Polymers and polymerization processes

Details Polymers and polymerization processes Polymers and polymerization processes

2001-06-21

2002-09-24

Boykin, Terressa M. (Department: 1711)

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

Synthetic resins

From carboxylic acid or derivative thereof

C528S271000

Reexamination Certificate

active

06455665

ABSTRACT:

The present invention relates to improved polymers and polymerization processes, and are particularly suitable for producing polymers for a variety of uses, including pharmaceuticals, medical devices, food packaging materials and the like. The improved polymers have reduced levels of contaminants as compared to the commercial polymers currently available, as demonstrated below, and thus are ideal for situations where the polymer, or compositions in contact with the polymer, are injected or inserted into, placed within or on, and/or ingested by a living organism. The ability to reduce contaminant levels according to the invention permits greater flexibility in terms of polymerization reaction conditions, including types and amount of catalysts and reactants, as well as expanding the fields of use for polymers and polymer preparations. See U.S. Ser. No. 60/228,729, the entirety of which is hereby incorporated by reference.
The present invention also relates to various polymers, which include the phosphopolymers, which are polymers containing phosphorous linkages. Phosphopolymers include the polyphosphoester polymers (“polyphosphoesters”). These polymers are considered to be biodegradeable polymers having phosphorous-based linkages.
Polyphosphoesters contain phosphate ester bonds, phosphonate ester bonds and/or phosphite ester bonds. Certain polyphosphoesters have hydrolyzable bonds, and as such are considered useful in in vivo contexts because they are biodegradable/biocompatible—at least in part by virtue of the labile phosphoester bond in the polymer backbone. New and useful biodegradable phosphopolymers have previously been produced. See U.S. Pat. Nos. 5,952,451 and 6,008,318; and PCT publications WO 98/44020, WO 98/44021, and WO 98/48859, which are hereby incorporated by reference in their entirety.
Polyphosphoesters have been produced using bulk melt polymerization processes, such as polymerizations using L-lactide, ethylene glycol and ethyl phosphorodichloridate:
This example is Poly(L-lactide-co-ethyl phosphate), referred to as Poly(LA-EG-EOP).
Similar approaches have been used to form Poly(L-lactide-co-hexyl phosphate), referred to as Poly(LAEG-HOP), except that hexyl phosphodichloridate (HOP) substitutes for ethyl phosphorodichloridate (EOP). The polymer is depicted below:
Many previous production methodologies have been comparatively energy and time consuming in terms of overall yield. Accordingly, there is a desire to improve production methodologies to provide greater efficiency and control over the polymerization process. The invention disclosed herein provides improved production methodologies, which result in more efficient production, enhanced purity, better polymer properties, increased yields and improved control over molecular weight and other properties.
For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected and explained here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art.
The terms “biocompatible polymer” and “biocompatibility,” in their various grammatical forms, when used in relation to polymers are art-recognized. For example, biocompatible polymers include polymers that are neither themselves toxic to the host (e.g., an animal or human), nor degrade (if the polymer degrades) at a rate that produces monomeric or oligomeric subunits or other byproducts at toxic concentrations in the host. In certain embodiments of the present invention, biodegradation generally involves degradation of the polymer in an organism, e.g., into its monomeric subunits, which may be known to be effectively non-toxic. Intermediate oligomeric products resulting from such degradation may have different toxicological properties in some instances, however, or biodegradation may involve oxidation or other biochemical reactions that generate molecules other than monomeric subunits of the polymer. Consequently, it may be desired in some circumstances to evaluate the toxicology of a biodegradable polymer intended for in vivo use, such as implantation or injection into a patient, which may be readily determined after one or more toxicity analyses. It is not necessary that any subject composition have a purity of 100% to be deemed biocompatible; indeed, it is only necessary that the subject compositions be biocompatible as set forth above. Hence, a subject composition may comprise a polymer comprising 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or even less of biocompatible polymers, e.g., including polymers and other materials and excipients described herein, and still be biocompatible.
As mentioned above, to determine whether a polymer or other material is biocompatible, it may be desirable to conduct a toxicity analysis. Such assays are well known in the art, and are performed routinely. One example of such an assay may be performed with live carcinoma cells, such as GT3TKB tumor cells, in the following manner: the sample is degraded in 1M NaOH at 37° C. until complete degradation is observed. The solution is then neutralized with 1M HCl. About 200 &mgr;L of various concentrations of the degraded sample products are placed in 96-well tissue culture plates and seeded with human gastric carcinoma cells (GT3TKB) at 10
4
/well density. The degraded sample products are incubated with the GT3TKB cells for 48 hours. The results of the assay may be plotted as % relative growth vs. concentration of degraded sample in the tissue-culture well. In addition, polymers and formulations of the present invention may also be evaluated by well-known in vivo tests, such as subcutaneous implantations in rats to confirm that they hydrolyze without significant levels of irritation or inflammation at the subcutaneous implantation sites.
In certain embodiments, polymeric formulations of the present invention biodegrade within a period that is acceptable in the desired application. In certain embodiments, such as in vivo therapy, such degradation occurs in a period usually less than about five years, one year, six months, three months, one month, fifteen days, five days, three days, or even one day on exposure to a physiological solution with a pH between 6 and 8 having a temperature of between 25 and 37° C. In other embodiments, the polymer degrades in a period of between about one hour and several weeks, depending on the desired application.
The term “biodegradable,” in its various grammatical forms, is art-recognized, and includes polymers, compositions and formulations, such as those described herein, that are intended to degrade during use. Biodegradable polymers typically differ from non-biodegradable polymers in that the former may be degraded during use. In certain embodiments, such use involves in vivo use, such as in vivo therapy, and in other certain embodiments, such use involves in vitro use. In general, degradation attributable to biodegradability involves the degradation of a biodegradable polymer into its component subunits, or digestion, e.g., by a biochemical process, of the polymer into smaller, non-polymeric subunits. In certain embodiments, two different types of biodegradation may generally be identified. For example, one type of biodegradation may involve cleavage of bonds (whether covalent or otherwise) in the polymer backbone. In such biodegradation, monomers and oligomers typically result, and even more typically, such biodegradation occurs by cleavage of a bond connecting one or more of subunits of a polymer. In contrast, another type of biodegradation may involve cleavage of a bond (whether covalent or otherwise) internal to side chain or that connects a side chain to the polymer backbone. For example, a therapeutic agent or other chemical moiety attached as a side chain to the polymer backbone may be released by biodegradation. In certain embodiments, one or the other or both generally types of biodegradation may occur during use of a polymer. As used herein, the term “biodegradation” encompasses bo

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