Branched biodegradable polymers, a macromonomer, processes for the preparation of same, and their use

The present invention relates to branched biodegradable polymers, to a process for the preparation of branched biodegradable polymers, to their use for medical and non-medical applications, to a process for the preparation of a macromonomer, and to the use of the macromonomer in the preparation of the branched biodegradable polymers.

S. Skaria et al (Macromol. Rapid Commun. 2002, 23, 292-296) discloses an enzyme-catalyzed synthesis of hyperbranched aliphatic polyesters. These copolyesters are prepared by copolymerization of ε-caprolactone with 2,2-bis(hydroxymethyl)butyric acid. This copolymerization is catalyzed by immobilized lipase B from Candida antarctica under mild conditions.

Trollsås et al (Macromolecules 1998, 31, 3439-3445; 1998, 31, 4390-4395; J. Am. Chem. Soc. 1998, 120, 4644-4651, J. Polym. Sci.: Part A: Polym. Chem., 1998, 36, 3187-3192) discloses several different processes for the preparation of hyperbranched poly(ε-caprolactone)s. In all cases, firstly protected 2,2-bis-(hydroxymethyl) propionic acid (bisMPA), 2,2-bis(phenyldioxymethyl)propionic acid or benzylidene-protected 2,2-bis-(hydroxymethyl) propionic acid, is synthesized and used to prepare a protected AB 2 -type functional α-carboxylic-ω-dihydroxy poly(ε-caprolactone) macromonomer. The protected macromonomer is subsequently deprotected via hydrogenolysis to yield α-carboxylic-ω-dihydroxy poly(ε-caprolactone). This AB 2 macromonomer is then condensed into hyperbranched polymers via a room temperature esterification synthesis using 1,3-dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridinium 4-toluenesulfonate (DPTS). The polymerization is carried out in CH 2 Cl 2 over a period of 48 hours.

Choi and Kwak (Macromolecules, 2003, 36, 8630-8637) disclose the preparation of hyperbranched poly(ε-caprolactone)s via a modified procedure of Trollsås et al. Similar to Trollsås et al, a AB 2 -type functional α-carboxylic-ω-dihydroxy poly(ε-caprolactone) macromonomer is firstly synthesized through steps of protection of bis-MPA, ring-opening polymerization of ε-caprolactone, and deprotection. Hyperbranched poly(ε-caprolactone)s are made by polyesterification of AB 2 macromonomer using p-toluenesulfonic acid (TSA) as a catalyst at 110° C. with continuous water removal.

Liu et al (Macromolecules, 1999, 32, 6881-6884) and Trollsås et al (Macromolecules, 1999, 32, 9062-9066) separately report the synthesis of hyperbranched poly(ε-caprolactone)s by so-called “self-condensing ring-opening polymerization” of 4-(2-hydroxyethyl)-ε-caprolactone and bis(hydroxymethyl)-substituted ε-caprolactone, respectively. The self-condensing polymerization is performed in bulk at 110° C. in the presence of a catalytic amount of stannous octoate.

Fumitaka et al (Macromol. Rapid Commun. 2001, 22, 820-824) reports the synthesis of branched polylactide by bulk copolymerization of lactide with mevalonolactone using stannous octoate or distannoxane as a catalyst.

The present invention has for its object to provide various types of branched biodegradable polymers via a novel process for their preparation. This process comprises a first step of ring-opening polymerization in the presence of a branching agent and a catalyst thereby forming a macromonomer, and a second step comprising a polycondensation of the macromonomer. This macromonomer is such that it is directly (without an intermediate deprotection step) used in the subsequent polycondensation step. This process is simple and can readily be scaled up. This two step process may be carried out in two pots but a one pot process is preferred. Furthermore, the process may be carried out in bulk or in solution. These branched polymers have relatively low viscosity, good solubility, and abundant reactive groups at the periphery. By varying monomers, branching agents, and monomer-to-branching agent ratios, branched biodegradable polymers with vastly different properties including hydrophilicity, thermal and mechanical properties, and degradation profiles can be obtained.

The cyclic esters and cyclic carbonates used in the first step of the process of the present invention preferably have the following general structure

in which h is from 2 to 16, i is from 1 to 4, j is from 0 to 4, and R 1 , R 2 , R 3 , R′ 1 and R′ 2 are the same or different and represent a hydrogen, or hydrocarbyl or substituted hydrocarbyl with protected O, N, and/or S functionality with a maximum of 30 carbon atoms.

R 1 , R 2 , R 3 , R′ 1 and R′ 2 may have the same or different meaning. Each may represent hydrogen, or hydrocarbyl, such as methyl, ethyl, and propyl. Hydrogen and methyl are preferred. The substituted hydrocarbyl with protected O, N, and/or S functionality, is preferably CH 2 O-Bz, (CH 2 ) 4 —NH—Z 1 , and CH 2 —S-MBz wherein Bz is benzyl, Z 1 is benzyloxycarbonyl, and MBz is p-methoxybenzyl. The total number of carbon atoms is at maximum 30 because larger monomers are difficult to polymerize. Preferably, the number of carbon atoms is less than 20, such as less than 15.

Examples of suitable cyclic esters are

Examples of suitable cyclic carbonates are

Preferred cyclic esters are β-propiolactone, β-butyrolactone, δ-valerolactone, alkyl-δ-valerolactone, ε-caprolactone, alkyl-ε-caprolactone, ω-pentadecalactone, dioxanone, lactide and glycolide. Preferred cyclic carbonates are trimethylene carbonate or 2,2-dimethyl trimethylene carbonate, and mixtures thereof. It is considered within the scope of protection of the present invention that mixtures of different cyclic esters and/or cyclic carbonates are used dependent on the desired properties of the branched biodegradable polymers according to the present invention.

The branching agent has the following formula

(Z) x —R 1 —(COOR 2 ) y

wherein Z is a hydroxyl, thiol, primary or secondary amine group, (x+y)≧3, R 1 is an aliphatic or aromatic moiety with or without ester, ether, amide, and/or ketone functionality, R 2 is a hydrogen, (C 1 -C 6 )-alkyl optionally substituted with halogen, or aryl such as phenyl optionally substituted with halogen or (C 1 -C 6 )-alkyl.

Preferably, Z is hydroxyl, (x+y) is 3 or 4 and x or y is 1, R 2 is a hydrogen, methyl or ethyl optionally substituted with halogen, or phenyl optionally substituted with methyl or halogen.

When the ring-opening polymerization comprises the ring-opening of the cyclic N-carboxyanhydride then it is preferred that the cyclic N-carboxyanhydride (NCA) has the following general structure

in which R represents a hydrogen, or hydrocarbyl, or hydrocarbyl with (protected) O, N, and/or S functionality, or hydrocarbyl with protected carboxylic acid, or aromatic group such as —CH 2 Ph, and the branching agent has the following formula:

(Z) x —R 1 —(COOR 2 ) y

wherein Z is a primary amine group, (x+y)≧3, R 1 is an aliphatic or aromatic moiety with or without ester, ether, amide, and/or ketone functionality, R 2 is (C 1 -C 6 )-alkyl optionally substituted with halogen, or aryl, such as phenyl, optionally substituted with halogen or (C 1 -C 6 )-alkyl. The NCA is preferably an alpha-amino acid N-carboxyanhydride.

Preferably for the N-carboxyanhydride R represents methyl, isopropyl, isobutyl, —CH 2 CH 2 SCH 3 , —(CH 2 ) 4 NHCO 2 C(CH 3 ) 3 , —CH 2 OCH 2 Ph, —CH 2 COOCH 2 Ph, —CH 2 CH 2 COOCH 2 Ph, or —CH 2 Ph, wherein Ph means phenyl.

Examples of branching agents are

The ring-opening polymerization of the cyclic ester and/or cyclic carbonate is carried out in the presence of the branching agent and of a catalyst. The catalyst is a traditional catalyst for ring-opening polymerization and may be selected from alkyls, oxides, alkoxides, halides, and carboxylates of metals such as tin, titanium, aluminum, zirconium, antimony, yttrium, lanthanide, iron, manganese, calcium, magnesium, and zinc. When the cyclic NCA is used the reaction does not require the use of a catalyst.

In the polycondensation step b) a macromonomer or a mixture of macromonomers may be used. This mixture of macromonomers may be obtained in one step a) of ring-opening polymerization or by mixing macromonomers obtained in different ring-opening polymerizations.

The polycondensation may be carried out without or with a catalyst. If a catalyst is used a traditional catalyst for polycondensation may be used and may be selected from alkyls, oxides, alkoxides, halides, and carboxylates of metals such as tin, titanium, aluminum, zirconium, antimony, yttrium, lanthanide, iron, manganese, calcium, magnesium, and zinc. Other suitable catalysts are catalysts which are effective for esterification reactions like Lewis acids, protonic acids, or catalysts which include sulfuric acids, phosphoric acids, p-toluenesulfonic acid, and metal oxides, alkoxides, carbonates, halides and carboxylates wherein the metals are tin, titanium, aluminum, zirconium, antimony, yttrium, lanthanide, iron, manganese, calcium, magnesium, and zinc. The catalyst for the ring-opening polymerization and for the polycondensation may be the same. Preferably, the catalyst for the ring opening and/or for the poly condensation is selected from stannous octoate, dialkyltin oxide, stannous chloride, dialkyltin diacetate, zinc acetate, zinc lactate, and titanium alkoxides. It is noted that the polycondensation may be carried out under reduced pressure.

The ring-opening polymerization is generally performed in bulk at a temperature from 60 to 220° C. or in solution at a temperature from 10 to 200° C., over a period of a few minutes up to 72 hours. The molar ratio of cyclic monomer and branching agent ranges from 1:1 to 100:1. The polycondensation reaction may be performed in solution preferably at a temperature from 0 to 140° C., although more preferably carried out in the bulk under reduced pressure preferably at a temperature from 110 to 240° C. and over a period of time of 4 up to 72 hours.

The first step of the process of the invention for the preparation of branched biodegradable polymers results in the preparation of a macromonomer. This macromonomer as an intermediate compound is subsequently used in the second step of polycondensation.

At the beginning or during the polycondensation reaction may be present a bi- or more functional core molecule. This will further modify the structure and properties of the end product. Accordingly, it is preferred that polycondensation of the macromonomer in step b) is carried out in the presence of a core molecule selected from a polyol, polyamine, polycarboxylic acid and/or polycarboxylic ester. The core molecule may be a polyol such as glycerol, polyglycerol, tris(methylol)propane, di(trimethylolpropane), pentaerythritol, ethoxylated pentaerythritol, sorbitol, mannitol, sucrose, and star-shaped poly(ethylene glycol), a polyamine such as poly(L-lysine), spermidine and trimethylene tetramine, and a polycarboxylic acid or ester such as 1,2,3-butanetricarboxylic acid, trimesic acid, pyromellitic acid, and mellitic acid.

Specific examples of the core molecule are

The branched biodegradable polymers according to the present invention have broad applications in biomedical and pharmaceutical areas. Particularly, the presence of many functional hydroxyl or carboxyl groups makes these polymers ideal for further modifications. For example, different biomolecules such as peptides and drugs can be covalently attached to these biodegradable polymers, to yield functional scaffolds for tissue engineering and controlled drug release systems. The attachment of hydrophilic polymers, such as polysaccharides and poly(ethylene glycol), will lead to a novel type of amphiphilic copolymers. The lower specific viscosity of branched polymers as compared to linear ones allows for easier melt fabrication of devices. Branched biodegradable polymers also have the advantage that the degradation and release kinetics can be adjusted without significantly changing the physical properties of the polymers relative to the corresponding linear polymers. Furthermore, these branched polymers are also useful as coatings for medical implants.

The branched polymers of this invention are also useful as processing aids for conventional biodegradable polymers, due to their low melt viscosity.

The process of the present invention will be further illustrated by way of an example which is used to illustrate the present invention and is to be considered not to limit the present invention in any respect.