Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From carboxylic acid or derivative thereof
Reexamination Certificate
2003-01-09
2004-03-16
Acquah, Samuel A. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From carboxylic acid or derivative thereof
C526S062000, C526S064000, C526S065000, C528S361000, C528S365000, C525S437000, C525S444000
Reexamination Certificate
active
06706854
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process for preparing reabsorbable polyesters by bulk polymerisation, wherein the reaction components are melted and homogenised in a stirred reactor, the reaction mixture is then transferred into a number of smaller-volume containers, the reaction mixture is polymerised in these containers and the polyester obtained is isolated by removing it from the containers.
BACKGROUND TO THE INVENTION
Reabsorbable polyesters for the purposes of the present process are aliphatic polyesters based on lactide (L-lactide, D-lactide, DL-lactide, meso-lactide) or glycolide as well as copolymers with two or more different comonomer units of the abovementioned monomers with one another and copolymers of the monomers with trimethylene carbonate (TMC) and/or &egr;-caprolactone. This group of polyesters is preferably used to prepare reabsorbable implants for use in human or animal bodies, such as for example for fixation elements, films, membranes, suture thread or also for pharmaceutical release systems.
Polymerisation processes for preparing reabsorbable polyesters are known from the prior art. In addition to polycondensation processes which can only be used to produce relatively low-molecular polyesters, they are preferably prepared by ring-opening polymerisation of the corresponding cyclic monomers, namely L-lactide, D-lactide, DL-lactide, meso-lactide, glycolide, trimethylene carbonate, &egr;-caprolactone with the addition of metal catalysts. A plurality of catalysts are known from the prior art. Preferably, tin or zinc compounds are used. According to the prior art additives which make it possible to control the molecular weight in the polymer (chain length moderators) may be added to the reaction mixture. Aliphatic alcohols such as ethanol, dodecanol, hydroxycarboxylic acids, such as glycol or lactic acid or also oligomeric lactic acids or water have proved suitable, inter alia.
A number of techniques for the ring-opening polymerisation of lactides and related lactones are also known from the prior art. Fusion polymerisation, bulk polymerisation, solution polymerisation and suspension polymerisation are described, for example (e.g. J. Nieuwenhuis, Clinical Materials, 10, 59-67, 1992). Of these, fusion and bulk polymerisation are of the greatest technical importance. The difference between the two techniques is the reaction temperature. Whereas all the reaction components are in a molten state in fusion polymerisation, the bulk polymerisation is carried out at a temperature situated between the melting points of the particular monomer and polymer. Depending on the type of monomer/polymer the temperature during bulk polymerisation may be between about 50° C. and 180° C., whereas for fusion polymerisation temperatures in the range from about 190 to 230° C. generally have to be selected.
The advantage of bulk polymerisation over fusion polymerisation is the lower reaction temperature: because of the more moderate temperature side reactions occur to a considerably lesser extent. Side reactions during polymerisation are detrimental on the one hand as they cause chain termination in the growth reaction and thereby reduce the molecular weight in the polymer. Reabsorbable polyesters with a very high molecular weight can therefore only be produced by bulk polymerisation and not in a melt. The high reaction temperatures of the fusion polymerisation also have the drawback that the resulting polymers may have some discoloration. These impurities produced at high temperatures are generally polymer-bound and cannot therefore be removed from the product in a subsequent purification step. With respect to the preferred use of the polyesters in the human body it is advantageous to avoid contamination of every kind.
Another advantage of a low reaction temperature may be the suppression of transesterifications during the polymerisation. In this way it is possible to prevent strong randomisation of the monomer sequences during copolymerisation. Because of the different reactivities of the individual monomers copolymers with a block-like sequence can be produced at low temperature.
It is known, particularly with regard to poly(L-lactide), e.g. from U.S. Pat. Nos. 4,539,981 and 4,550,449 as well as from J. Leenslag, A. Pennings, Makromol. Chem. 188, 1809-1814, 1987, that by a suitable choice of the reaction conditions such as the reaction time and temperature as well as the concentration of the catalyst and the chain length moderator, the bulk polymerisation can be controlled accordingly in terms of the molecular weight of the reaction product and the speed of the reaction.
Whereas fusion polymerisation can readily be carried out either continuously or discontinuously on a large scale in suitable polymerisation apparatus, bulk polymerisation presents major problems when performed on a large scale. As the reaction mass solidifies during the polymerisation, it is not possible to carry out the reaction in stirred reactors. The reaction product takes on the shape of the inner wall of the reactor and has to be removed from the reactor as a compact block. Thus, as the reaction mixtures are scaled up, ever larger blocks of material are produced. The handling and also subsequent grinding up into workable granules therefore becomes impossible upwards of a certain order of magnitude. A further difficulty is the removal of the heat of the reaction. As these polymerisation reactions are strongly exothermic, and moreover the polymer mass formed has very poor conductivity, in larger reactors temperature gradients may be formed which give rise to serious and unacceptable inhomogeneities in the product. These inhomogeneities may take the form of different molecular weights and, in the case of copolymers, in different molar compositions as well. According to reference (1) the temperature increase on the inside may be up to 80° C.
Whereas the literature contains sufficient information on the choice of suitable reaction parameters for bulk polymerisation in a small-scale reaction, particularly for poly(L-lactides), the prior art contains no teaching as to how the reaction can be carried out on an industrial scale. The Examples in the literature are carried out on a small scale up to a maximum of a few hundred grams and are, moreover, carried out in test tubes in a laboratory.
The problem is therefore to provide a process which can be used on an industrial scale for preparing reabsorbable polyesters by bulk polymerisation at moderate temperatures by which high quality reabsorbable polyesters can be produced on a large scale.
DETAILED DESCRIPTION OF THE INVENTION
When developing the process it was found, surprisingly, that the problems described above can be overcome by spatially and physically separating the polymerisation reaction into a larger reactor for melting and homogenising the reaction components and into a number of smaller subreactors, preferably made of plastics, for the actual reaction of polymerisation.
In this process the cyclic monomers are reacted, in a manner known per se, with the addition of metal catalysts and optionally chain length moderators to form the respective polymers at temperatures at which the monomer is present in molten form but the reaction product is solid or virtually solid.
The present invention thus relates to a process for preparing reabsorbable polyesters by bulk polymerisation, while the reaction components are melted and homogenised in a stirred reactor, then the reaction mixture is converted into a plurality of smaller-capacity containers, preferably plastic bottles, the reaction mixture is polymerised in these containers and the polyester obtained is isolated by removing it from the containers.
The invention also relates to the use of a reabsorbable polyester for preparing reabsorbable implants by the process according to the invention.
A preferred process comprises the following steps:
(a) melting the monomer(s) in a stirred reactor;
(a1) adding the catalyst;
(a2) optionally adding a chain length moderator;
(a3) homogenising the reaction m
Buchholz Berthold
Schellhorn Matthias
Weber Andreas
Acquah Samuel A.
Boehringer Ingelheim Pharma GmbH & Co. KG
Devlin Mary-Ellen M.
Raymond Robert P.
Stempel Alan R.
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