Patent GB-1123445-A (GB)
Title: Synthetic lactide copolymer ribbons and filaments
IPC: D01F6/62
Filed: 1966-04-19
Abstract: Oriented filaments or ribbons suitable for use as or in surgical sutures are made from a lactide copolymer containing 85 to 98.5% of repeating units of a single antipodal species of alphahydroxy propionic acid and 1.5% to 15% of repeating units of the formula: <FORM:1123445/C3/1> where R is lower alkylene, m is 0 or 1, R1 is a hydrogen atom or a lower alkyl group, and R11, which can be the same as or dirferent from R1, is a hydrogen atom or an alkyl group of up to 22 carbons when m is 0 and, when m is 1, R11 is a hydrogen atom or a lower alkyl group, lower herein meaning having up to 6 carbon atoms, and the repeating units of the said formula including at least one which is different from the said antipodal species, said copolymer before being oriented having an inherent viscosity of at least 1.0 at 0.1% concentration in benzene at 25 DEG  C. and said filament losing at least water for a period of 100 hours.  The copolymer may contain up to 12% of repeating units derived from glycolide.  A preferred copolymer is a poly-L(-)-lactide copolymer containing up to 15% of repeating units derived from DL-lactide, or alternatively a 95/5 copolymer of L(-)-lactide and DL-lactide.  Minor proportions of inert colouring agents and plasticizers may be present, especially glyceryl triacetate, ethyl benzoate and diethylphthalate. Comonomers which can be employed with the lactide providing the single antipodal species referred to above to form copolymers useful in preparing the filaments include glycolide, beta-propiolactone, tetramethylglycolide, beta - butyrolactone, gamma-butyrolactone, pivalolactone, and intermolecular cyclic esters of alpha-hydroxybutyric acid, alpha - hydroxyisobutyric acid, alpha - hydroxyvaleric acid, alphahydroxyisovaleric -acid, alpha-hydroxycaproic acid, alpha - hydroxy - alphaetylbutric acid, alpha - hydroxyisocaproic acid, alpha - hydroxy - beta - methylvaleric -acid, alpha - hydroxyheptanoic -acid, alpha-hydroxyoctanoic acid, alpha - hydroxydecanoic acid, alphahydroxy myristic acid, alpha-hydroxy stearic acid, and alpha-hydroxy lignoceric acid.  In preparing the copolymers, the appropriate intermolecular cyclic ester or intramolecular cyclic ester (lactone) of the hydroxy acid is employed These can be derived rom pure D(-)- or L(+)-lactic lactic acids, the optically inactive DL-lactic acid mixture, mixtures of pure D(-)- and L(+)-lactic acids, and other alpha, beta or gamma-hydroxy acids. In making copolymers, the repeating units derived from the comonomers listed above are introduced by use of the appropriate cyclic esters.  For repeating units derived from alpha-hydroxy acids, these are usually the intermolecular cyclic esters containing six-membered rings, e.g. glycolide, and for repeating units derived beta- or gamma-hydroxy acids, the monomeric lactones, e.g. beta-propiolactone, and gamma-butyrolactone, are usually used. Polymerization may be effected by heating the lactide above its melting point, but below about 215 DEG  C. in the presence of a polyvalent metal oxide or compound thereof, under anhydrous conditions in an inert atmosphere. Specified catalysts include zinc oxide, zinc carbonate, basic zinc carbonate, diethylzinc, titanium, magnesium or barium compounds, and litharge. In one preparation, purified lactide, with one or more solid comonomers in substantially the theoretical proportions to give a copolymer of the desired formula, is placed in a thoroughly dried reactor equipped with a stirring bar, nitrogen inlet tube, and a drying tube filled conveniently with anhydrous magnesium sulphate or calcium chloride, nitrogen, previously dried by passage through anhydrous magnesium sulphate or calcium chloride is introduced immediately above the reaction mixture and heating and stirring are started.  When a temperature of 100 DEG  C. is reached, the nitrogen inlet is replaced by a thermometer, and from 0.01 to 2 weight per cent of an oxide or salt, of a Group II metal of atomic number 12 to 56, or litharge is added.  For copolymerization with a liquid comonomer the liquid comonomer is preferably added after the lactide has melted. Heating is continued until polymer having the required inherent viscosity is obtained, which may require from a few minutes up to 25 or more hours.  The polymer produced is cut into small pieces, dissolved in a suitable solvent, e.g. benzene, toluene, or xylene, and the polymer precipitated by pouring the solution into a large volume of a non-solvent for the polymer, desirably hexane.  The precipitated polymer is removed by filtration, transferred to a blender and a non-solvent for the polymer is added. The blender is started and after a homogeneous dispersion has been obtained, the dispersion is filtered.  The polymer is allowed to dry on the filter, and is then transferred to a vacuum oven.  After drying overnight at 100 DEG  C., the polymer is removed from the oven and allowed to cool to room temperature.  In Example I, a mixture of 95 parts of L(-)-lactide and five parts of DL-lactide are fused under nitrogen, and there is added 0.125 parts of diethylzinc as a 25% solution in heptane.  The mixture is heated at 105 DEG  C. for one hour at atmospheric pressure in an atmosphere of nitrogen, to obtain a solid copolymer.  Examples 2 to 9 describe the preparation of L(-)-lactide copolymers with such comonomers as DL-lactide, glycolide, beta-propiolactone, m gamma-butyrolactone, and pivalolactone. In Examples 10 and 11 copolymers of L-lactide with the intermolecular cyclic esters of alpha-hydroxy butyric acid and alpha-hydroxyheptonoic acid are made by essentially the method of Example 1.  Example 12 describes the preparation of a composition comprising a mixture of a powdered L-lactide/DL-lactide (90/10) copolymer and, as colouring matter, the monosodium salt of 4-[4-(N-ethyl-p - sulphobenzylamino) diphenylmethylene]-[1 - (N - ethyl - N - p - sulphoniumbenzyl) D 2,5-cyclohexadienimine] to obtain a green composition. In the examples bulk polymerization is used to make the polylactides, but polymerization can also be effected in solution or suspension. When the solution method is used the ratio of monomer to solvent can be from 1:1 to 5:1.  Suitable media are aromatic hydrocarbons e.g. the xylenes and ethers such as tetrahydrofuran, dioxane, and 1,2-dimethoxyethane.ALSO:Surgical sutures are made from oriented filaments or ribbons of lactide copolymers containing 85 to 98.5% of repeating units of a single antipedal species of alpha hydroxy propionic acid and 1.5% to 15% of repeating units of the formula:-  <FORM:1123445/A5-A6/1> where R is lower alkylene, m is 0 or 1, R\sv is a hydrogen atom or a lower alkyl group, and R\yF, which can be the same as or different from R\sv, is a hydrogen atom or an alkyl group of up to 22 carbons when m is 0 and, when m is 1, R\yF is a hydrogen atom or a lower alkyl group, lower herein meaning having up to 6 carbon atoms, and the repeating units of the said formula including at least one which is different from that derived from the said antipedal species, said copolymer before being oriented having an inherent viscosity of at least 1.0 to 0.1% concentration in benzene at 25 DEG C. and said filament losing at least 20% of its weight on treatment with boiling water for a period of 100 hours. Suitably, orientation is effected by drawing a filament of said polylactide at a temperature of 70 to 140 DEG C. at a draw ratio of 5 to 11 times.  The copolymer may contain up to 12% of repeating units derived from glycolide.  A preferred copolymer is a polyL(-)-lactide copolymer containing up to 15% of repeating units derived from DL-lactide.  Another preferred copolymer is a 95/5 copolymer of L(-)-lactide and DL-lactide.  Inert colouring agents and plasticisers, especially glyceryl triacetate, ethyl benzoate and diethyl phthalate, may be present.  A suture may comprise a monofilament having a diameter of 0.1 to 45 mils especially 1 to 20 mils and a tensile strength of 25,000 to 100,000 psi.  Alternatively, a surgical suture may comprise a plurality of such filaments braided together, and if desired including also a plurality of unoriented filaments of said copolymer, the oriented filaments comprising in number at least 50% of the braided suture.  In such a suture, the individual filaments preferably have diameters in the range 0.1 to 45 mils and said suture may have a tensile strength of 25,000 to 100,000 psi.  For the method of making filaments, (see Division B5).  By varying the type and proportion of comonomer employed, the rate of absorption of the suture can be controlled.