Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Biocides; animal or insect repellents or attractants
Reexamination Certificate
2002-03-01
2004-03-09
Pryor, Alton N. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Biocides; animal or insect repellents or attractants
C424S486000, C424S484000, C424S093700, C606S230000, C606S231000
Reexamination Certificate
active
06703035
ABSTRACT:
FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
This invention relates to crystalline, low melting, &egr;-caprolactone polymers bearing basic amine functionalities which are linked to the ester chain ionically or covalently to induce catalyzed hydrolysis. The ester components can be derived from &egr;-caprolactone with or without small amounts of glycolide, and/or or similar lactones. Such polymers with accelerated absorption profiles are especially adapted for use as transient coatings for absorbable multifilament surgical sutures (and other medical implants).
Multifilament surgical sutures such as Dexon® polyglycolide multifilament suture typically require a surface coating to improve their handling and knotting characteristics. Capitalizing on the desirable low melting temperature, crystallinity, and rheological properties of polycaprolactone and its copolymers as coating materials, several compositions based on this polymer were investigated as coatings for surgical sutures. Recognizing the fact that the &egr;-caprolactone homopolymer is essentially non-absorbable led to the development of copolymers of &egr;-caprolactone with variable amounts of more absorbable monomers to improve the coating absorbability. U.S. Pat. No. 4,624,256 discloses a suture coating copolymer of at least 90 percent &egr;-caprolactone and a biodegradable monomer and optionally a lubricating agent. Examples of monomers for the biodegradable polymers disclosed include glycolic acid and glycolide, as well as well-known monomers typically used to prepare absorbable polymer fibers or coatings for multifilament sutures. U.S. Pat. Nos. 4,788,979 and 4,791,929 disclose a bioabsorbable coating of a copolymer of at least 50 percent &egr;-caprolactone and glycolide. Sutures coated with such polymers are reported to be less stiff than sutures coated with other materials and the physical properties of the coated suture are also reported to be acceptable. U.S. Pat. No. 4,994,074 discloses copolymers of a predominant amount of &egr;-caprolactone, the balance being glycolide and glycolic acid. The use of glycolic acid as a comonomer into the copolymers of this invention was reported to increase the rate of absorption of the copolymer when used as a coating for multifilament surgical sutures.
Unfortunately, the problem of adequate bioabsorbability of &egr;-caprolactone-based polymers without detrimental effects on their desirable properties as coatings still remains. Specifically, the use of sufficient amounts of glycolide to achieve sufficient absorbability of the copolymeric coating can compromise its crystallinity and melting characteristics, for it may become amorphous or liquid near room temperature. On the other hand, the strategy of using glycolic acid to achieve the reported results in coating absorbability does limit the ability to produce sufficiently long chain molecules to achieve optimum frictional properties, due to glycolic acid's known properties as both a ring-opening initiator chain terminator. Thus, a totally new approach to modifying the absorbability of polycaprolactone and its copolymers without affecting their desirable properties as suture coatings (or coatings for surgical devices) would be a more desirable goal.
SUMMARY OF THE INVENTION
The present invention provides a bioabsorbable, crystalline, nitrogenous copolyester lubricant coating for surgical devices, wherein the lactone derived component of the chain sequences are based on 90 percent to 98 percent &egr;-caprolactone-based units and 2 percent to 10 percent of glycolide-based units, having improved absorbability, as measured by rate or duration of sustained autocatalytic. In one embodiment of the present invention, improved absobabilility is provided the central location of the nitrogen of a tertiary amine, to which the polymer chains are covalently linked. The central, highly basic amine provides the maximum continued, sustained autocatalytic effect for the hydrolytic degradation of the copolyester chain. This embodiment of the invention is made using triethanolaine (TEA) as an initiator for the ring-opening polymerization of a mixture of cyclic monomers containing more than 85% &egr;-caprolactone.
In another embodiment of the present invention, improved absorbability is achieved by a copolyester polymer having two or more carboxylic groups per chain to which is ionically or covalently bound a basic amino acid. The increased number of basic amino acid groups per chain produces the improved absorbability. This structure highly absorbable structure is made using di- or tri- hydroxy acids as initiators. Use of these initiators doubles or triples the the carboxylic content of the polymeric chain over chains of comparable molecular weight made using glycolic acid.
The polymer molecular weight is less than 20 kDa. The coating may be advantageously applied to a variety of surgical devices, such as surgical sutures and staples, or facia fasteners as well as other surgical closure devices, and endovascular stents. In addition, the polyesters bearing the amine-functionalities which are the subject of this invention, and coatings derived therefrom, can be used alone or as carriers or matrices for viable cells and vaccines, or as a coating containing bioactive agents such as growth factors, antimicrobials and antibiotics.
DETAILED DESCRIPTION OF THE INVENTION
Polyesters comprising predominantly &egr;-caprolactone polymer sequences generally refers to polymers with &egr;-caprolactone-based sequences of greater than 80 mole percent, the monomer compositions from which the polymers of this invention are derived. &egr;-Caprolactone is the predominant component of the polyester because of its low melting, exceptionally low glass transition temperature (T
g
) and its ability to enhance the surface physical properties of coated multifilament sutures. Preferably, the amount of &egr;-caprolactone used in the synthesis of the polyester ranges from 90 to 99, more preferably, 96 to 99 mole percent. For copolyesters, of this invention, the remaining comonomers are preferably glycolide and/or glycolic acid. Other lactones such as lactide and p-dioxanone and/or their corresponding hydroxy acids can be used. The hydroxy acids can be used, specifically as chain initiators to control the polyester molecular weight, as determined in terms of their inherent viscosities (I.V.) as approximately 0.1 dl/g solutions in chloroform, and/or to provide chains with a carboxylic end group. The basic nitrogenous polyesters that are the subject of this invention, are to have I.V. or 0.05 to 0.35 dl/g and, preferably, 0.05 to 0.25 and, more preferably 0.10 to 0.20 dl/g.
The present invention deals with two definite improvements over the prior art disclosed in U.S. Pat. No. 6,197,320. The first improvement deals with use of di- or tri-carboxylic hydroxy acids as initiators for the ring-opening polymerization of a mixture of cyclic monomers containing more than 85% &egr;-caprolactone. Using di- or tri-carboxylic hydroxy acids as initiators, results in doubling or tripling the carboxylic content of the polymeric chain of comparable molecular weight made under similar conditions using glycolic acid. This, in turn, allows for including higher amounts of the basic amino acid per chain as counter ions of the carboxylate anions and hence, increases the rate of autocatalytic hydrolysis of the copolyester. The second improvement deals with the use of triethanolamine (TEA) as an initiator for the ring-opening polymerization of a mixture of cyclic monomers containing more than 85% &egr;-caprolactone. Using TEA as an initiator yields a nitrogenous copolyester with (1) symmetrically branched structure; and (2) a central 3° amine group. This, in turn, increases the degree of toughness of the crystalline coating and minimizes its tendency to delaminate, particularly when used as a coating for braided sutures. Having a central, highly basic amine insures the availability of the amine group through most of the life of the copolyester and hence maximizes the continued sustained autocata
Poly-Med, Inc.
Pryor Alton N.
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