EP2838576A1

EP2838576A1 - Composition, moulded article, thread, medical kit and medical product with improved degradation profile

Info

Publication number: EP2838576A1
Application number: EP13712581.1A
Authority: EP
Inventors: Sven Oberhoffner; Erhard Müller
Original assignee: ITV DENKENDORF PRODUKTSERVICE GmbH
Current assignee: ITV DENKENDORF PRODUKTSERVICE GmbH
Priority date: 2012-04-18
Filing date: 2013-03-28
Publication date: 2015-02-25
Also published as: DE102012206400A1; KR20150004380A; US20150100086A1; WO2013156293A1; US10124086B2

Abstract

The invention further relates to a moulded article comprising the composition, a thread comprising the composition, a medical kit comprising the composition, and a medicinal product comprising the composition.

Description

description

Composition, body, thread, medical kit and medical product with improved degradation profile

The invention relates to a composition comprising polydioxanone and / or a copolymer thereof, a shaped article comprising the composition, a thread comprising the composition, a medical kit comprising the composition and a medical product comprising the composition.

Polydioxanone (PDO) is a resorbable, synthetic polymer with numerous medical uses.

Compared with polyglycolide and polylactide, polydioxanone has the fundamental advantage of greater flexibility (lower flexural rigidity), which is why monofilament surgical suture materials are also manufactured and used.

In contrast to polyglycolide and its copolymers, polydioxanone additionally shows a slower hydrolytic degradation, which is of particular advantage in particular with indications with a delayed wound healing process.

Important determinants of the degradation behavior of polydioxanone are its morphology and crystallinity. It is known that the crystallinity and the crystallization rate of p-dioxanone-containing copolymers are reduced compared to the homopolymer ("Crystallization Study on Absorbable Poly (p. Dioxanone) Polymers by Differential Scanning Calormetry "; Andjelic et al .: Journal of Applied Polymer Science, Vol. 79, 742-759 (2001)).

Furthermore, it is known that hydrolytic degradation in polydioxanone proceeds approximately in two stages insofar as amorphous regions are subject to faster hydrolytic degradation than crystalline regions (Influence of in Vitro Hydrolytic Degradation on the Morphology and Crystallization Behavior of Poly (p. dioxanone) "; Sabino et al .: Biomacromolecules 2004, 5, 358-370)).

In addition, it is known that addition of inorganic materials such as calcium carbonate, β-tricalcium phosphate and calcium sulfate or boron nitride, talc or hydroxyapatite can contribute to accelerate the crystallization of PDO polymer ("poly (para-dioxanones) / inorganic particle composites as a Novel Biomaterial "; Bai et al .: Journal of Biomedical Materials Research Part B: Applied Biomaterials, 945-951 and" Heterogeneous Nucleation and Self-nucleation of poly (p-dioxanone); Sabino et al.: Journal of Materials Science 35 (2000) 5071-5084) Furthermore, US Pat. No. 4,444,927 discloses the use of sucrose or lactose as nucleating agent for use in a production process (injection molding) for moldings made of polydioxanone.

In medical technology, suture materials based on polydioxanone are used, which are dyed to improve their handling properties (visualization in the operating field) by means of a dye. Such sutures are, for example, under the names Mono Plus ^® (B.Braun Aesculap), PDS II ^® (Ethicon) or vetsu- ture PDX ^® (VETSUTURE) commercially available. In the case of PDS II, the dyed suture materials have a higher resistance to degradation than the undyed suture materials, which is also desirable depending on the indication. With regard to certain indications, such as, for example, in the field of cosmetic surgery, in particular in face-lifting, but also in the closure of cutaneous and subcutaneous wounds, it is more advantageous to use undyed suture materials since the use of dyed suture materials does not preclude a tattooing effect can be. However, there is also a need for sutures having a delayed degradation profile in the treatment of such indications. Even in patients with known allergy to the dye used, the choice of an undyed suture is indicated.

It is therefore an object of the present invention to provide a composition, a molded article, a thread, a medical kit and a medical product which avoid as far as possible known deficiencies of the prior art and in particular take into account the needs mentioned in the previous paragraph.

This object is achieved according to the invention by a composition having the features of independent claim 1. Preferred embodiments of the composition are the subject matter of dependent claims 2 to 12. Furthermore, the subject matter of the invention is a shaped body having the features of claim 13. A preferred embodiment of the shaped body is reproduced in claim 14. A further subject of the invention is a thread with the features of claim 15. A preferred embodiment of the thread is the subject of claim 16. Further subject matters relate to a medical kit with the features of claim 17 and a medical product having the features of claim 18. Eine preferred embodiment of the medical product is the subject of claim 19. The composition proposed according to the invention comprises polydioxanone (poly-para-dioxanone or PDO) and / or a copolymer thereof. In addition, the composition comprises at least one carboxylic acid salt.

For the purposes of the present invention, the term "copolymer" is to be understood as meaning a polymer which, besides para-dioxanone, is formed from at least one further monomer component According to the invention, the term "copolymer" may therefore include bipolymers, tripolymers, tetrapolymers, in particular with random or segmented distribution of the monomers, or the like.

For the purposes of the present invention, the term "at least one carboxylic acid salt" is to be understood as meaning a carboxylic acid salt or a plurality, that is, two or more different carboxylic acid salts.

The present invention is based on the following surprising findings: With particular advantage, the composition according to the invention is distinguished by a slowed-down or delayed, preferably hydrolysis-based degradation profile (degradation profile). This is presumably due to an increased formation of smaller crystals or smaller spherulites in the composition or the polymer (PDO and / or copolymer thereof), as a result of which a more homogeneous and overall accelerated crystallization takes place. Due to the higher number and the dimensionally smaller formation of the crystallites and spherulites, the aqueous degradation medium seems to be able to penetrate the composition only more slowly and spatially more limited, which slows down the degradation rate becomes. In that regard, the at least one carboxylic acid salt can also be understood as a nucleating agent.

Thus, the composition proposed according to the invention is also suitable as starting material for the production of shaped articles, in particular in the form of medical products such as surgical threads or sutures, guide rails, nets, stents and stent grafts or injection-molded articles such as staples, clips or vascular occlusion plugs, with a delayed degradation behavior.

For example, filaments prepared from the composition according to the invention, even after several weeks of storage in Sörensen buffer, showed Knot Pull Tensile Strength (KPTS) and Linear Tensile Strength (LTS), which were each significantly higher than for filaments which had no carboxylic acid salt, this difference being greater in undyed compared to colored threads.

The composition according to the invention is furthermore distinguished by good handling properties, in particular processing properties. Thus, for example, after extrusion and in particular further processing steps such as drawing, the composition has a residual monomer content and an inherent viscosity or molecular weight which are comparable to the residual monomer content and the inherent viscosity or molecular weight of not containing a carboxylic acid salt additized polydioxanone. In other words, no significant degradation of the polymer is induced by the at least one carboxylic acid salt during the processing of the composition, for example into a thread, with particular advantage. This is shown by For example, at the nozzle pressures during extrusion, which remained at the same level.

If the composition is extruded to form a shaped article, for example a thread, then a subsequent stretching, with particular advantage, does not lead to any thread breakage. On top of that, the stretching can be carried out without appreciable deviations in the draw ratios. In other words, the presence of the at least one carboxylic acid salt in the composition does not or does not significantly affect the mechanical integrity of products made from the composition, such as filaments, for example, and promotes processability. · If a thread is formed from the composition, then this is characterized with particular advantage by a smooth surface and an optimized under medical aspects Biegeschlaffheit. The smooth surface with a low coefficient of friction facilitates in particular the atraumatic pulling of the thread through the fabric.

The at least one carboxylic acid salt in a preferred embodiment is a metal salt, preferably alkali metal and / or alkaline earth metal salt, of a carboxylic acid.

The at least one carboxylic acid salt is preferably selected from the group consisting of barium salt of a carboxylic acid, magnesium salt of a carboxylic acid, calcium salt of a carboxylic acid, strontium salt of a carboxylic acid and mixtures thereof.

Preferably, the at least one carboxylic acid salt is a colorless or non-coloring carboxylic acid salt. In principle, however, a colored or coloring carboxylic acid salt may also be considered. The at least one carboxylic acid salt may further be the salt of an aliphatic and / or aromatic carboxylic acid.

In particular, the at least one carboxylic acid salt may be the salt of a saturated or unsaturated, in particular double and / or triple bond-containing, carboxylic acid. Furthermore, the at least one carboxylic acid salt may be the salt of a branched or unbranched carboxylic acid.

According to the invention, it may be preferred if the at least one carboxylic acid salt is the salt of an aliphatic, in particular saturated, and preferably unbranched carboxylic acid.

The at least one carboxylic acid salt may in further embodiments be selected from the group consisting of fatty acid salt, amino acid salt, oxalic acid salt, salicylic acid salt, benzoic acid salt, nicotinic acid salt, resin acid salt and mixtures thereof.

According to the invention, it is particularly preferred if the at least one carboxylic acid salt is a fatty acid salt, preferably a salt of a saturated and in particular unbranched fatty acid.

The fatty acid may in principle be a lower fatty acid, ie a fatty acid having 1 to 7 carbon atoms, middle fatty acid, ie a fatty acid having 8 to 12 carbon atoms, and / or a higher fatty acid, ie a fatty acid having more than 12 carbon atoms , In principle, the fatty acid salt can be selected from the group consisting of formic acid salt, acetic acid salt, propionic acid salt, butyric acid salt, isobutyric acid salt, valeric acid salt, isovaleric acid salt, capronic acid salt, oenanthic acid salt, caprylic acid salt, pelargonic acid salt, capric acid salt, undecanoic acid salt, lauric acid salt, tridecanoic acid salt, myristic acid salt, pentadecanoic acid salt , Palmitic acid salt, oleic acid salt, linoleic acid salt, linolenic acid salt, magaric acid salt, stearic acid salt, nonadecanoic acid salt, archic acid salt, acid salt, lignoceric acid salt, cerotic acid salt, and mixtures thereof.

Preferably, however, the at least one carboxylic acid salt is selected from the group consisting of lauric acid salt, myristic acid salt, palmitic acid salt, magaric acid salt, stearic acid salt, and mixtures thereof.

More preferably, the at least one carboxylic acid salt is an alkaline earth metal stearate, in particular selected from the group consisting of barium stearate, magnesium stearate, calcium steate, strontium stearate and mixtures thereof. Calcium stearate is preferred according to the invention.

The at least one carboxylic acid salt may have a content of 0.1 to 10% by weight, in particular 0.2 to 8% by weight, preferably 0.4 to 5% by weight, based on the total weight of the composition. A carboxylic acid salt content of from 0.4 to 5% by weight is suitable in particular for delaying or slowing down a degradation of the composition which is preferably based on hydrolysis. In order to suppress or reduce a matting effect, which may be due to the at least one carboxylic acid salt, and / or to increase the transparency of the composition, a Carboxylic acid content of 0.1 to 0.4 wt .-%, based on the total weight of the composition, be advantageous.

In a preferred embodiment, the at least one carboxylic acid salt is contained in the paradioxanone and / or the copolymer.

Particularly preferably, the polydioxanone and / or the copolymer thereof is provided with the at least one carboxylic acid salt, additized or compounded.

In an advantageous embodiment, the at least one carboxylic acid salt is distributed homogeneously or substantially homogeneously within the composition, in particular within the polydioxanone and / or the copolymer thereof. In other words, it is preferred that there are no significant local concentration differences and / or agglomerates with respect to the at least one carboxylic acid salt.

The copolymer may be a static copolymer, segmented copolymer or block copolymer.

Preferably, the copolymer is formed mainly from para-dioxanone. For example, the para-dioxanone may have a content of at least 55%, in particular from 60 to 98%, preferably from 70 to 95%, based on the total number of monomer units present in the copolymer.

In addition to para-dioxanone, the copolymer is preferably formed from at least one further monomer component, preferably a resorbable monomer component. The monomer component may be selected from the group consisting of glycolide, lactide, ε-caprolactone, trimethylene carbonate, hydroxybutyrate, in particular 3-hydroxybutyrate and / or 4-hydroxybutyrate, and combinations thereof. Furthermore, the copolymer may be formed in addition to para-dioxanone of ethylene glycol and / or diethylene glycol.

According to the invention, it can be provided, in particular, that the copolymer has polyethylene glycol units, in particular in the form of blocks.

The polydioxanone or copolymer thereof preferably forms the main constituent of the composition. The term "main constituent" is to be understood here as meaning a polydioxanone or copolymer fraction of at least 50% by weight, based on the total weight of the composition.

The polydioxanone or copolymer thereof, in a further embodiment, a proportion of 50 to 99.9 wt .-%, preferably 65 to 99.8 wt .-%, particularly preferably 80 to 99.8 wt .-%, based on the total weight of the composition.

The composition may further comprise additives. Suitable additives may be selected from the group consisting of fillers, in particular inorganic fillers, X-ray contrast agents, antimicrobially active compounds, polymers, chemical and / or physical blowing agents and mixtures of these additives. Examples of suitable fillers may be selected from the group consisting of calcium carbonate, .beta.-tricalcium phosphate, calcium sulfate, hydroxyapatite and mixtures thereof.

Examples of antimicrobial compounds may be selected from the group consisting of guanidines, especially polyhexamethylene biguanide (PHMB), metals or metal salts such as silver or silver salts, antibiotics and mixtures thereof. Chemical and / or physical blowing agents may generally be of interest for producing foam structures, for example, with regard to injection molding applications of the composition. Suitable physical blowing agents are, in particular, blowing gases such as, for example, nitrous oxide, carbon dioxide, oxygen, nitrogen or the like. Suitable chemical blowing agents are mixtures of carbonate and bicarbonate salts, preferably of alkali and alkaline earth metals, in particular in combination with citric acid and / or thereof Salts (passive chemical blowing agents), dar.

In particular, X-ray contrast agents such as, for example, barium sulfate are suitable as contrast agents.

In a supplementary or alternative embodiment, the composition has as an additive a resorbable or at least water-soluble homopolymer, copolymer or terpolymer which differs from polydioxanone (PDO) and preferably its copolymer. In this embodiment, the composition can be present in particular as a compatible or incompatible polymer blend (blend).

According to the invention it can further be provided that the composition in addition to the polydioxanone and / or copolymer thereof has no further polymers or is formed from no further polymer.

In a further embodiment, the composition consists of polydioxanone or a copolymer thereof and the at least one carboxylic acid salt and optionally one or more additives. With regard to suitable additives, reference is made to the additives described in the previous embodiments. In particular, the composition of any of the preceding Embodiments described material combinations or mixtures exist.

The composition can, in particular after a shaping step such as, for example, extrusion, and in particular after a subsequent aftertreatment such as, for example, a residual monomer content of 0.5 to 6%, in particular of at most 3%, preferably of at most 2%, especially preferably of not more than 1.2%.

Furthermore, the composition may have an inherent viscosity of from 0.7 to 2.2 dl / g, in particular from 1.0 to 2.0 dl / g, preferably from 1.2 to 1.8 dl / g. The viscosity values relate to the measurement of the viscosity of a hexafluoroisopropanol (HFIP) solution which contains the composition in a concentration of 0.5% by weight, at a temperature of 30 ° C. by means of an Oa viscometer.

A second aspect of the invention relates to a shaped article comprising a composition according to the present invention or consisting of such a composition. The shaped body may be a half-part, finished part or end product.

The shaped body may have anchoring structures on its surface for anchoring in human or animal tissue, in particular in the form of Barbs or barbs.The anchoring structures are preferably formed as incisions in the shaped body surface The incisions and / or punches (from which the anchoring structures are formed) are preferably made in the unstretched state of the shaped body, and subsequent stretching results in the anchoring structures being particularly advantageous and in particular exhibiting particular advantages The anchoring structures allow in particular the performance of wound closures and / or bone and / or organ fixations.

With regard to further features and advantages, in particular with regard to the composition, reference is made to the previous description in order to avoid unnecessary repetition.

A third aspect of the invention relates to a thread, in particular a medical thread, preferably surgical thread or a surgical suture. The suture comprises a composition according to the present invention or consists of such a composition.

According to the invention, it may in particular be provided that the yarn, in addition to the polydioxanone and / or copolymer thereof, has no further polymers or is formed from no further polymer.

The thread may be formed as monofilament, pseudomonofiler or multifilament, in particular braided, thread.

Furthermore, the thread may have anchoring structures on its surface for anchoring in human or animal tissue, in particular in the form of barbs or barbs, etc. The anchoring structures are preferably formed as incisions in the thread surface Alternatively, the anchoring structures can also be formed by punching.The incisions and / or punches (from which the anchoring structures form) are preferably made in the unstretched state of the thread The anchoring structures allow, in particular, the performance of wound closures and / or bone and / or organ fixations. "Hiding (stretching)" is generally understood in textile technology as a process step in the production of man-made fibers, in which the polymer chains present in the spun yarn are generally disordered and knit-shaped, generally with an increase in crystallization, by stretching the unstretched spun yarn over a plurality of fibers In addition, elements of the drafting system may be heatable to heat the wire over its glass transition point and to draw it in that condition. When drawn, a diameter decrease usually takes place approximately by the factor of root of the draw ratio The strength of the drawn thread is usually several times higher and its elongation at break is usually many times lower than that of the spun thread The drawing can be done in one or in m more stages. At the end you can either fix or relax.

Furthermore, the thread may have a circular or non-circular, for example oval or polygonal, cross-section.

In principle, the thread may have a thread thickness which is selected from the group consisting of USP 1 1 -0 (0.010-0.019 mm), USP 10-0 (0.020-0.029 mm), USP 9-0 (0.030-0.039 mm), USP 8-0 (0.040-0.049 mm), USP 7-0 (0.050-0.069 mm), USP 6-0 (0.070-0.099 mm), USP 5-0 (0.100-0, 149 mm), USP 4-0 (0.150-0, 199 mm), USP 3-0 (0.200-0.249 mm), USP 2-0 (0.300-0.339 mm), USP 0 (0.350-0.399 mm), USP 1 (0.400-0.499 mm), USP 2 (0.500-0.599 mm), USP 3/4 (0.600-0.699 mm) and USP 5 (0.700-0.799 mm). (Table for Synthetic Absorbable Sutures of USP 35)

Preferably, the thread has a thread thickness between USP 6-0 and USP 2. The thread may have a core-shell structure in another embodiment. The composition may be contained in the core and / or sheath, or the core and / or sheath may consist of the composition.

According to the invention, however, it is preferred if the composition is contained only in the sheath or only the sheath of the thread consists of the composition. In this way, the mechanical integrity of the thread core remains completely untouched.

In an alternative embodiment, the thread has an "islands-in-the-sea" structure, with the "sea" regions of the thread preferably containing or consisting of the composition. With regard to further features and advantages of the thread, in particular with regard to the composition, the polydioxanone and / or copolymer thereof, the at least one carboxylic acid salt and / or any additives, reference is likewise made in full to the previous description.

The invention also relates to a medical, in particular surgical, set comprising at least one, in particular one, needle and at least one, in particular, thread according to the present invention.

With regard to further features and advantages of the set, in particular with regard to the thread and / or the composition, reference is likewise made in full to the previous description. Finally, the invention relates to a medical product comprising or consisting of a composition according to the present invention. Alternatively, the product may comprise at least one thread, in particular a plurality of threads (ie, two or more threads) according to the present invention, or consist of at least one such thread or a plurality of such threads. The medical product is preferably a surgical implant.

Furthermore, the medical product is preferably a textile implant, in particular a two-dimensional or three-dimensional textile implant.

In a further embodiment, the medical product can be designed as a flat structure, in particular a textile fabric, or as a hollow body replacement structure, in particular a textile hollow body replacement structure. The hollow body replacement structure is furthermore preferably tubular, tubular or cylindrical.

In a further embodiment, the medical product has a textile structure, which is preferably selected from the group consisting of woven, knitted fabric, in particular warp knit, braid, knitted fabric and combinations thereof.

Alternatively, the medical product may have a non-woven structure which is preferably selected from the group consisting of spunbonded nonwoven, spunbond nonwoven, nonwoven spunbond, meltblown nonwoven, electroformed nonwoven, or spunbond nonwoven.

The medical product may also have a non-textile structure and be formed, for example, as a film, membrane, in particular capillary membrane, hose or the like.

The medical product can furthermore be designed as a network, preferably a medical network, particularly preferably a surgical network. For example, the medical product may be selected from the group consisting of hernia mesh, prolapse mesh and incontinence mesh. Furthermore, it may be preferred if the medical product is designed as a prosthesis, in particular an endoprosthesis such as, for example, a vascular prosthesis, stent or stent-graft.

Furthermore, the medical product can be a surgical staple, a surgical clip, a surgical anchor, in particular a bone anchor, or a vascular occlusion plug.

With regard to further features and advantages, in particular with regard to the composition and / or the at least one thread, reference is likewise made in full to the preceding description.

Further features and advantages of the invention will be explained with reference to the following embodiments in the form of examples. In each case, individual features can be realized on their own or in combination with each other.

Example Part The monofilaments listed in the Examples section are in most cases sorted over the diameter compared to the USP classes, such as the industrial standard.

example 1

Preparation of a Non-Additized D & C Violet 2 Colored Monofilament of the Strength USP 3-0 (Comparative Example 1) A PDO homopolymer having an inherent viscosity of 1.67 dl / g and a dye content of 0.091 wt.% Was used. The monomer content (NMR 300 MHz from Bruker, CDCI ₃ ) before drying was 1.6 mol%. The polymer was dried for 18 h at a temperature of 80 ° C in a vacuum oven at 3 mbar and then transferred under a nitrogen atmosphere in a granular bottle. This was attached via an adapter to the feed zone of a single-screw extruder with two heating zones. To the extruder, a spinning head with a spinning pump 4 x 0.25 ccm / U, provided with a 4 on 2 adapter, flanged. The spinnerets used had a diameter of 1.0 mm with L / D = 4. After leaving the spinneret, the extruded strand first passed through an air gap of 3-5 cm and then a cooling bath (T = 20 °). After being pulled over a gala duo, the spun yarn was wound up.

The extrusion parameters were as follows:

Temperature extruder zone 1: 140 ° C

Temperature extruder Zone 2: 160 ° C

Temperature spinner: 180 ° C

Spinning pump: 5.5 rpm

Withdrawal speed: 7.0 m / min The spun yarn had a diameter of 0.686 mm and a monomer content of 1.8%. The die pressure in the extrusion was 63 bar and the inherent viscosity of the spun yarn was 1.54 dl / g.

The stretching was carried out on a line consisting of delivery blanket, drawing furnace 1, septet 1, drawing furnace 2, septet 2 and winder. At a feed rate of 5 m / min, the temperature of the first drafting oven was 80 ° C and that of the second drafting oven was 95 ° C, the main draw ratio in stage 1 was 5.3 and the total draw ratio was 5.6. The draw point (neck-point) was stable on the Liefergalette and there were no thread breaks. The diameter of the drawn yarn 1 -1 was 0.297 mm ± 0.003 mm and the yarn surface was absolutely smooth. After a post-treatment step for fixation and demonomerization, the monomer content was 0.6 mol%. The mechanical properties of the monofilament are shown in Table 1.

Example 2:

Preparation of a non-additized, undyed monofilament of

Starch USP 3-0 (Comparative Example 2)

The extrusion of the undyed PDO polymer having a viscosity of 1.65 dl / g and a monomer content of 1.8 mol% was carried out analogously to Example 1.

The spun yarn had a diameter of 0.684 mm and a monomer content of 2.0%. The die pressure in the extrusion was 61 bar and the inherent viscosity of the spun yarn was 1.52 dl / g. The stretching was started with the parameters from Example 1. It was found that the draw point from the delivery galette wandered all the way into the drafting furnace 1, but from time to time also looked out of the furnace again, which is an indication of a thread tension that is not constant over time. The surface of the monofilament 2-1 thus obtained had rough spots, and diameter irregularities were clearly felt. The diameter was 0.296 mm ± 0.01 1 mm. A thread break did not occur under these settings. In order to minimize the diameter variations, eliminate the rough spots and locate the draw point on the delivery godet, the main draw ratio in Stage 1 had to be increased to 5.9 and the total draw ratio to 6.6. The diameter of the monofilament 2-2 was 0.277 mm ± 0.005 mm. Increasing the draw ratio increased the ovality of the monofilament from 0.003 mm to 0.021 mm. Already after three minutes running time, it came to the first thread break. After re-application, this was repeated at intervals of 2 - 10 minutes. A reduction in the draw ratio did not improve this situation as long as the draw point was kept on the delivery roll. Upon further reduction to the draw ratios of Example 1, the draw point again began to migrate to form rough spots and diameter variations.

After a post-treatment step for fixation and demonomerization, the monomer content was 0.5 mol%. The mechanical properties of monofilaments 2-1 and 2-2 are shown in Table 1.

Example 3:

Preparation of colored with 0.07 wt .-% calcium stearate additivierten

Monofilaments of strength USP 3-0

The calcium stearate CPR-2-V from Greven (Germany) and the PDO polymer from Example 1 were used. The additive (0.7 g) was added to 1000 g of polymer and then distributed as homogeneously as possible with shaking and tumbling , Subsequently, as described in Example 1 dried and extruded.

The spun yarn had a diameter of 0.684 mm and a monomer content of 1.8%. The die pressure in the extrusion was 61 bar and the inherent viscosity of the filament was 1.52 dl / g. This shows that no degradation of the polymer took place in the extruder due to the additive. Drawing and aftertreatment were carried out under the conditions of Example 1. There were no yarn breaks and the draw point was stable on the feed roll. The diameter of the drawn yarn 3-1 was 0.296 mm ± 0.004 mm. The thread surface was absolutely smooth and felt in comparison to Example 1 a little softer, which may be due to reduced surface friction by the addition of fatty acid salt. After a post-treatment step for fixation and demonomerization, the monomer content was 0.5 mol%. The mechanical properties of monofilament 3-1 are shown in Table 1. Example 4

Preparation of 0.40% by weight calcium stearate additized USP 3-0 dyed monofilament The monofilament preparation and use of the materials required therefor corresponded to Example 3, but using 4.0 g of calcium stearate based on 1000 g PDO polymer.

The spun yarn had a diameter of 0.684 mm and a monomer content of 1.7%. The die pressure in the extrusion was 62 bar and the inherent viscosity of the spun yarn was 1.50 dl / g. This shows that even by the higher concentration of additive no increased degradation of the polymer took place in the extruder. Drawing and aftertreatment were carried out under the conditions of Example 1. There were no yarn breaks and the draw point was stable on the feed roll. The diameter of the drawn yarn 3-1 was 0.296 mm ± 0.003 mm. The thread surface was absolute Lut smoothed and felt softer compared to Example 1, probably due to reduced surface friction due to the addition of fatty acid salt. After a post-treatment step for fixation and demonomerization, the monomer content was 0.6 mol%. The mechanical properties of monofilament 4-1 are shown in Table 1.

Example 5:

Preparation of 0.07 wt .-% calcium stearate additivated, undiluted monofilament of the strength USP 3-0

1000 g of the unstained polymer from Example 2 were mixed with 0.7 g of calcium stearate as described in Example 3 and extruded. The spun yarn had a diameter of 0.685 mm and a monomer content of 1.8%. The die pressure in the extrusion was 59 bar and the inherent viscosity of the spun yarn was 1.50 dl / g.

Surprisingly, in comparison to the non-additized, uncolored PDO from Example 2, it was found that the draw point under the standard drawing conditions of Example 1 was constant on the delivery roller, so that an increase in the draw ratio was not necessary. Also, in contrast to Example 2-1, no rough spots and diameter variations occurred and, in contrast to Example 2-2, no thread breaks and no appreciable ovality. Experimentally, the draw ratio in stage 1 was lowered from 5.3 to 5. 1. Thanks to the addition of calcium stearate, however, the draw point remained stable on the delivery roll. The diameter of the drawn yarn 5-1 was 0.295 mm ± 0.004 mm. The thread surface was absolutely smooth and felt somewhat softer compared to Example 2, probably due to reduced surface friction due to the addition of fatty acid salt. After a post-treatment step for fixation and demonomerization, the monomer content was 0.5 mol%. The mechanical properties of the monofilament 5-1 are shown in Table 1. Example 6

Preparation of 0.40% by weight of calcium stearate additized USP 3-0 undyed monofilament The preparation of the monofilament and the use of the requisite materials corresponded to Example 5 but using 4.0 g of calcium stearate based on 1000 g PDO polymer.

The spun yarn had a diameter of 0.684 mm and a monomer content of 1.9%. The die pressure in the extrusion was 58 bar and the inherent viscosity of the spun yarn was 1.48 dl / g.

As in Example 5, it was also surprising here that the draw point under the standard drawing conditions of Example 1 was constant on the delivery roll, so that an increase in the draw ratio was not necessary. Also, in contrast to Example 2-1, no rough spots and diameter variations occurred and, in contrast to Example 2-2, no thread breaks and no appreciable ovality. As an experiment, the draw ratio in stage 1 was also reduced from 5.3 to 5.0 here. Thanks to the increased addition of calcium stearate, however, the draw point remained stable on the delivery roll.

The diameter of the drawn yarn 6-1 was 0.295 mm ± 0.003 mm. The thread surface was absolutely smooth and felt softer compared to Example 2, probably due to reduced surface friction due to the increased addition of fatty acid salt. After a post-treatment step for fixation and demonomerization The monomer content was 0.6 mol%. The mechanical properties of monofilament 6-1 are shown in Table 1.

Example 7:

Preparation of an uncolored monofilament of the strength USP 3-0, which was additized with 1.00% by weight of calcium stearate

The preparation of the monofilament and the use of the materials required for this corresponded to Example 5, but using 10.0 g of calcium stearate based on 1000 g of PDO polymer.

The spun yarn had a diameter of 0.685 mm and a monomer content of 1.7%. The die pressure in the extrusion was 63 bar and the inherent viscosity of the spun yarn was 1.52 dl / g.

As in Example 5, it was also surprising here that the draw point under the standard drawing conditions of Example 1 was constant on the supply roll, so that an increase in the draw ratio was not necessary. Also, in contrast to Example 2-1, no rough spots and diameter variations occurred and, in contrast to Example 2-2, no thread breaks and no appreciable ovality. As an experiment, the draw ratio in stage 1 was also reduced from 5.3 to 5.0 here. Thanks to the increased addition of calcium stearate, however, the draw point remained stable on the delivery roll. There was also a tentative increase in the main draw ratio from 5.3 to 5.9 without yarn breakage, but with an increase in ovality. The diameter of the drawn yarn 7-1 was 0.294 mm ± 0.003 mm. The thread surface was absolutely smooth and felt much softer compared to Example 2, which was probably due to reduced surface friction or reduced bending strength. is due to the increased addition of fatty acid salt. After a post-treatment step for fixation and demonomerization, the monomer content was 0.5 mol%. The mechanical properties of monofilament 7-1 are shown in Table 1.

Tab. 1: Mechanical properties of the PDO monofilaments USP 3-0 (v) = violet (u) = undyed KPTS = knot breaking strength LTS = linear tearing force.

Example 1 -1 essentially corresponds to commercially available, violet colored surgical suture materials such as the PDS II ^® (Ethicon) or mono Plus ^® (B.Braun Aesculap) As Table 1 shows, the mechanical properties of undyed monofilaments without additive compared to violet Industrial Standard 1 -1 (v) unsatisfactory. Add to this the poor stretchability of 2-2 (u) and the frequent occurrence of thread breaks. This problem could be surprisingly solved by the addition of calcium stearate, whereby an increase in the knot-pull breaking strength compared to the industrial standard could also be achieved with violet polymer. The most significant improvements occurred with undyed monofilaments with an increasing content of additive, which thus also meets the strength requirements of EP and USP. Example 8:

In vitro degradation tests on the monofilaments of the examples

1 - 7:

Degradation means loss of mechanical strength in connection with resorbable materials. To measure the degradation profile, a buffer solution consisting of potassium dibutyl phosphate (13.14 mmol / l) and disodium hydrogen phosphate (53.5 mmol / l) with pH = 7.4 was used. The previously cut to length monofilaments (n = 7) were stored for 4 weeks in this buffer solution at 37 ° C. Subsequently, their mechanical strength was again determined as retention (percentage retention) of the original breaking forces.

The measured values are shown in Table 2:

Tab.2: Results of the degradation test: 4 weeks at pH 7.4 and 37 ° C

The results from the degradation test show that, even with violet material, starting from a high retention level, the degradation rate increases with the addition of small concentrations Calcium stearate reduced and thus the degradation behavior can be delayed.

This effect is particularly pronounced with undyed material: Whereas the uncolored monofil without additive had almost no strength after 4 weeks and was extremely brittle, the degradation behavior between 0.07 and 1.00 wt.% Of calcium stearate could even be increased with increasing proportion of additive Be increased beyond the violet industrial standard.

Example 9:

Determination of the flexural modulus of the monofilaments from the examples

1 - 7:

The flexural modulus of the monofilaments was determined on a flexural strength tester from Franckh (Germany) under standard conditions with a clamping length of 5 mm and a bending angle of 30 °. The flexural modulus was calculated from the bending stiffness by means of the moment of inertia of cylindrical bodies. The results are shown in Table 3:

Tab. 3: Flexural modulus of the PDO monofilaments USP 3-0 Here, too, it can be seen that as the calcium stearate content increases, the flexural modulus of both the violet and uncolored monofilaments decreases, which is an important criterion for monofilament sutures, since this improves the handling properties of the knot and, in most cases, also increases knot security. In addition, a weaker memory effect on removal of the suture material from the packaging is to be expected.

Example 10:

Preparation of an undyed monofilament of starch USP 2, which was additized with 1.00% by weight of calcium stearate

A PDO homopolymer with an inherent viscosity of 1.18 dl / g and a monomer content of 1.6 mol% was used. The polymer was dried for 20 h at a temperature of 80 ° C in a vacuum oven at 3 mbar and then transferred under nitrogen atmosphere in a granular bottle. This was attached via an adapter to the feed zone of a single-screw extruder with two heating zones. To the extruder, a spinning head with a spinning pump 4 x 0.25 ccm / U, provided with a 4 on 2 adapter, flanged. The spinnerets used had a diameter of 2.0 mm with L / D = 4. After leaving the spinneret, the extruded strand first passed through an air gap of 3 cm and then a cooling bath (T = 20 °). After the deduction of a pair of godfathers the spun yarn was wound up.

The extrusion parameters are as follows:

Temperature extruder zone 1: 130 ° C

Temperature extruder Zone 2: 160 ° C

Temperature spinner: 180 ° C Spinning pump: 15.8 rpm

Withdrawal speed: 5.0 m / min

The spun yarn had a diameter of 1. 316 mm and a monomer content of 1.2%. The nozzle pressure during the extrusion was 75 bar.

The stretching was carried out on a line consisting of delivery blanket, stretching furnace 1, septet 1, drawing furnace 2, septet 2 and winder.

At a feed rate of 5 m / min, the temperature of the first draw furnace was 95 ° C and that of the second draw furnace 1 15 ° C, the main draw ratio in stage 1 was 5.3, as well as the total draw ratio, since in the 2nd stage only was fixed. The draw point (neck-point) was stable on the Liefergalette and there were no thread breaks. The diameter of the drawn yarn 8-1 was 0.595 mm ± 0.005 mm and the yarn surface was absolutely smooth. After a post-treatment step for further fixation and demonomerization, the monomer content was 0.5 mol%. The mechanical properties and the retention of the knot-pull breaking strength after 4 weeks of degradation in the phosphate buffer at pH 7.4 at 37 ° C. of the monofilament are shown in Table 4.

Example 1 1:

Preparation of 0.40% by weight of calcium stearate additized unscented monofilament USP 5-0

A PDO homopolymer having an inherent viscosity of 1.18 dl / g and a monomer content of 1.6 mol% was used. The polymer was vacuum dried for 20 hours at a temperature of 80 ° C dried cabinet at 3 mbar and then transferred under a nitrogen atmosphere in a granular bottle. This was attached via an adapter to the feed zone of a single-screw extruder with two heating zones. A spinning head with a spinning pump 4 x 0.25 ccm / U was flanged to the extruder. The extrusion was carried out in four digits. The spinnerets used had a diameter of 0.5 mm with L / D = 4. After leaving the spinneret, the extruded strands first passed through an air gap of 8 cm and then a cooling bath (T = 20 °). After the withdrawal via a pair of goddesses, the spun threads were wound up.

The extrusion parameters were as follows:

Temperature extruder zone 1: 140 ° C

Temperature extruder Zone 2: 160 ° C

Temperature spinner: 180 ° C

Spinning pump: 5.5 rpm

Withdrawal speed: 10.0 m / min

The spun yarn had a diameter of 0.390 mm and a monomer content of 1.6%. The nozzle pressure during the extrusion was 73 bar.

The stretching was carried out on a line consisting of delivery blanket, drawing furnace 1, septet 1, drawing furnace 2, septet 2 and winder.

At a feed rate of 10 m / min, the temperature of the first drafting oven was 70 ° C and that of the second drafting oven was 80 ° C, the main draw ratio in stage 1 was 5.2, the total draw ratio was 5.3. The draw point (neck-point) was stable on the delivery godet and there was only one thread break at a total production of about 15,000 m. The diameter of the stretched Thread 9-1 was 0.172 mm ± 0.003 mm and the thread surface was absolutely smooth. After a post-treatment step for further fixation and demonomerization, the monomer content was 0.6 mol%. The mechanical properties and the retention of the knot-pull breaking strength after 4 weeks of degradation in the phosphate buffer at pH 7.4 at 37 ° C. of the monofilament are shown in Table 4.

Tab. 4: Properties of undyed PDO monofilaments USP 2 and USP 5-0

Table 4 shows that the addition of carboxylic acid salts is feasible even with small and large USP starches and leads there as well to the excellent results, as they were surprisingly found at the average strength USP 3-0 (Examples 1-7). It should be noted that in monofilaments, both the knot breaking strength and the linear breaking strength, both related to the cross-sectional area of the monofilament, decrease with increasing diameter. Example 8-1, an undyed PDO monofilament of starch USP 2 additized with carboxylic acid salt, is somewhat above the violet, industrial standard in terms of strength and retention after a 4-week degradation.

Example 12:

Preparation of an unstained, non-additized PDO barb suture of the strength USP 3-0 by means of incision in the unstretched state with subsequent drawing (comparative example 3) Barbed sutures have the advantage of saving time during surgery and a uniform tension pattern in the wound, which minimizes scarring and necrosis compared to traditional (single or continuous suture) sutures.

To prepare a barb thread, the extruded, unstretched strand from Example 2 was cut to a length of 30 cm. Subsequently, the strand was provided by means of a prototype cutting machine testweise with 50 cuts at a distance of 0.25 mm in the middle part of the strand, wherein the intersection angle to the thread surface was 25 ° and the depth of cut in relation to the diameter of the strand was 30%. The cuts were arranged offset by 120 ° to each other. Subsequently, it was planned to stretch the strand in a heated oven at 80 ° C discontinuously to a Gesamtverstreckverhältnis of 3.5 to 4.3, which barbs should form and straighten up. While this was possible with the violet comparative material of Example 1 without any problems and without thread breakage, 8 of 10 samples broke during drawing. It was only by further reducing the draw ratio to 2.8 that no yarn breakage occurred in 10 out of 10 samples, but the cross-sectional strength was reduced by 45% over that of Example 1, which is unacceptable. Example 13:

Preparation of an unstained, 0.4% calcium stearate addtivated USP 3-0 PDO barb suture by incising in the unstretched state and then drawing

To prepare a barb thread, the extruded, unstretched strand of Example 6 was cut to 30 cm in length. Subsequently, the strand was tested using a prototype cutting machine. wise provided with 50 cuts at a distance of 0.25 mm in the middle part of the strand, wherein the intersection angle to the thread surface was 25 ° and the depth of cut in relation to the diameter of the strand was 30%. The cuts were arranged offset by 120 ° to each other. In contrast to Example 10, the strand provided with the cuts could be stretched discontinuously in a heated oven at 80 ° C. without the occurrence of yarn breakage to a draw ratio of 3.5 to 4.3. The linear strength achieved was 5% above that of a yarn formed from the violet strand of Example 1.

Example 14:

Production of injection molded molded articles from undyed PDO without and with 1, 0% addition of calcium stearate.

On an injection molding machine of the type Arburg Allrounder, 20 cm long rods with a diameter of 1.0 mm as well as thin platelets in the dimensions with a side length a = 1 cm and a side length b = were used by means of a special mold for the production of test specimens 10 cm and a thickness d = 1 mm. For this purpose, the cylinder was heated to 175 ° C and the mold to 40 ° C (maximum of the crystallization rate). The time from injection of the melt into the mold until ejection or removal of the moldings was initially reduced at intervals of 10 seconds, starting at 150 s, until the molding could no longer be ejected or removed in a regular manner or the molding was still so little dimensionally stable that he thereby deformed permanently. This time was 70 s for the non-additized PDO, while only 30 s was required for the likewise undyed polymer additized with 1.0% carboxylic acid. Example 15:

Production of Surgical Moldings With Anchoring Structures From The Moldings Without And With Addition Of Carboxylic Acid Salt

Into the 1 .0 mm diameter rods of Example 14, incisions were made as described in Example 13 by means of the prototype cutting machine. Both chopsticks without and with 1, 0 wt .-% addition of carboxylic acid salt were used. The incised rods were stretched as described in Example 13. An alternative stretching method was to clamp the ends of the sliced rods into the clamps of a tensile tester and to heat the area between the clamps with hot air to 80 ° C and after a tempering time of 15 seconds move the clamps apart so that a draw ratio of 3.75 results. In both drawing methods, the breakage rate for the non-additized moldings was at least 75%, while the 1, 0% additized moldings did not break during the drawing. When stretched without breakage, the anchoring structures formed during stretching and posed.

The shaped bodies having anchoring structures produced in this way can, for example, be used as resorbable, self-fixing bone pins, as suture anchors, as self-fixing closure plugs for vessels, but also as surgical suture material, without restricting the possibilities of use.

In the platelets were punched over the entire thickness of the platelets at least in the middle of the platelets at a distance of 8 mm by means of a small punch (shape of an open arrowhead) with side length a = 3 mm and a tip angle of 75 °. For every second plate, additional punching holes were also made on the side edge of the plate, so that here already formed anchoring structures directly. Both platelets without and with 1, 0 wt .-% addition of carboxylic acid salt were used. The thus punched platelets were stretched as described in Example 13. An alternative stretching method was to clamp the ends of the serrated plates into the clamps of a tensile tester and heat the area between the clamps to 80 ° C with hot air and, after a 15 second soaking time, pull the clamps apart so that a Draw ratio of 3.75 results. In both drawing methods, the breakage rate for the non-additized moldings without lateral punching was 60% and with lateral punching 90%, while the 1, 0% additized shaped bodies did not break during the drawing.

For non-fracture draws, the planar anchoring structures formed and positioned in the center of the plate, with one part on the back and another part of the planar anchoring structures on the front of the platelets. The lateral, likewise punched out anchoring structures were given an additional shape by the stretching.

The flat shaped bodies with anchoring structures produced in this way can, without restricting their use, serve, for example, to fix organs or bones according to the principle of a cable tie. Furthermore, for example, they can serve for lifting in cosmetic surgery by having either bidirectional anchoring structures or unidirectional anchoring structures with a stopper or a loop on a side opposite to the needle or the insertion tip and introduced linearly into the tissue. Quite generally, the anchorage mentioned in the example section can be used. Barb structures in addition to the process of punching by mechanical cutting, for example by means of blades, by laser cutting, by thermal cutting, for example by means of a heated over the melting point of the polymer wire, or produced by injection molding. The same applies to the anchoring structures mentioned in the general part of the description.

Summary

The experimental results described above show the following: The monomer content and the molecular weight (indicator: nozzle pressure extrusion) of the extrudates were in the normal range. Thus, the added calcium stearate did not cause any appreciable degradation of the PDO polymer during extrusion. · In contrast to undyed PDO polymer, which was not additized with carboxylic acid salt, the orientation could be carried out analogously to violet-colored PDO polymer virtually without yarn breakage and without any significant deviation in the process parameters.

• The neckpoint (drawing point) was stable on the delivery galette during the stretching tests on the monofilaments, despite the variation in the draw ratios in the case of additivation with carboxylic acid salt.

The quality of the thread surface was rated as good to very good. The addition of calcium stearate reduced bending stiffness by up to 17%. The original tear forces, in particular the knot-pull breaking strength which is important for surgical sutures, could be increased by the addition of the carboxylic acid salt with respect to the violet industrial standard and markedly increased compared to non-dyed, non-additized polymer. At the same time, the flexural modulus could be reduced.

The retention of the knot and linear tensile strength of monofilaments from the compositions according to the invention could be significantly increased in comparison to uncoloured PDO monofilaments without the addition of carboxylic acid salts.

By adding 0.4 and more weight percent of calcium stearate to the undyed PDO, retention of knot and linear tear strength in the degradation test could be achieved after 4 weeks of degradation, at 52% - 77% at least close to or even above that of the violet industrial Standards were. On the other hand, undyed PDO monofilaments without calcium stearate showed only retentions between 10 and 15%.

In contrast to violet-colored PDO, no unwanted traces of the additive could be found on disposable surgical gloves after pulling through the undyed filaments of the invention additivated with carboxylic acid salt, while the violet suture left a strong color trace. A tattoo effect can thus be excluded.

In the production of moldings by injection molding, the cycle time could be significantly reduced by adding calcium stearate to undyed PDO. The necessary Tied period between injection of the melt and ejection of the molding from the mold could be more than halved. Shaped bodies and threads made of undyed PDO polymer with anchoring structures, in particular when the incisions and / or punches were made in the unstretched state and subsequently drawn, can be produced only after the addition of carboxylic acid salt in sufficient strength and without thread breaking during drawing.

Claims

claims

A composition comprising polydioxanone and / or a copolymer thereof and at least one carboxylic acid salt.

2. Composition according to claim 1, characterized in that it is the at least one carboxylic acid salt is a metal salt, preferably alkali and / or alkaline earth metal salt, a carboxylic acid.

3. A composition according to claim 1 or 2, characterized in that the at least one carboxylic acid salt is selected from the group consisting of barium salt of a carboxylic acid, magnesium salt of a carboxylic acid, calcium salt of a carboxylic acid, strontium salt of a carboxylic acid and mixtures thereof.

4. Composition according to one of the preceding claims, characterized in that the at least one carboxylic acid salt is selected from the group consisting of fatty acid salt, amino acid salt, oxalic acid salt, salicylic acid salt, benzoic acid salt, nicotinic acid salt, resin acid salt and mixtures thereof. 5. Composition according to one of the preceding claims, characterized in that the at least one carboxylic acid salt is a fatty acid salt, preferably a salt of a saturated and in particular unbranched fatty acid. 6. Composition according to one of the preceding claims, characterized in that the at least one carboxylic acid salt is selected from the group consisting of lauric acid. resalt, myristic acid salt, palmitic acid salt, margarine acid salt, stearic acid salt and mixtures thereof.

Composition according to any one of the preceding claims, characterized in that the at least one carboxylic acid salt is an alkaline earth metal stearate, preferably calcium stearate.

Composition according to one of the preceding claims, characterized in that the at least one carboxylic acid salt is a proportion of 0.1 to 10 wt .-%, in particular 0.2 to 8 wt .-%, preferably 0.4 to 5 wt .-%, based on the total weight of the composition.

Composition according to one of the preceding claims, characterized in that the at least one carboxylic acid salt is homogeneously or substantially homogeneously distributed within the composition, in particular within Polydioxanon or the copolymer.

Composition according to any one of the preceding claims, characterized in that the copolymer is a random copolymer, segmented copolymer or block copolymer.

Composition according to one of the preceding claims, characterized in that the copolymer in addition to para-dioxanone from at least one other monomer component, in particular resorbable monomer component, preferably selected from the group consisting of glycolide, lactide, ε-prolacton, trimethylenecarbonate, hydroxybutyrate and Combinations thereof, is formed.

12. The composition according to any one of the preceding claims, characterized in that the copolymer is formed in addition to para-di-oxanone of ethylene glycol, wherein the copolymer preferably comprises blocks of polyethylene glycol.

13. A molded article comprising a composition according to any one of the preceding claims.

14. Shaped body according to claim 13, characterized in that on the shaped body anchoring structures are formed, which allow anchoring in human or animal tissue, wherein the anchoring structures are preferably formed by incisions and / or punches in the unstretched state of the shaped body and preferably by a follow - Formed stretching of the molding are formed and placed.

15. Thread, in particular medical thread, preferably surgical thread, comprising a composition according to one of claims 1 to 12.

16. A thread according to claim 15, characterized in that on the thread anchoring structures are formed, which allow anchoring in human or animal tissue, wherein the anchoring structures are preferably formed by cuts and / or punches in the unstretched state of the thread, and preferably by a subsequent Drawing of the thread are formed and set up.

Medical, in particular surgical, set comprising at least one needle and at least one thread according to claim 15 or 16.

18. A medical product, preferably a surgical implant, comprising a composition according to any one of claims 1 to 12 or at least one thread according to claim 15 or 16. 19. Medicinal product according to claim 18, characterized in that the medical product is a textile construct, preferably selected from the group consisting of woven, knitted, knitted, braided, nonwoven and combinations thereof.