Biomedical polyurethane, its preparation and use

Details Biomedical polyurethane, its preparation and use Biomedical polyurethane, its preparation and use

2001-06-19

2004-08-31

Gorr, Rachel (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

From reactant having at least one -n=c=x group as well as...

C560S158000, C521S173000, C606S213000

Reexamination Certificate

active

06784273

ABSTRACT:

The invention is directed to biomedical polyurethanes and the use thereof in various applications.
Biomedical polyurethanes (PUs) have been used for a wide range of applications. Examples include nerve guides, meniscal reconstruction materials, artificial skin and artificial veins.
For these applications, usually commercially available polyurethanes are used. These materials frequently exhibit good mechanical properties but an important disadvantage is that they contain aromatic diphenylmethane diisocyanate (MDI). MDI based polyurethanes are known to release carcinogenic and mutagenic products on degradation. Furthermore, they often show low resistance to tearing. A high resistance to tearing is important to prevent sutures from tearing out of a biomaterial. The development of new medical grade polyurethanes with good mechanical properties is therefore highly desirable.
Further an important aspect of the biomedical polyurethanes is the requirement that they can be processed into porous shaped bodies, e.g. as implants.
In the development of the novel materials of the invention, first porous 50/50 copoly(&egr;-caprolactone/L-lactide) materials were used for the reconstruction of meniscal lesions. They showed a very good adhesion to the meniscal tissue and, therefore, a good healing of the meniscal lesion. The mechanical properties of this copolymer resemble the mechanical properties of polyurethanes because of the high molecular weight and the presence of crystallisable L-lactide sequences. The polymer had, however, certain drawbacks. First, the degradation rate was somewhat too high New meniscal tissue, the so called fibrocartilage, is formed after an induct,on time of 10 to 20 weeks.
Second, due to the very high molecular weight of the polymer a maximum concentration of 5% could be reached. This resulted in very low compression moduli of porous materials. For the ingrowth of fibrocartilage higher moduli were needed. Finally, the L-lactide crystals, which are still present after 8 years of in-vitro degradation, may induce an inflammatory reaction since cells cannot digest them unlike poly(&egr;-caprolactone) and polyglycolide crystals.
To avoid lactide crystallinity, an amorphous 50/50 copoly(&egr;-caprolactone/85,15 L,D-lactide) was used for the production of nerve guides. Due to the absence of crystals, however, this polymer showed swelling upon degradation. Therefore, the focus was put on the synthesis of &egr;-caprolactone and L-lactide based polyurethanes. The urethane hard segments crystals are likely to be small and susceptible to enzymatic degradation. In addition, by making an &egr;-caprolactone and L-lactide based PU the biocompatibility may be improved.
When the copolymer was simply chain extended with diisocyanates, the mechanical properties of the resulting polymer were poor due to the absence of a phase separated morphology. Phase separated morphologies can be reached when an isocyanate terminated polyol is chain extended with a diamine or diol resulting in a polyurethane urea and polyurethane respectively. However, the L-lactide and &egr;-caprolactone based prepolymer showed a deviant behavior with respect to chain extension using a diamine and diol. It appeared that the prepolymer was susceptible to aminolysis and transesterification unlike &egr;-caprolactone and glycolide/trimethylene carbonate prepolymers.
The invention is directed to novel biomedical polyurethanes, suitable for implants, not having the disadvantages discussed above.
Further it is an aspect of the invention to provide a novel intermediate for this polyurethane, as well as a novel way of producing the polyurethane.
In a first aspect the invention is directed to novel biomedical polyurethanes, based on diisocyanate linked polyester (co)polymer and diol components, said diol component having a uniform block-length.
According to a preferred embodiment, the polyurethane may be represented by the following formula:
&Parenopenst;A—B—C—B&Parenclosest;
n
wherein the B denote diisocyanate moieties, A denotes a polyester moiety, C denotes a diol moiety and n is the number of recurring units.
In a most preferred embodiment the polyurethane consists of repeating units of the following formula
{C(O)—N—R
1
—N—C(O)—O—D—O—C(O)—N—R
1
—N—C(O)—O—E—O}
n
,
wherein R
1
is an n-butylene moiety, D is a polyester moiety, E is an n-butylene diol, an n-hexylene diol or a diethylene glycol based moiety and n indicates the number of repeating units.
With respect to the above formulae it is to be noted that they represent the recurring units of the polyurethane. The endgroups are not represented thereby. The nature of the endgroups will vary according to the type of (co)polyester and diol, as well as with the production process.
Further preferred embodiments of the invention are indicated in the dependent claims.
The products of the present invention show a good balance between the properties necessary for use thereof in biomedical applications, such as good modulus, tensile strength and compression modulus. It has been found possible to process these materials into porous implants by salt-leaching and freeze-drying, resulting in a material having macropores in the range of 150 &mgr;m to 300 &mgr;m. The material can also be produced in situ in an extruder, even in combination with generating macropores in situ.
As has been indicated above, the conventional methods of producing polyurethanes may result in transesterification and aminolysis, with the consequence that the material has insufficiently balanced properties. More in particular the uniformity of block-length gets lost, resulting in loss of phase separation. The consequence thereof is that the mechanical properties deteriorate to a level below that which is acceptable for numerous biomedical applications.
An important feature of these polyurethanes is that they owe their good mechanical properties to the phase separated morphology. Because the soft segments (e.g. polyesters, polycarbonates or polyethers) are chemically incompatible with the hard segments (urethane, urea or amide moieties) phase separation occurs. The hard segments crystallize and form strong hydrogen bonds with other hard segments resulting into physical cross-links.
The behavior of these polyurethanes is n strong contrast with other polyurethanes often applied. A well-known example is polyurethanes in which 2 different, chemically incompatible, soft segments (e.g. polyesters and polyethers) are coupled by a diisocyanate. An example thereof is disclosed in U.S. Pat. No. 4,2844,506. In this case, also a certain extent of phase separation will occur, but these materials do not owe their mechanical properties to the ability of the urethane functionality to form hydrogen bonds but to the contribution of entanglements and phase separation between the different soft segments. The reason why the urethane functionalities can not contribute to the mechanical properties of the material is that the urethane moieties are too small to crystallize and form hydrogen bonds.
Polyurethanes with a micro-phase separated morphology frequently exhibit good mechanical properties and are generally easy to process due to the relatively low melting point.
Mechanical properties of polyurethane ureas are usually even better resulting from the increased crystallizability and hydrogen bonding ability of the urea moieties. The polymers, however, frequently have melting points that are close to the degradation temperature, leading to a small processing window.
The polymers of the present invention, contain long urethane-based hard segments of uniform size. This results into a system wherein the hard segments have increased crystallizability and hydrogen bonding ability compared to “classical” polyurethanes. The mechanical properties are comparable to those of polyurethane ureas. However, the melting point is still rather low which makes processing relatively easy.
It should be noted that the uniformity of the urethane-based hard segments is the crucial factor for the mechanical properties of the materials. The preferred

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