Bone sealants

Details Bone sealants Bone sealants

1999-12-03

2002-07-16

Szekely, Peter (Department: 1714)

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

Synthetic resins

Processes of preparing a desired or intentional composition...

C523S105000, C523S113000, C524S377000, C524S378000, C427S002260, C427S002300

Reexamination Certificate

active

06420454

ABSTRACT:

The present invention relates to improved bone sealants for staunching local hemorrhages on the bone and as a carrier material for active compounds.
Bone sealants or bone waxes are used for the mechanical closure of hemmorrhaging bone wounds. Absorbable bone sealants have the advantage compared with non-absorbable bone waxes that they are completely metabolized by the body, without inflammatory symptoms, in particular macrophage-induced foreign-body reactions.
Absorbable waxes of this type for mechanical hemostasis on endogenous hard tissue, in particular bone, are known and, for example, are the subject of EP 0 100 981. The waxes or sealants described there are distinguished in that they consist of waxy polyester oligomers of lower hydroxycarboxylic acids, which are highly viscous to solid at body temperature. On account of their structure, these waxes are degradable by endogenous metabolic mechanisms, the rate of degradation being adjustable in a manner known per se. Oligomers of glycolic acid are degraded more rapidly by the endogenous metabolism than those of lactic acid. The degradation rate is thus regulatable, for example, by mixed esterification of the two known hydroxycarboxylic acids. The preferred waxes have average molecular weights in the range from about 200 to 1500 and in particular in the range from about 300 to 1000.
The regulate the average molecular weight of these polyester oligomers, the patent mentioned proposes additionally using monofunctional and/or difunctional alcohols or carboxylic acids or carboxylic anhydrides and/or primary or secondary monoamines. In a manner known per se, it is then possible by choice of suitable mixing ratios of hydrooxycarboxylic acids and additional monofunctional or difunctional components to predetermine an average molecular weight which finally established itself.
German Patent 37 16 302 relates to a continuing optimization of absorbable waxes of this type. It is described in this patent that body- and tissue-compatible waxes are particularly obtained if—observing the general legalities of the previously mentioned patent—a very specific trifunctional alcohol, namely glycerol, is empolyed for adjustment of the average molecular weight. The combination of glycerol with oligoesters of lactic acid and/or of glycolic acid leads to degradable waxy components of the type mentioned, which are distinguished on implantation into living body tissue by a particularly highly pronounced physical tolerability.
Disadvantages, however, are furthermore also seen in the practical use of these known and highly tolerable substances, such as, for example, strong adhesion to plastics, poor extrudability or alternatively a non-optimum viscosity at room temperature.
The teaching of the present invention therefore starts from the object of furthermore improving body-absorbable bone sealants in a number of ways. In particular, bone sealant materials are to be made available which do not have the disadvantages of strong adhesion to plastics, such as, for example, surgical gloves, and furthermore have an improved extrudability from packaging materials together with improved mechanical properties, in particular the viscosity at room temperature and at body temperature, while maintaining the haemostatic properties.
The teaching of the invention for solving this many-sided objective starts from the knowledge that such a demanding bone sealant can only be obtained in a very specific formulation of the individual components.
Surprisingly, it has now been found that the blending of polyester oligomers of very specific compositions with water-soluble polymers leads to the bone sealant materials which are improved in many respects.
The invention accordingly relates to a bone sealant for staunching local hemorrhages on the bone, which comprises a polyester oligomer, synthesized from polyol, lactide, and glycolide and water-soluble polymers.
The oligomer segments of the optimized bone waxes described according to the invention are derived from lactic acid and glycolic acid. In general, the readily handleable dimerization products, i.e., the lactide and the glycolide, are employed, but it is also possible to take the monomeric hydroxycarboxylic acids as starting materials. Lactic acid or lactic acid dimers can be used as the optically active component or alternatively as a mixture of the optically active compounds as the D, L-lactide.
As the third component, i.e., as the coreactant, a polyol is added in a known manner for the adjustment of the desired degree of oligomerization. Glycerol is preferably employed as a polyfunctional alcohol.
In accordance with the invention, the described polyester oligomers are blended with water-soluble polymers.
Suitable water-soluble polymers are polyethylene glycol or copolyethers of ethylene glycol and propylene glycol. These preferably have a molecular weight of 1,000 to 10,000, especially 6,000 to 10,000. In particularly preferred embodiment of this invention, PEG 8000 is used. Either a water-soluble polymer or alternatively a mixture of a number of water-soluble polymers can be used.
Blending with the polyester oligomers is preferably carried out such that the content of water-soluble polymers is 5-50%. Particularly preferably, the content is 15-30%.
In particularly preferred embodiments of the present invention, the polyester oligomers are synthesized from 1 part of glycerol and X parts of lactide and Y parts of glycolide, where X and Y in each case independently of one another can be 1, 2 or 3.
In this case, in particular, those are particularly preferred in which X+Y is ≦4.
The polyester oligomers are prepared by the customary condensation processes, which are known and descirbed in the patents cited above, and therefore do not have to be described in greater detail here. The polyester oligomers are thus also characterized by an average molecular weight in the range from 200 to 1500 and preferably in the range from 300 to 1000.
Particularly preferred embodiments are those in which the polyester oligomers are composed of 1 part of glycerol, 2 parts of lactide and 1 part of glycolide or alternatively of 1 part of glycerol and 2 parts of lactide and glycolide in each case.
In a very particularly preferred embodiment, the polyester oligomer consists of 1 part of glycerol, 1 part of lactide and 3 parts of glycolide.
Furthermore, it was surprisingly found that preferred products can also be prepared if, during the condensation reaction, a temperature of 140° C. to 160° C., preferably of 145° C. to 155° C., is chosen. These temperatures are lower in comparison with the temperatures otherwise customary in condensation reactions.
The oligomers can then either be sterilized—preferably &ggr;-sterilization—or else alternatively directly further processed.
The blending of polyester oligomers of this type with 15-30% of water-soluble polymer leads to particularly preferred bone sealant materials according according to the invention.
The blending of the polyester oligomers with the water-soluble polymers can be carried out either by kneading by hand or—which is preferred and simpler to handle—by means of a kneader at somewhat elevated temperatures. Preferably, for complete degassing, vacuum is additionally applied.
The products are preferably stored in sterilized form, &ggr;-sterilization preferably being carried out.
The bone sealants according to the invention are used for staunching local hemorrhages on the bone. They exhibit many improved properties with respect to their use.
The properties according to the invention are tested in the customary manner on anaesthetized pigs by direct application to the sternum after thoracotomy. Inter alia, the adhesion properties of the blend to the spongy bone of the sternum, the assessment of the stickiness on the surgical glove, the application properties, the assessment of the hemostasis after specific time intervals as well as the assessment of the penetration power into the spongiosa and assessment of the surface film are the test criteria.
The improved bone waxes now exhibit a low

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