGE.SUB.28

[0169] In a 50 ml Schlenk flask with septum, 0.1 g (0.65 mmol, 1 eq.) of benzyloxyethanol (BnO), 66 mg (0.59 mmol, 0.9 eq.) of potassium tert-butoxide and 521 mg (1.97 mmol, 3 eq.) of [18]crown-6 crown ether were dissolved in 10 ml of benzene and 1.5 ml of methanol. A gentle, static vacuum was applied to the flask so that the benzene began to boil and the mixture was subsequently stirred at 60 C. for 30 minutes. The reaction mixture was dried overnight at 60 C. in a high vacuum. After drying was complete, the reaction flask was flooded with argon, and 3.25 ml (11.82 mmol, 18 eq.) of dodecyl glycidyl ether (DDGE) was added through the septum by means of a syringe. The reaction mixture was subsequently stirred at 80 C. for 24 hours under an argon atmosphere. After the reaction was complete, 3.12 ml (21.4 mmol, 28 eq.) of ethoxyethyl glycidyl ether (EEGE) were added and the mixture was stirred at 80 C. for 24 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was dissolved in 3 ml of dichloromethane at a temperature of 25 C. and subsequently added dropwise to about 40 ml of methanol. After allowing to stand at 20 C. for 5 hours, the precipitated polymer was centrifuged and decanted. The remaining solvent was removed at 40 C. under reduced pressure.

[0170] * Eluent: DMF, calibration: PEG

[0171] ** Eluent: THF, calibration: PEG

Uptake Efficiency

[0172] 100 mg of the ABA triblock copolymer PDDGE.sub.5-b-PEG.sub.227-b-PDDGE.sub.5 (hereinafter referred to as PV119) were dissolved in 0.5 ml of a Nile red/THF solution having a concentration c=1.0 g/l, introduced into a dialysis tube composed of regenerated cellulose from Spectrum Laboratories, Biotech, of the type CE Tubing, MWCO: 100-500 D having a flat width of 31 mm, diameter of 20 mm, specific volume of 3.1 ml/cm and length of 10 m and dialyzed for 2 days (2 d) against 1 l of deionized water at a temperature of 30 C. The dialysis water was replaced once by deionized water over the period of 2 d.

[0173] For comparison, 100 mg of PEG.sub.227 (hereinafter referred to as PEG10k) were dialyzed in Nile red/THF solution (c=0.1 g/l) under the same experimental conditions in deionized water in an identical dialysis tube.

[0174] After dialysis for two days, the swollen, violet-colored hydrogel of the triblock copolymer PDDGE.sub.5-b-PEG.sub.227-b-PDDGE.sub.5 was taken from the dialysis tube. 33 mg of gel were dissolved in 3 ml of dichloromethane and subsequently analyzed by means of HPLC.

[0175] In an analogous way, 122 mg of the colorless PEG.sub.227 solution which had been dialyzed for two days were dissolved in 3 ml of dichloromethane and analyzed by means of HPLC.

[0176] The HPLC measurements were carried out using a 1260 Infinity System from Agilent Technologies in semipreparative configuration with 1260 QuatPump, 1260 ALS Autosampler, 1260 VWD UV-Vis detector with variable wavelength setting and Softa 1300 evaporative light scattering detector (ELSD). The UV detector was set to a wavelength of 254 nm and the column oven was set to a temperature of 50 C. A silica column from MZ Analysentechnik model PerfectSil having dimensions of 250 mm4.6 mm, 300 Si 5 m, was used for the analysis. A mixture of n-hexane (inlet C) and chloroform (inlet B) was used as mobile phase.

[0177] An HPLC calibration line was recorded by means of a dilution series of Nile red in dichloromethane. The concentration of the dissolved hydrogel sample was determined by linear regression. The content of Nile red was subsequently calculated on the basis of the total weight of the gel. The measurement results are shown below.

TABLE-US-00001 TABLE 1 Calibration values for Nile red in dichloromethane UV signal after base Concentration line correction 3.91 10.sup.3 0.1794 1.95 10.sup.3 0.0915 9.77 10.sup.4 0.0480 4.88 10.sup.4 0.0259 2.44 10.sup.4 0.0145 1.22 10.sup.4 0.009 6.10 10.sup.5 0.0066

[0178] A concentration of the solution of PV119/Nile red in dichloromethane of c=1.910.sup.4 g/l was found.

[0179] In an analogous way, a concentration of the solution of PEG10k/Nile red in dichloromethane of c=8.810.sup.6 g/l was found.

[0180] Based on these figures, an amount of 1.810.sup.3 mg of Nile red in 33 mg of PV119 and correspondingly 0.0277 mg in 512 mg of PV119 was determined.

[0181] A value of

0.0277 mg/(0.1 mg/l0.5 ml)=0.554 (55.4%)

[0182] is found for the ratio of the amount of Nile red in the dialyzed PV119/Nile red gel to the amount of Nile red initially added.

Triblock Copolymers

[0183] In a manner analogous to the above examples of synthesis for PHDGE.sub.6-b-PEG.sub.136-b-PHDGE.sub.6, PDDGE.sub.7-b-PEG.sub.227-b-PDDGE.sub.7, PDDGE.sub.7-b-PEG.sub.454-b-PDDGE.sub.7 and PHDGE.sub.14-b-PEG.sub.454-b-PHDGE.sub.14, further triblock copolymers shown in Table 2 were produced and characterized.

TABLE-US-00002 TABLE 2 T.sub.m.sup.a M.sub.n.sup.b M.sub.n.sup.c M.sub.n.sup.d .sup.e Triblock copolymer [ C.] [g .Math. mol.sup.1] [g .Math. mol.sup.1] [g .Math. mol.sup.1] PDDGE.sub.3-b-PEG.sub.136- 0/53 7436 7400 10 600 1.17 b-PDDGE.sub.3 PDDGE.sub.5-b-PEG.sub.136- 8/52 8888 8400 13 000 1.13 b-PDDGE.sub.5 PDDGE.sub.5-b-PEG.sub.227- 2/57 12 892 12 400 20 200 1.12 b-PDDGE.sub.5 PDDGE.sub.8-b-PEG.sub.227- 10/56 13 860 13 800 24 600 1.14 b-PDDGE.sub.8 PDDGE.sub.6-b-PEG.sub.454- 0/61 22 880 22 900 27 000 1.31 b-PDDGE.sub.6 PDDGE.sub.12-b-PEG.sub.454- 11/61 26 752 25 800 30 000 1.34 b-PDDGE.sub.12 PHDGE.sub.3-b-PEG.sub.136- 33/52 7772 7800 12 000 1.20 b-PHDGE.sub.3 PHDGE.sub.5-b-PEG.sub.136- 38/50 9560 9000 17 000 1.19 b-PHDGE.sub.5 PHDGE.sub.5-b-PEG.sub.227- 37/52 13 564 13 600 23 000 1.14 b-PHDGE.sub.5 PHDGE.sub.9-b-PEG.sub.227- 40/54 15 948 15 400 28 000 1.14 b-PHDGE.sub.9 PHDGE.sub.5-b-PEG.sub.454- 34/62 23 552 23 000 32 000 1.20 b-PHDGE.sub.5 PHDGE.sub.14-b-PEG.sub.454- 41/57 28 320 28 300 43 000 1.22 b-PHDGE.sub.14 .sup.afirst and second melting point for alkyl glycidyl ether and polyethylene glycol; .sup.bcalculated molar mass; .sup.cmolar mass measured by .sup.1H NMR (300 MHz, CDCl.sub.3); .sup.dmolar mass measured by SEC (eluent THF, calibrated with PEG); .sup.e polydispersity.