BIOABSORVIBLE POLYMERIC MIXTURE, BIOABSORVIBLE MEDICAL DEVICE AND MANUFACTURING METHOD FOR THAT DEVI

专利摘要:
bioabsorbable polymeric compositions, processing methods, and medical devices therefor. the present invention relates to innovative bioabsorbable polymer blends. the blends have a first component which is a polylactide polymer or copolymer of lactide and glycolide and a second component which is a polymer of poly (p-dioxanone). innovative polymer blends provide medical devices having dimensional stability. innovative bioabsorbable medical devices produced from these innovative polymer blends, as well as innovative manufacturing methods are presented.
公开号:BR112013006716B1
申请号:R112013006716-0
申请日:2011-09-21
公开日:2020-02-11
发明作者:Brian M. Kelly；Dennis D. Jamiolkowski；Christopher DeFelice
申请人:Ethicon, Inc；
IPC主号:

专利说明:

Descriptive Report of the Invention Patent for BIOABSORVIBLE POLYMERIC MIXTURE, BIOABSORVIBLE MEDICAL DEVICE AND METHOD OF MANUFACTURING THE AVAILABLE DEVICE.
FIELD OF THE INVENTION [0001] The field of art to which this invention relates is a bioabsorbable polymer, in particular bioabsorbable polymer mixtures useful for the manufacture of medical devices.
BACKGROUND OF THE INVENTION [0002] Bioabsorbable polymers and medical devices produced from such polymers are known in the art. Conventional bioabsorbable polymers include polylactic acid, poly (p-dioxanone), polyglycolic acid, lactide, glycolide, p-dioxanone, trimethylene carbonate, ε-caprolactone copolymers, in various combinations, etc. Bioabsorbable polymers are created to have a chemical composition, so that the decomposition of polymers in vivo is metabolized or otherwise decomposed, for example by hydrolysis and eliminated from the patient's body. The advantages of using implantable medical devices made from bioabsorbable polymers are numerous and include, for example, eliminating the need for additional surgery to remove an implant after it has done its job. Ideally, when a temporary presence of the implant is desired, support can be provided until the tissue heals.
[0003] The bioabsorbable polymers used for the manufacture of medical devices have on occasion been polymeric mixtures of absorbable polymers and copolymers designed to provide specific characteristics and properties for the manufactured medical device, including rates of bio-absorption, retention of tear strength and dimensional stability, etc.
[0004] There are many conventional processes used for the factory
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2/65 medical devices made of polymers and bioabsorbable polymer mixtures. Processes include injection molding, solvent casting, extrusion, machining, cutting, and various combinations and equivalents. A particularly useful and common manufacturing method is thermal formation using conventional injection molding processes. It is known in the art that manufacturing processes such as thermal injection molding can result in molded parts that have inferior properties, especially, for example, unacceptable dimensional stability, mechanical properties, and retention of mechanical properties over time of post-implantation. There are a number of reasons for reduced dimensional stability. They include the presence of residual stresses induced during the manufacturing process. Another reason is if at least one of the polymeric components has a very low glass transition temperature, especially if the polymeric component does not crystallize easily after molding.
[0005] Therefore, there is a need in this technique for innovative bioabsorbable polymeric mixtures that can be used in thermal injection molding processes, and other conventional processes to manufacture bioabsorbable medical devices that have superior tear strength retention, excellent bioabsorbability, mechanical properties superior strengths such as rigidity and strength, fabricability and superior dimensional stability.
[0006] It is known in the art through the use of thermal injection modeling processes, that the process conditions and design elements that reduce the shear stress when filling the cavity typically help to reduce the residual stress induced by the flow. Similarly, these conditions that promote sufficient compaction and uniform cooling of the mold, typically also tend to reduce residual thermal stress.
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3/65 specifically induced. It is often very difficult, if not impossible, to completely eliminate residual stress in injection molded parts. The approaches that have been applied include: (1) trying to crystallize the part while it is still in the mold to increase the mechanical stiffness to resist distortion; and, (2) apply resins that have a high glass transition temperature (Tg).
[0007] The latter case describes the situation where chain mobility is only achieved at much higher temperatures, thereby protecting the part at moderate temperatures that the part is expected to withstand during ethylene oxide (EtO sterilization) ), transport and storage. Materials that have high glass transition temperatures may not necessarily have other characteristics that are desirable, such as absorbency. Residual stresses are recognized as the main cause of shrinkage and warp of the part. Parts can warp or distort dimensionally by ejecting the mold during the injection molding cycle, or by exposing it to high temperatures, encountered during normal storage or product transportation.
[0008] There have been attempts in prior art to address the problem of lack of dimensional stability in medical devices thermally formed with bioabsorbable polymers mixed in a molten state. Smith, US patent No. 4,646,741, presents a fused mixture of a lactide / glycolide copolymer and the poly (pdioxanone) used to make surgical clips and staples in two pieces. Smith's molten mixtures provide molded articles that have dimensional stability; Smith demands that the amount of poly (p-dioxanone) in the mixture be greater than 25 weight percent, and does not recommend smaller quantities. Smith's polymeric mixtures have disadvantages associated with their uses for the manufacture of
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4/65 medical devices, including: limited stiffness or Young's modulus, less retention of mechanical properties upon implantation, greater sensitivity to moisture limiting the time allowed for storage after opening during manufacture and, although it is difficult to quantify, it is more difficult thermal processing.
[0009] As mentioned earlier, residual stresses are recognized as the main cause of shrinkage and warping of the part. It is known in the art that residual stresses induced by flow can have an effect on a thermally molded polymeric medical device. Long-stranded polymer molecules tend to adapt to an equilibrium state of the random coil at temperatures higher than the melting temperature (i.e., in a molten state). During thermal processing (for example, injection molding), the molecules orient themselves towards the flow, while the polymer is sheared and elongated. Solidification usually occurs before the polymer molecules are completely relaxed in their equilibrium states and some molecular orientation is then confined within the molded part. This type of tension state and latent tension is often referred to as flow-induced residual stress. Anisotropic mechanical and non-uniform shrinking properties in the directions parallel and perpendicular to the flow direction are introduced because of the stretched molecular structure.
[00010] Cooling can also result in residual stresses. For example, variation in the cooling rate from the mold wall to its center can cause thermally induced residual stress. In addition, asymmetric thermally induced residual stress can occur if the cooling rate of the two surfaces is unbalanced. Such unbalanced cooling will result in an asymmetric stress-compaction pattern across the part, causing
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5/65 a moment of bending that tends to cause the piece to be warped. Consequently, parts with non-uniform thickness or poorly cooled areas are prone to unbalanced cooling, and thus cause residual thermal stresses. For moderately complex parts, the distribution of thermally induced residual stress is further complicated by the uneven wall thickness, the cooling of the mold and the confinement of the molds.
[00011] It should be noted that a conventional and common method of sterilization is exposure to ethylene oxide gas in a cycle of the sterilization process. Absorbable polymeric devices are often sterilized upon exposure to ethylene oxide gas (EtO). EtO can act as a plasticizer of lactide-glycolide copolymers, and can slightly decrease Tg; this can result in 'shrinkage' and / or 'warp' of an injection molded part, especially when exposed to higher temperatures than Tg. This adds additional processing and having to deal with challenges when using lactide-glycolide polymeric materials for absorbable medical devices. It should be noted that the EtO sterilization process not only exposes the part to EtO gas, it also exposes the part to high temperatures. This usually requires treatment at slightly elevated temperatures. Because EtO can act as a plasticizer for absorbable synthetic polyesters, the problems of shrinkage and warping and general dimensional instability are often exacerbated.
[00012] There are several processing methods conventionally used to reduce or eliminate shear stresses during processing. Processing conditions and design elements that reduce shear stress during cavity filling will help to reduce residual stress induced by
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6/65 flow. Polymeric parts are often heat treated (thermally annealed) to change their performance characteristics. The reason for heat treatment processing is to mature morphological development, for example, crystallization and / or stress relaxation. If done successfully, the resulting part may have better dimensional stability and may have better mechanical strength.
[00013] Injection molded parts ejected from the injection molding machine that are not yet distorted, can be cooled / abruptly cooled to room temperature and may appear to be dimensionally correct. Stresses, however, are still generally present and can lead to distortion at any time when the polymer chains can move. As previously described, this can happen with an increase in temperature or exposure to plasticizer, such as EtO gas. In order to overcome this potential driving force for dimensional distortion, numerous strategies have been used; this includes (thermal) annealing.
[00014] If the part can be dimensionally constricted, thermal annealing can be applied towards two objectives: one is to try to reduce the amount of molecular orientation in the polymer chains, also known in the art as stress reduction; and another is to increase the crystallinity in the part to increase the mechanical stiffness to resist distortion.
[00015] With some polymers that readily crystallize, you may be able to crystallize the part while it is still in the mold, but this is an unusual situation. Here the mold cavity not only acts to define the shape of the piece, it can act to limit the shape of the piece during the crystallization process. With polymers more difficult to crystallize, the cycle time becomes unreasonably long, and
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7/65 the injection molding process becomes impractical. Thus, the part needs to be expelled from the mold before the complete development of the polymer morphology takes place.
[00016] Injection molded parts prepared from semicrystalline polymers can often be annealed by heat treatment to increase the level of crystallinity and complete their development of the polymer morphology. The parts often need to be physically confined to avoid the distortion you are trying to avoid. Once crystallized, the part has increased mechanical stiffness to resist distortion, if exposed to normal conditions of distortion. Providing adequate physical confinement is often difficult, as it is often labor intensive and economically costly.
[00017] It is preferable to anneal the expelled part without the need for physical confinement; however, what often happens is that the part distorts during the annealing process, making the part unacceptable for many needs.
[00018] It is known in the parts annealing industry to reduce residual stresses by thermal relaxation. The time and temperature required to relieve tension varies, but it often needs to be done below Tg to avoid gross distortion. Even so the results can vary a lot. It is more difficult to reduce stress levels without causing distortion, in higher molecular weight resins. It would be relatively easy to reduce residual stresses through thermal relaxation in low molecular weight and high flow polyesters, when compared to higher molecular weight polyesters.
[00019] With respect to the molecular weight of the polymer mixture, the higher molecular weight generally develops higher stress levels and requires longer times / higher temperatures for stress relaxation. Although this is the case, the soft weight
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Higher 8/65 is often necessary to obtain high mechanical properties and biological performance. This situation often presents a problem for the device manufacturer.
[00020] In order to provide more crystallinity to increase mechanical stiffness to better resist distortion, or to reduce molecular orientation in order to decrease the propulsion force for distortion, the parts would ideally be processed by heat treatment (annealing) to a temperature that does not cause distortion. Unfortunately, due to the nature of the commonly used absorbable synthetic polyesters, this treatment often needs to be above its glass transition temperature, where distortion is almost impossible to avoid.
[00021] Consider for example, polylactide homopolymer or poly (lactide-coglycolide) copolymer devices. The strained polymer chains of these injection molded parts will tend to relax and return to their natural state (three-dimensional random coils) when heated to, or above their glass transition temperatures. This will be seen as warp, shrinkage or general dimensional deformation. It is a general practice in the industry when producing molded parts based on polylactide, not annealing them because of this potential deformation. These polylactide molded parts have very low crystallinity, if not clearly amorphous or non-crystalline, and will then tend to deform if exposed to temperatures greater than or equal to their respective glass transition temperatures. It would be advantageous to be able to anneal such parts to induce crystallinity so that they can develop high rigidity to remain dimensionally stable under the conditions normally encountered during EtO sterilization, transport and storage.
[00022] There are medical applications that require the device
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9/65 doctor demonstrates sufficient column strength, as in the case of a staple or an implantable tack. Clearly, for a device with such requirements with a smaller cross-sectional area, the polymer from which it was formed must be inherently rigid if the tack must work properly for the intended application. [00023] To obtain greater rigidity in a molten mixture of a lactide / glycolide and poly (p-dioxanone) copolymer, it is necessary to minimize the amount of poly (p-dioxanone). Contrary to what Smith teaches, it was found that dimensional stability can be achieved in molded parts from a mixture of a lactide-rich copolymer and poly (p-dioxanone), where the levels of poly (p-dioxanone) are higher lower than 25% by weight. The addition of poly (p-dioxanone), even at these low levels, improves the ability to achieve dimensional stability in the final piece.
[00024] While such polymeric mixtures are known, there is a continuing need in this technique for innovative absorbable polymeric materials that provide a medical device with enhanced characteristics, including stiffness, retained in vivo (in situ) strength, dimensional stability, absorbance in vivo, and manufacturability, with the need for innovative medical devices produced from such polymeric materials, and innovative methods for manufacturing medical devices from such polymeric materials.
SUMMARY OF THE INVENTION [00025] An objective of the present invention is to provide innovative bioabsorbable polymer mixtures that can be used in manufacturing processes to produce absorbable medical devices and components for clinical devices through innovative casting processes, such as injection molding and other processes, in which devices or components have superior mechanical properties (such as high rigidity and column strength), retention of resis
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10/65 superior rupture strength, acceptable bioabsorbation rates, and superior dimensional stability.
[00026] Consequently, an innovative bioabsorbable polymer blend composition is presented. The polymeric mixture has a first bioabsorbable polymer and a second bioabsorbable polymer. The first polymer contains from about 76%, by weight, to about 92%, by weight, of a lactide-rich polymer containing from about 100 mol% to about 70 mol% of polymerized lactide and about 0 Spring% about 30 mol% of polymerized glycolide. The second polymer is poly (p-dioxanone). The maximum% by weight of poly (p-dioxanone) in the mixture is about 24% by weight, and the minimum% by weight of poly (p-dioxanone) in the mixture depends on the molar amount of polymerized lactide in the mixture. lactide-rich polymer, and is calculated by the expression:
%, by Weight, Polj (p-djoxanone) = (215.6212 /% mol Mol Polymerized Lactide) ² ' ⁷⁰²⁷ [00027] The polymeric mixture provides dimensional stability to a manufactured article.
[00028] Another aspect of the present invention is a thermally processed bioabsorbable polymer blend composition. The polymeric mixture has a first bioabsorbable polymer and a second bioabsorbable polymer. The first polymer contains from about 76%, by weight, to about 92%, by weight, of a lactide-rich polymer containing from about 100 mol% to about 70 mol% of polymerized lactide and about 0 mol% to about 30 mol% of polymerized glycolide. The second polymer is poly (p-dioxanone). The maximum% by weight of poly (p-dioxanone) in the mixture is about 24% by weight, and the minimum% by weight of poly (p-dioxanone) in the mixture depends on the molar amount of polymerized lactide in the polymer. rich in lactide, and is calculated by the expression:
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11/65% by weight, Poly (p-dioxanone) = (215.6212 / mol% Polymerized Lactide) ² ' ⁷⁰²⁷ [00029] The thermally processed polymeric mixture provides dimensional stability to a manufactured article.
[00030] Yet another aspect of the present invention is an innovative bioabsorbable medical device. The medical device has a structure. The medical device comprises a bioabsorbable polymeric mixture of a first bioabsorbable polymer and a second bioabsorbable polymer. The first polymer contains from about 76%, by weight, to about 92%, by weight, of a lactide-rich polymer containing from about 100 mol% to about 70 mol% of polymerized lactide and about 0 mol% to about 30 mol% of polymerized glycolide. The second polymer is poly (p-dioxanone). The maximum% by weight of poly (p-dioxanone) in the mixture is about 24% by weight, and the minimum% by weight of poly (p-dioxanone) in the mixture depends on the molar amount of polymerized lactide in the polymer. rich in lactide, and is calculated by the expression:
%, by Weight, Poly (p-dioxanone) = (215.6212 / mol% Polymerized Lactide) ² ' ⁷⁰²⁷ [00031] The polymeric mixture provides dimensional stability to the medical device.
[00032] Yet another aspect of the present invention is a method for making a medical device. The method includes the steps of processing a bioabsorbable polymeric mixture. The polymeric mixture has a first bioabsorbable polymer and a second bioabsorbable polymer. The first polymer contains from about 76%, by weight, to about 92%, by weight, of a lactide-rich polymer containing from about 100 mol% to about 70 mol% of polymerized lactide and about 0 mol% to about 30 mol% of polymerized glycolide. The second polymer is poly (p-dioxanone). THE
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12/65 maximum% by weight of poly (p-dioxanone) in the mixture is about 24% by weight, and the minimum% by weight of poly (p-dioxanone) in the mixture depends on the molar amount of polymerized lactide in the lactide-rich polymer, and is calculated by the expression:
%, by Weight, Poly (p-dioxanone) = (215.6212 / mol% Polymerized Lactide) ² ' ⁷⁰²⁷ [00033] A bioabsorbable medical device is formed from the polymeric mixture. The polymeric mixture provides dimensional stability to the formed medical device.
[00034] Additional aspects of the present invention include the medical device and method described above, wherein the polymeric mixture is thermally processed.
[00035] These and other aspects and advantages of the present invention will be more apparent from the following description and the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS [00036] Figure 1 is a photomicrograph obtained under scanning electron microscopy (SEM) of the poly (p-dioxanone) structures, collected from the injection molded articles of the polymer mixture at 20% by weight of poly (p-dioxanone) and 80% by weight of poly (lactide-glycolide), where the poly (lactide-cholactide) is 85% by mol of polymerized lactide and 15% by mol of polymerized glycolide.
[00037] Figure 2 is a drawing of an implantable clamp or tack demonstrating the present invention, and shows a device with a small cross-sectional area.
[00038] Figure 3 is a drawing of the device of Figure 2 showing critical dimensions of said device.
[00039] Figure 4 is a graph showing the effects of compositional changes to the injection molded device, when related to the retention of the rupture resistance, or RRR, after having undergone
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13/65 to the in vitro test.
[00040] Figure 5 is a graph of mol% of the polymerized lactide in the lactide / glycolide copolymer component versus the% by weight of poly (p-dioxanone); the area bounded by the curves contains the innovative polymer compositions of the present invention.
[00041] Figure 6a is a photograph of an injection molded tack in EXAMPLE 8C (ie, prior to annealing) produced from the polymer composition of EXAMPLE 6C that provided injection molded studs showing unacceptable warping after annealing.
[00042] Figure 6b is a photograph of an injection molded tack in EXAMPLE 9C (similar to the tack in Figure 6a, but after annealing) produced from the polymer composition of EXAMPLE 6C that provided injection molded studs with unacceptable warping after annealing.
[00043] Figure 7a is a photograph of an injection molded tack in EXAMPLE 8D (ie, prior to annealing) produced from the polymer composition of EXAMPLE 6D that provided injection molded studs that have superior dimensional stability and a level acceptable warp after annealing.
[00044] Figure 7b is a photograph of an injection molded tack in EXAMPLE 9D (similar to the tack in Figure 7a, but after annealing) produced from the polymer composition of EXAMPLE 6D that provides injection molded studs that exhibit stability dimensional dimension and an acceptable level of warp after annealing.
[00045] Figure 8a is a photograph of an injection molded tack in EXAMPLE 8N (ie, prior to annealing) produced from the polymer composition of EXAMPLE 6N that provided injection molded studs that have dimensional stability.
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14/65 higher and an acceptable warp level after annealing.
[00046] Figure 8b is a photograph of an injection molded tack in EXAMPLE 9N (similar to the tack in Figure 8a, but after annealing) produced from the polymer composition of EXAMPLE 6N that provided injection molded articles that exhibit stability dimensional dimension and an acceptable level of warp after annealing.
[00047] Figure 9a is a photograph of an injection molded tack in EXAMPLE 8S (ie, prior to annealing) produced from the polymer composition of EXAMPLE 6S that provided the injection molded studs showing unacceptable warping after annealing.
[00048] Figure 9b is a photograph of an injection molded tack in EXAMPLE 9S (similar to the tack in Figure 9a, but after annealing) produced from the polymer composition of EXAMPLE 6S, which provided the injection molded studs featuring unacceptable warp after annealing.
[00049] Figure 10a is a photograph of an injection molded tack in EXAMPLE 8T (ie, prior to annealing) produced from the polymer composition of EXAMPLE 6T that provided the injection molded studs that have superior dimensional stability and a acceptable warp level after annealing.
[00050] Figure 10b is a photograph of an injection molded tack in EXAMPLE 9T (similar to the tack in Figure 10a, but after annealing) produced from the polymer composition of EXAMPLE 6T that provided the injection molded studs that feature superior dimensional stability and an acceptable warp level after annealing.
[00051] Figure 11a is a photograph of an injection molded tack in EXAMPLE 8X (ie, prior to annealing) produced at
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15/65 from the polymer composition of EXAMPLE 6X that provided the injection molded tacks that present superior dimensional stability and an acceptable level of warp after annealing.
[00052] Figure 11b is a photograph of an injection molded tack in EXAMPLE 9X (similar to the tack in Figure 11a, but after annealing) produced from the polymer composition of EXAMPLE 6X that provided the injection molded studs that feature superior dimensional stability and an acceptable warp level after annealing.
[00053] Figure 12 is a drawing of a dumbbell test article. DETAILED DESCRIPTION OF THE INVENTION [00054] The innovative polymeric blends of the present invention are produced from bioabsorbable polyester polymers and copolymers. Preferably, one of the components of the mixture is a poly (L (-) - lactide) copolymer, or a lactide-rich lactide / glycolide copolymer. Another component of the mixture is the bioabsorbable poly (p-dioxanone) polymer.
[00055] The poly (L (-) - lactide) copolymer, or a lactide-rich lactide / glycolide copolymer will be manufactured in a conventional manner. A preferred manufacturing method is as follows: the lactone monomers are charged with an initiator alcohol, a suitable catalyst and dye if desired, in a reactor with stirring vessel. After purging to remove oxygen, under a nitrogen atmosphere the reagents are heated with agitation to conduct ring-opening polymerization. After a suitable time, the resin formed is discharged and sized accordingly. The resin particles are subjected to a devolatilization process and are subsequently stored under vacuum. The mol% of the polymerized lactide and the polymerized glycolide in the lactide-rich polymer useful in the innovative mixtures of the present
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The invention can be varied to provide the desired characteristics. Typically, the mol% of the lactide polymerized in the lactide rich polymer will be about 70 percent to about 100 percent, more typically about 80 percent to about 90 percent, and preferably about 83 percent to about 87 percent. When the lactide polymerized in the lactide-rich polymer is 100 percent, the polymer is the polylactide; poly (L (-) - lactide) is preferred for some surgical applications. Typically, the mol% of the polymerized glycolide in the lactide-rich polymer will be about 0 percent to about 30 percent, more typically about 10 percent to about 20 percent, and preferably about 13 percent to about 17 percent.
[00056] The poly (L (-) - lactide) homopolymer, or a lactide-rich lactide / glycolide copolymer is characterized by chemical analysis. These characteristics include, but are not limited to, an inherent viscosity ranging from about 0.80 to about 2.25 dL / g, as measured in hexafluoroisopropanol at 25 ° C and at a concentration of 0.1 g / dL . The gel permeation chromatography analysis demonstrated an average molecular weight ranging from approximately 35,000 to 120,000 Daltons. It is to be understood that higher molecular weight resins can be applied, as long as the processing equipment used to form the mixture, and to form the medical device, is capable of handling the melt viscosities inherent in these higher molecular weights and can desirable for certain applications. For example, in some applications, a resin with an inherent viscosity of 2.5 dL / g may be required to produce medical devices that require certain characteristics, such as the highest strength. Differential scanning calorimetry demonstrated a glass transition temperature ranging from 20 ° C to 65 ° C and a melting transition of approximately
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120 ° C to 180 ° C. The analysis of nuclear magnetic resonance confirmed that the copolymeric resin is a random copolymer of L (-) - lactide and glycolide. The X-ray diffraction analysis showed a crystallinity level of approximately 20 to 45 percent.
[00057] It is to be understood that the polylactide homopolymer component of the mixture, or a lactide-rich lactide / glycolide copolymer component of the mixture can be based on the lactide monomer of LL configuration, i.e., L (-) - lactide. However, other stereoisomers can be substituted, provided that in the final device the polymer component based on lactide has sufficient crystallinity to provide dimensional stability. In this way, the poly (D (+) - lactide) homopolymer based on the DD configuration can be used instead of poly (L (-) - lactide). A lactide / glycolide copolymer component can be based entirely on the DD isomer, or have mixtures of the DD isomer and the LL isomer, as long as the crystallinity requirement in the final device is met. Mesolactide, the DL isomer can also be used in small proportions, again as long as the crystallinity requirement in the final device is met.
[00058] The poly (p-dioxanone) polymer useful in the innovative polymer mixtures of the present invention is manufactured in a conventional manner. A preferred method of making such a polymer is as follows: the lactone monomer is charged with an initiator alcohol, a suitable catalyst, and dye if desired, in a reactor with stirring vessel. The dye should be acceptable for use in clinical testing; these include D&C Violet No. 2 and D&C Blue No. 6. After purging to remove oxygen, the reagents are heated under a nitrogen atmosphere with stirring to conduct ring-opening polymerization. After a suitable time, the resin formed is discharged into suitable containers, and
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18/65 additionally polymerized under conditions known in the art as solid state polymerization. An alternative method can include polymerization in the melt. After this reaction period is complete, the polymer resin is sized properly. The resin particles are subjected to a devolatilization process to remove the unreacted monomer and are subsequently stored under vacuum. Polydioxanone polymers useful in the mixtures of the present invention will have an inherent viscosity of at least about 0.80 dL / g, as measured at 25 ° C and a concentration of 0.1 g / dL. Polydioxanone polymers particularly useful in the mixtures of the present invention will have the following characteristics: These characteristics should include, but are not limited to: an inherent viscosity ranging from about 0.80 to about 2.30 dL / g, as measured in hexafluoroisopropanol at 25 ° C and at a concentration of 0.1 g / dL. The gel permeation chromatography analysis demonstrated an average molecular weight ranging from approximately 35,000 to 120,000 Daltons. It is to be understood that higher molecular weight resins can be applied as long as the processing equipment used to form the mixture, and to form the medical device is capable of handling the melt viscosities inherent in these higher molecular weights and may be desirable for certain applications. For example, in some applications, a resin with an inherent viscosity of 2.5 dL / g may be required to produce medical devices that require certain characteristics, such as the highest strength. Differential scanning calorimetry demonstrated a glass transition temperature ranging from -15 ° C to 8 ° C and a melting transition of approximately 100 ° C to 107 ° C. Nuclear magnetic resonance analysis confirmed that the resin is a poly (p-dioxanone) homopolymer, with a composition of approximately 98 percent polymerized p-dioxanone, and
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19/65 approximately 0 to 2 percent of p-dioxanone monomer, as measured on a molar basis. X-ray diffraction analysis typically demonstrated a crystallinity level of approximately 25 to 40 percent, although levels of 55 percent or higher were observed.
[00059] The innovative polymeric mixtures of the present invention with enhanced dimensional stability will typically contain a first bioabsorbable polymer and a second bioabsorbable polymer, the first polymer containing about 76% by weight to about 92% by weight of a lactide-rich polymer containing about 100 mol% to about 70 mol% of polymerized lactide and about 0 mol% to about 30 mol% of polymerized glycolide, and the second polymer containing poly (p-dioxanone) , where the maximum% by weight of poly (p-dioxanone) in the mixture is about 24 and the minimum% by weight of poly (p-dioxanone) in the mixture depends on the molar amount of the polymerized lactide in the rich polymer lactide and is calculated by the expression:
%, by Weight, Polj (p-djoxanone) = (215.6212 / mol% Polymerized Lactide) ² ' ⁷⁰²⁷ [00060] To be clear, the innovative polymeric mixtures of the present invention are typically a mixture of a lactide / glycolide copolymer rich in lactide or a polylactide homopolymer, and poly (p-dioxanone). For example, the lactide / glycolide copolymer can be poly (L (-) - lactide-cholactide) with a composition of 85 mol% of polymerized lactide and 15 mol% of polymerized glycolide. The maximum% by weight of poly (p-dioxanone) in the mixture is about 24 and the minimum% by weight of poly (p-dioxanone) in the mixture can be calculated depending on the molar amount of the polymerized lactide in the copolymer lactide / glycolide, using the equation above. Thus, in the case of an 85/15 lactide / glycolide copolymer (mol basis):
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Minimum%, by Weight, Polj (p-djoxanone) = (215.6212 /% in mol Polymerized Lactide) ² ' ⁷⁰²⁷ = (215.6212 / 85) ² ' ⁷⁰²⁷ = 12.4%, by weight, Poly (p -dioxanone) [00061] Thus, for the innovative polymer mixtures of the present invention employing an 85/15 lactide / glycolide copolymer (mol-based), the weight% of poly (p-dioxanone) would vary between about 12 , 4 and about 24.
[00062] The polymeric mixtures of the present invention will more typically contain about 76% by weight to about 84% lactide-rich polymer, and about 16% by weight to about 24% by weight , of the poly (p-dioxanone) in which the lactide-rich polymer contains about 80 mol% to about 90 mol% of polymerized lactide and about 10 mol% to about 20 mol% of polymerized glycolide .
[00063] The innovative polymeric mixtures of the present invention will preferably contain about 78% by weight to about 82% lactide-rich polymer, and about 18% by weight to about 22% by weight. weight of the poly (p-dioxanone) in which the lactide-rich polymer contains about 83 mol% to about 87 mol% of polymerized lactide and about 13 mol% to about 17 mol% of glycolide polymerized.
[00064] The mixtures of the present invention demonstrated a level of crystallinity of at least about 15 percent, typically greater than about 25 percent, and more preferably, greater than about 35 percent, as measured by ray diffraction X.
[00065] The innovative polymeric mixtures of the present invention can be manufactured from the individual components in a variety of conventional ways using equipment for conventional processing. Examples of manufacturing processes include chemical reactions of the ring opening and the type of polycon
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21/65 densification, devolatilization and drying of resin, dry mixing in a dryer, mixing in solution, melt extrusion, injection molding, thermal annealing, and ethylene oxide gas sterilization processes. An alternative to dry mixing with subsequent mixing in the molten state of the mixture may include the use of two or more feeders, preferably gravimetric feeders for weight loss, which supply the components to be mixed in an extruder; the extruder can be of the single screw or double screw variety. Alternatively, multiple extruders can be used to dose the molten materials of the mixture components, as in coextrusion.
[00066] The mixtures of the present invention can be produced by thermal processes. Examples of thermal processes for producing the polymeric mixtures of the present invention would be the molten state mixture in an extruder which may include double-screw mixing or single-screw extrusion, coextrusion, double-screw mixing with simultaneous hollow-thread vacuum devolatilization, drying vacuum with thermal devolatilization, monomer removal by solvent extraction at elevated temperatures, and resin annealing.
[00067] The polymer components as well as mixtures of the present invention can be sized by conventional means such as pelletizing, granulating, and crushing.
[00068] An additional embodiment of the present invention would be to properly measure the sized particles of the components of the mixture directly in the hopper of the injection molding machine. It would be obvious to the person skilled in the art to apply this technique to other processing methodologies, such as, but not limited to, film or fiber extrusion. Limiting the thermal history of the components of the polymeric mixture is advantageous since this avoids the possibility of
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22/65 premature gradation. Additional methods of thermal processing may include a process selected from the group consisting of injection molding, compacting modeling, blow molding, blown film, thermoforming, film extrusion, fiber extrusion, blade extrusion, profile extrusion, meltblown, coextrusion, tube extrusion, foaming, rotation molding, calendering and extrusion. As noted earlier, properly sized particles of the mixture components can be mixed with the melt using these thermal processing means.
[00069] Although not wishing to stick to scientific theory, it is believed that the morphological development in the final piece is greatly influenced by the device formation process, such as injection molding. In this way, the melt resin in the molten state can have a morphology with a very low aspect ratio for the secondary phase, poly (p-dioxanone). It may be that the high aspect ratio of the secondary phase happens only after the process of forming the device in high shear (for example, injection molding), is realized.
[00070] Other examples of manufacturing process equipment include chemical reactors ranging in size from 7.6 L (two gallons) to 283.9 L (seventy-five gallons) in capacity, dryers by devolatilization process in the range of one cubic feet to twenty cubic feet, single and double screw extruders about 2.54 cm (one inch) to about 7.6 cm (three inches) in diameter, and injection molders in the range of about 6,350.3 kg to about 36,287.4 kg (from about seven to about 40 tons in size). A preferred method and the associated equipment for making polymeric mixtures of the present invention can be found in EXAMPLE 1 through EXAMPLE 6.
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23/65 [00071] If desired, the polymeric mixtures of the present invention can contain other conventional components and agents. The other components, additives or agents will be present to provide additional effects for the polymeric mixtures and medical devices of the present invention, including antimicrobial characteristics, controlled drug elution, radio opacification and bone integration.
[00072] Such other components will be present in an amount sufficient to effectively provide the desired effects or characteristics. Typically, the amount of the other auxiliary compounds will be from about 0.1% by weight to about 20% by weight, more typically from about 1% by weight to about 10% by weight, and preferably about 2% by weight to about 5% by weight.
[00073] Examples of antimicrobial agents include phenolic polyphenol phenols, such as 5-chloro-2- (2,4-dichlorophenoxy) phenol (also known in the art as triclosan).
[00074] Examples of radio opacifying agents include barium sulfate while examples of bone integrating agents include tricalcium phosphate.
[00075] The variety of therapeutic agents that can be used in the polymeric mixtures of the present invention is wide. In general, therapeutic agents that can be administered via pharmaceutical compositions of the invention include, but are not limited to, anti-infectives, such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; anthelmintics; antiarthritics; antiasthmatic agents; adhesion preventives; anticonvulsants; anti-depressants; antidiuretic agents; antidiarrheals; antihistamines; anti-inflammatory agents; anti-migraine preparations; contraceptives; anti-nauseating agents; antineoplastics; antiparkinsonian drugs; anti-rashes; antipsychotics; antipyretics, antispasmodics; anticoli
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Nourished 24/65; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta blockers such as pindolol and antiarrhythmic agents; antihypertensive drugs; diuretics; vasodilators, including central, peripheral and cerebral coronary arteries; central nervous system stimulants; cough and cold preparations, including decongestants; hormones, such as estradiol and other steroids, including corticosteroids; hypnotics; muscle relaxant immunosuppressants; parasympatholytics; psychostimulants; sedatives; tranquilizers; naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins; oligonucleotides, antibodies, antigens, cholinergics, chemotherapy, hemostatics, anticoagulant agents, radioactive and cystostatic agents. Therapeutically effective dosages can be determined by in vitro or in vivo methods. For each specific additive, individual determinations can be made to determine the optimal dosage required. Determination of effective dosage levels to obtain the desired result will be within the skill of the art. The rate of release of the additives can also be varied within the skill of the person skilled in the art to determine an advantageous profile, depending on the therapeutic conditions of the treatment.
[00076] Glass or ceramics include, but are not limited to, phosphates such as hydroxyapatite, substituted apatites, tetracalcium phosphate, alpha-beta tricalcium phosphate, octacalcium phosphate, brushite, monetite, metaphosphates, pyrophosphates, phosphate glasses, carbonates, sulphates and calcium and magnesium oxides, and combinations thereof.
[00077] Suitable polymers that can be included in the polymeric mixtures of the present invention include: suitable biocompatible and biodegradable polymers that can be synthetic or natural polymers. Suitable biocompatible and biodegradable synthetic polymers include polymers selected from the group consisting of
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25/65 aliphatic polyesters, poly (amino acids), copoly (ether-esters), polyalkylene oxalates, polyamides, polycarbonate-derived tyrosine, poly (iminocarbonates), poly-polyesters, poly-polyester, poly-polyester, poly-polyester containing amine groups, poly (anhydrides), polyphenols , poly (diglycolates), and combinations thereof. It is to be understood that the inclusion of additional suitable polymers depends on obtaining dimensional stability in the manufactured device.
[00078] For the purposes of this invention, the above optional aliphatic polyesters include, but are not limited to, lactide homopolymers and copolymers (which include lactic acid, D-, L- and meso-lactide) glycolide (including glycolic acid) epsilon -caprolactone, pdioxanone (1,4-dioxane-2-one) trimethylene carbonate (1,3-dioxane-2one) alkyl derivatives of trimethylene carbonate and mixtures thereof.
[00079] Suitable natural polymers include, but are not limited to, collagen, elastin, hyaluronic acid, laminin, gelatin, keratin, chondroitin sulfate and decellularized tissue.
[00080] Although not preferred, the medical devices of the present invention may contain non-absorbable polymers in addition to the absorbable polymer mixtures of the present invention. Examples of such devices may include, but are not limited to, nets, sutures, and staples, in which the properties of both absorbable and non-absorbable polymers are advantageous.
[00081] Suitable non-absorbable polymers include, but are not limited to, acrylics; polyamide-imide (PAI); polyarylethylketones (PEEK); polycarbonates; thermoplastic polyolefins such as polyethylene (PE), polypropylene (PP), polymethyl pentene (PMP), and polybutene-1 (PB-1); polyolefin elastomers (POE) such as polyisobutylene (PIB), ethylene propylene rubber (EPR); polybutylene terephthalate (PBT); polyethylene terephthalate (PET); polyamides (PA) such as nylon 6 and nylon 66; fluoride
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26/65 polyvinylidene (PVDF); polyvinylidene-cohexafluoropropylene fluoride (PVDF / HFP); polymethyl methacrylate (PMMA) and combinations thereof and equivalents.
[00082] The bioabsorbable medical devices of the present invention which are produced from the polymeric mixtures of the present invention include, but are not limited to, conventional medical devices, especially implantable medical devices, including staples, tacks, clips, sutures, tissue fixation, mesh attachment devices, anastomosis devices, suture and bone supports, tissue and bone screws, bone plates, prostheses, support structures, tissue augmentation devices, tissue ligation devices, patches, substrates, nets, tissue engineering frameworks, drug delivery devices, and stents.
[00083] An example of a medical device that can be molded from the polymeric mixtures of the present invention is a fabric stud 10, as seen in Figure 2. Figure 2 is a drawing of a staple or implantable stud demonstrating the present invention. , and shows a device with a small cross-sectional area. The material in this device must be inherently rigid for the tack to work properly for the intended application.
[00084] Stud 10 is seen with two leg elements 20, connected by a connecting belt member 30 at their proximal ends 22. The distal ends 26 are seen with barb elements 50 extending distally from them. Barb elements 50 have distal perforating fabric tips 60 and proximal barbs 70 with tips 72. With reference to Figure 3, barb elements 50 are seen as a length 74 shown as dimension Y. Tips 60 are seen spaced apartPetition 870190087583 , of 09/05/2019, p. 30/81
27/65 over a distance 76, shown as dimension X.
[00085] Suitable tacks that can be produced from polymeric mixtures of the present invention are also presented and described in the commonly assigned US patent applications serial numbers 12 / 464,143; 12 / 464,151; 12 / 464,165; and, 12 / 464,177, which are incorporated by reference.
[00086] The ability of injection molded articles to develop some levels of crystallinity prior to annealing, allows the parties to undergo an annealing cycle to further crystallize the poly (lactide-coglycolide) phase of the mixture, without unduly warping or shrinking, that is, while maintaining dimensional integrity.
[00087] Injection molded parts of the mixtures of the present invention can advantageously be subjected to an annealing cycle to mature the polymer morphology. This often increases the level of crystallinity in the part. This process helps to ensure that when the part is exposed to moderately high temperatures, especially when exposed to ethylene oxide gas during sterilization, dimensional stability will be acceptable. Although there is no desire to stick to scientific theory, it is believed that directly after injection molding, under many processing conditions, the articles are almost completely amorphous, but when stored at room temperature the poly (pdioxanone) phase in mixture starts to crystallize. Polymeric materials will only crystallize when stored at temperatures above their glass transition temperatures. The glass transition temperature of the poly (p-dioxanone) is about minus 10 ° C, allowing the poly (pdioxanone) to begin to crystallize during storage at room temperature. In some processing conditions, typically in a longer retention time in the mold, the component p
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28/65 li (p-dioxanone) can crystallize. The expelled parts then have a small amount of crystallinity due to this phase substantially.
[00088] The ability of the poly (p-dioxanone) phase in the mixture to develop some level of crystallinity prior to annealing allows the crystallization of the poly (lactide-coglycolide) phase without excessive distortion of the molded article. This is due to the fact that the formation of an organized and semi-crystalline molecular structure increases the part's resistance to distortion at high temperatures. For example, if an amorphous, 100% poly (lactide-coglycolide) article is to be annealed, the piece will likely warp during the annealing process if even moderate levels of tension are present. The semi-crystalline and interdispersed poly (pdioxanone) in the mixture maintains the dimensional stability of the piece during exposure to the high temperatures necessary to crystallize the poly (lactide-coglycolide) phase of the mixture. The end result is a semi-crystalline and dimensionally stable injection molded article.
[00089] The medical devices of the present invention can be thermally tempered at a temperature of at least 45 degrees centigrade for at least one minute. Most preferably, the medical devices of the present invention are thermally annealed at a temperature of about 60 degrees centigrade for about 8 hours, followed by annealing at a temperature of about 70 degrees centigrade for about 4 hours, followed by annealing at a temperature of about 80 degrees Fahrenheit for about 4 hours.
[00090] The medical device of the present invention will have a level of crystallinity of at least about 15 percent, typically greater than about 25 percent, and more preferably, greater than about 35 percent, as measured by diffraction of X ray.
[00091] To further inhibit the warp during the process of
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29/65 annealing, the article can also be mechanically constrained through the use of an annealing accessory. Speculatively, it may be possible to anneal the part completely confined, or constricted. This would require the equivalent of annealing in the mold. This, of course, is often economically impractical. However, confining a limited number of dimensions during annealing may be economically possible. The articles in EXAMPLE 8 were annealed using an annealing accessory that supported the distortion parts in the horizontal plane of the part. Although this annealing accessory is intended to assist in resisting distortion at elevated temperatures during annealing, it will not prevent the dimensionally unstable parts of the warp.
[00092] As the lactide level in the poly (lactide-glycolide) portion of the mixture decreases, crystallization of the poly (lactide-glycolide) phase becomes more difficult. In mixtures using a poly (lactide-coglycolide) copolymer less rich in polymerized lactide, a weight% increase in poly (p-dioxanone) may be necessary to maintain the dimensional stability of the molded article. Such copolymers include 70/30 poly (lactide-coglycolide).
[00093] As noted earlier, the greater the amount of molecular orientation, or tension, present in the formed medical device, the greater the propulsion force to shrink or warp; shrinking and warping are generally seen as disadvantageous phenomena.
[00094] In the formation of devices using processing means that induce at least a moderate level of molecular orientation, or tension, it would be an advantage to maintain dimensional stability. Such a manufacturing methodology that generally induces at least a moderate level of stress is injection molding. To be clear, when a molten polymer flow is forced through a route that is
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30/65 narrow, and finally inside a cavity, high shear rates and high stress levels are generally encountered. When this happens, the molecular chains tend to orient themselves in the direction of flow, thereby preparing the system for further shrinkage or warping when subjected to slightly elevated temperatures, above the glass transition temperature, particularly during exposure to EtO gas while being sterilized. [00095] The evidence of a high shear formation process is the presence of high residual stresses in the part; these can be measured in a variety of ways. One way is to visualize a piece through crossed polarizing films. Other ways to assess residual stresses use scanning electron microscopy (SEM) techniques. The phase architecture of the substantially immiscible polymeric mixtures of lactide / glycolide and poly (p-dioxanone) copolymers provides additional evidence of the stress level that the mixture was subjected to during processing. When in high shear situations, the secondary phase is generally not spherical in nature. The secondary phase generally distorts elongated ellipsoids with L / Ds greater than about 3 for vermiform structures with L / D values of 50 or greater. The medical devices of the present invention will typically have representation ratios of the secondary phase greater than about 3, more typically greater than about 5, and preferably greater than about 20. Depending on the shear field, non-cross sections can be viewed circular ones that are more ribbon-shaped. When the secondary phase is substantially spherical in nature, it can be concluded that: (1) the shear level to which the polymeric melt material was subjected was a little low or (2) the processing conditions applied allowed the polymer melt to relax , and the subsequent elongated domains remodeled into L / D structures
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Much smaller. In either case, the residual stress level is expected to be low. A secondary phase morphology with beads alone can then be evidence of low residual stress.
[00096] Methods for ascertaining the phase architecture in immiscible polymeric mixtures include phase contrast microscopy (polarized light microscopy); atomic force microscopy (MFA); electron microscopy including scanning, tunneling and transmission electron microscopy (SEM, MET, MET). Other techniques potentially include high-resolution digital optical microscopy.
[00097] Sample preparation can be through cryogenic fracture or through microtomy techniques, including cryogenic microtomy. Solvent etching has proven to be a useful sample preparation methodology in numerous systems.
[00098] As it would be known to the person skilled in the art, when accessing the morphology of the secondary phase, it is important to realize that it is necessary to make measurements on the sample from different angular perspectives. Specifically, in parts with elongated characteristics, as can be found in the present article of this invention, an examination observing only the cross section can incorrectly indicate that the secondary phase is spherical in nature. Only when evaluated longitudinally will it be revealed that the secondary phase is really of an elongated nature, with a high aspect ratio.
[00099] The medical devices of the present invention will have an inherent viscosity of at least about 0.8 dL / g, as measured in hexafluoroisopropanol at 25 degrees centigrade, at a concentration of 0.1 g / dL. Additionally, the inherent viscosity of the lactide-rich polymer will be at least about 0.8 dL / g and the inherent viscosity of the poly (p-dioxanone) will be at least about 0.8 dL / g, both as measured in hexafluoroisopropanol at 25 degrees centigrade, at a concentration of 0.1 g / dL.
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[000100] The medical devices of the present invention will remain dimensionally stable when subjected to immersion in water, at an elevated temperature. Preferably, they will remain dimensionally stable when subjected to immersion in water, at 49 degrees centigrade. With the utmost preference, they will remain dimensionally stable when subjected to immersion in water, at 70 degrees centigrade.
[000101] In a preferred embodiment of the invention (EXAMPLE 7), the injection molded part is visible in the surgical field because the polymeric mixture has a violet dye, or coloring, interspersed throughout the part. This color, Violet D&C # 2, is introduced to the mixture as part of the poly homopolymer (p-dioxanone), which comprises from about 7% to about 24%, by weight, of the mixture. Alternatively, the dye can be introduced to the mixture as part of the lactide-based polymer. In yet another variation, staining can be added to the time that the polymer components are mixed together, such as during a mixture melt or dry mixing process. It will be apparent to the person skilled in the art that dyes can be added to the polymeric compositions of the present invention in a variety of conventional ways, in addition to the approaches described above. Dyes can include D&C Violet No. 2 and D&C Blue No. 6, in amounts ranging from about 0.01% by weight to about 0.3% by weight of the polymer mixture or the medical device. For surgical applications in which color is not necessary or desirable, the non-colored homopolymer poly (p-dioxanone) is used in the mixture, so that the surgical article has no color. [000102] The following examples are illustrative of the principles and practice of the present invention, although not limited to this.
Example 1
Synthesis of Poly (L (-) - lactide)
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33/65 [000103] Inside a suitable 56.8 L (15-gallon) jacketed stainless steel oil reactor equipped with stirring, 25.0 kg of L (-) - lactide were added together with 58.77 g of dodecanol and 4.38 ml of a 0.33M solution of stannous octoate in toluene. The reactor was closed and a purging cycle, together with agitation at a rotation speed of 12 RPM in an upward direction, was initiated. The reactor was subjected to vacuum at pressures below 26.7 Pa (200 mTorr), followed by the introduction of nitrogen gas. The cycle was repeated several times to ensure a dry atmosphere.
[000104] At the end of the last introduction of nitrogen, the pressure was adjusted to be slightly above an atmosphere. The vessel was heated at a rate of 180 ° C per hour until the oil temperature had reached approximately 130 ° C. The vessel was maintained at 130 ° C until the monomer was completely melted and the batch temperature had reached 110 ° C. At this point, the rotation by agitation was switched to the downward direction. When the batch temperature reached 120 ° C, the agitator speed was reduced to 7.5 RPM and the vessel was heated using an oil temperature of approximately 180 ° C, with a heating rate of approximately 60 ° C per hour. When the melt reached 178 ° C, the oil temperature was maintained at approximately 180 ° C, for an additional 3 hours.
[000105] At the end of the reaction period, the agitator speed was reduced to 5 RPM, the oil temperature was increased to 190 ° C, and the polymer was discharged from the container into suitable containers for subsequent annealing . The containers were introduced into the nitrogen annealing furnace set at 80 ° C for a period of approximately 16 hours; during this stage, the nitrogen flow inside the oven was maintained to reduce degradation due to moisture.
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34/65 [000106] Once this annealing cycle was completed, the polymer containers were removed from the oven and allowed to cool to room temperature. The crystallized polymer was removed from the containers and placed in a freezer adjusted to approximately -20 ° C, for a minimum of 24 hours. The polymer was removed from the freezer and placed inside a Cumberland granulator fitted with an ironing screen to reduce the polymer granules to approximately 0.48 cm (3/16 inches) in size. The granules were then sieved to remove any fine solids, and weighed. The net weight of the ground polymer was 18.08 kg, which was then placed in a Patterson - Kelley dryer, 85.0 L (3 cubic feet).
[000107] The dryer was closed and the pressure was reduced to less than 26.7 Pa (200 mTorr). When the pressure was below 26.7 Pa (200 mTorr), the dryer rotation was activated at a rotation speed of 5 to 10 RPM without heat, for 10 hours. After the 10 hour period, the oil temperature was adjusted to 120 ° C, at a heating rate of 120 ° C per hour. The oil temperature was maintained at approximately 120 ° C for a period of 32 hours. At the end of this heating period, the batch was cooled naturally over a period of 4 hours, while rotation and vacuum were maintained. The polymer was discharged from the dryer by pressurizing the container with nitrogen by opening the discharge valve and allowing the polymer granules to descend into the containers for long-term storage.
[000108] The containers for long-term storage were airtight and equipped with valves, allowing evacuation so that the resin was stored under vacuum. The resin was characterized. It showed an inherent viscosity of 1.84 dL / g, as measured in hexafluoroisopropanol at 25 ° C, and at a concentration of 0.10 g / dL. THE
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35/65 analysis by gel permeation chromatography demonstrated an average molecular weight of approximately 121,000 Daltons. Differential scanning calorimetry revealed a glass transition temperature of 65 ° C and a melting transition at 182 ° C. Nuclear magnetic resonance analysis confirmed that the resin was poly (L (-) lactide) with a residual monomer content less than 1.0 percent. X-ray diffraction analysis showed a crystallinity level of approximately 64 percent.
Example 2
Synthesis of Poly (L (-) - lactide-coglycolide) 85/15 [000109] Inside a suitable jacketed stainless steel reactor of 56.8 L (15-gallons) equipped with agitation, 43.778 kg of L ( -) - lactide and 6.222 kg of glycolide were added together with 121.07 g of dodecanol and 9.02 mL of a 0.33M solution of stannous octoate in toluene. The reactor was closed and a purge cycle, together with agitation at a rotation speed of 12 RPM in an upward direction, was initiated. The reactor was subjected to vacuum at pressures below 26.7 Pa (200 mTorr) followed by the introduction of nitrogen gas. The cycle was repeated several times to ensure a dry atmosphere.
[000110] At the end of the last introduction of nitrogen, the pressure was adjusted to be slightly above an atmosphere. The vessel was heated at a rate of 180 ° C per hour, until the oil temperature had reached approximately 130 ° C. The vessel was maintained at 130 ° C until the monomer was completely melted and the batch temperature had reached 110 ° C. At this point, the rotation by agitation was switched to the downward direction. When the batch temperature reached 120 ° C, the agitator speed was reduced to 7.5 RPM and the vessel was heated using an oil temperature of approximately 185 ° C, with a rate of
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36/65 heating of approximately 60 ° C per hour, until the melt reached 180 ° C. The oil temperature was maintained at approximately 185 ° C for a period of 2.5 hours.
[000111] At the end of the reaction period, the agitator speed was reduced to 5 RPM, the oil temperature was increased to 190 ° C, and the polymer was discharged from the container into suitable containers for subsequent annealing. The containers were introduced into the nitrogen annealing oven set at 105 ° C, for a period of approximately 6 hours; during this stage, the nitrogen flow inside the oven was maintained to reduce degradation due to moisture.
[000112] Once this annealing cycle was completed, the polymer containers were removed from the oven and allowed to cool to room temperature. The crystallized polymer was removed from the containers and placed in a freezer adjusted to approximately -20 ° C, for a minimum of 24 hours. The polymer was removed from the freezer and placed inside a Cumberland granulator fitted with an ironing screen to reduce the polymer granules to approximately 0.48 cm (3/16 inches) in size. The granules were then sieved to remove any fine solids and then weighed. The net weight of the ground polymer was 39.46 kg, which was then placed in a Patterson - Kelley dryer of 85.0 L (3 cubic feet).
[000113] The dryer was closed and the pressure was reduced to less than 26.7 Pa (200 mTorr). When the pressure was below 26.7 Pa (200 mTorr), the rotation was activated at a rotation speed of 8 to 15 RPM and the batch was vacuum conditioned for a period of 10 hours. After 10 hours of vacuum conditioning, the oil temperature was adjusted to a temperature of 120 ° C over a period of 32 hours. At the end of this warm-up period, the batch was
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37/65 cooled naturally over a period of at least 4 hours, while rotation and high vacuum were maintained. The polymer was discharged from the dryer by pressurizing the container with nitrogen, opening the sliding door and allowing the polymer granules to descend into the containers for long-term storage.
[000114] The containers for long-term storage were airtight and equipped with valves, allowing evacuation in a baited manner the resin was stored under vacuum. The resin was characterized. It showed an inherent viscosity of 1.64 dL / g, as measured in hexafluoroisopropanol at 25 ° C and at a concentration of 0.10 g / dL. Gel permeation chromatography analysis showed an average molecular weight of approximately 96,200 Daltons. Differential scanning calorimetry revealed a glass transition temperature of 56 ° C and a melting transition at 154 ° C. Nuclear magnetic resonance analysis confirmed that the resin was a random copolymer of polymerized L (-) - lactide and glycolide, with a composition of 83.1 percent polymerized L (-) - lactide, 15.2 percent glycolide. polymerized, 1.6 percent lactide monomer, and 0.1 percent glycolide monomer, as measured on a molar basis. The total residual monomer content was approximately 1.7 percent. The X-ray diffraction analysis showed a crystallinity level of approximately 48 percent.
Example 3
Synthesis of Poly (L (-) - lactide-coglycolide) 75/25 [000115] Inside a suitable jacketed stainless steel reactor of 56.8 L (15-gallons) equipped with agitation, 19.709 kg of L ( -) - lactide and 5,291 kg of glycolide were added together with 61.77 g of dodecanol and 4.60 ml of a solution of 0.33M stannous octoate in toluene. The reactor was closed and a purge cycle,
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38/65 together with stirring at a rotation speed of 12 RPM in an upward direction, was started. The reactor was subjected to vacuum at pressures below 26.7 Pa (200 mTorr) followed by the introduction of nitrogen gas. The cycle was repeated several times to ensure a dry atmosphere.
[000116] At the end of the last introduction of nitrogen, the pressure was adjusted to be slightly above an atmosphere. The vessel was heated at a rate of 180 ° C per hour until the oil temperature had reached approximately 130 ° C. The vessel was maintained at 130 ° C until the monomer was completely melted and the batch temperature had reached 110 ° C. At this point the stirring rotation was switched to the downward direction. When the batch temperature reached 120 ° C, the agitator speed was reduced to 7.5 RPM, and the vessel was heated using an oil temperature of approximately 185 ° C, with a heating rate of approximately 60 ° C per hour . When the melt reached 180 ° C, the oil temperature was maintained at approximately 185 ° C for an additional 2.5 hours.
[000117] At the end of the reaction period, the agitator speed was reduced to 5 RPM, the oil temperature was increased to 190 ° C, and the polymer was discharged from the container into suitable containers for subsequent annealing. The containers were introduced into the nitrogen annealing oven set at 105 ° C, for a period of approximately 6 hours; during this stage, the nitrogen flow inside the oven was maintained to reduce degradation due to moisture.
[000118] Once this annealing cycle was completed, the polymer containers were removed from the oven and allowed to cool to room temperature. The crystallized polymer was removed from the containers and placed in a freezer adjusted to
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39/65 approximately -20 ° C for a minimum of 24 hours. The polymer was removed from the freezer and placed inside a Cumberland granulator fitted with a screen ironing to reduce the polymer granules to approximately 0.48 cm (3/16 inches) in size. The granules were then sieved to remove any fine solids and then weighed. The net weight of the ground polymer was 17.89 kg, which was then placed in a 85.0 L (3 cubic feet) Patterson - Kelley dryer.
[000119] The dryer was closed and the pressure was reduced to less than 26.7 Pa (200 mTorr). When the pressure was below 26.7 Pa (200 mTorr), the rotation was activated at a rotation speed of 5 to 15 RPM and the polymer was conditioned for 16 hours in a vacuum without heat. The dryer temperature was then adjusted to 60 to 65 ° C at a heating rate of 100 ° C per hour. The oil temperature was maintained at 60 to 65 ° C for a period of approximately 9 hours. At the end of this heating period, the batch was cooled naturally for a period of at least 4 hours, while rotation and high vacuum were maintained. The polymer was discharged from the dryer by pressurizing the container with nitrogen, opening the sliding door and allowing the polymer granules to descend into the containers for long-term storage.
[000120] The containers for long-term storage were airtight and equipped with valves, allowing evacuation so that the resin was stored under vacuum. The resin was characterized. It showed an inherent viscosity of 1.56 dL / g, as measured in hexafluoroisopropanol at 25 ° C and at a concentration of 0.10 g / dL. The gel permeation chromatography analysis showed an average molecular weight of approximately 102,000 Daltons. Differential scanning calorimetry revealed a glass transition temperature of 48 ° C and a melting transition at 132 ° C. The analysis of
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40/65 nuclear magnetic resonance confirmed that the resin was a random copolymer of polymerized L (-) - lactide and glycolide, with a composition of 70.1 percent polymerized L (-) - lactide, 25.2 percent glycolide polymerized, 4.5 percent lactide monomer, and 0.2 percent glycolide monomer, as measured on a molar basis. The total residual monomer content was less than 5 percent. X-ray diffraction analysis showed a crystallinity level of approximately 26 percent.
Example 4
Synthesis of Poly (p-Dioxanone) [000121] Inside a suitable 246.1 L (65 gallon) jacketed stainless steel oil reactor equipped with stirring, 164.211 kg of monomer p-dioxanone (PDO) was added together with 509 grams of dodecanol, 164 grams of D&C Violet dye # 2, and 100 grams of a 0.33M solution of stannous octoate in toluene. The reactor was closed and a purging cycle, together with agitation at a rotation speed of 12 RPM in an upward direction, was initiated. The reactor was subjected to vacuum at pressures below 66.7 Pa (500 mTorr) followed by the introduction of nitrogen gas. The cycle was repeated several times to ensure a dry atmosphere.
[000122] At the end of the last nitrogen introduction, the pressure was adjusted to be slightly above an atmosphere. The vessel was heated at a rate of 180 ° C per hour until the oil temperature had reached approximately 100 ° C. The vessel was maintained at 100 ° C until the batch temperature had reached 50 ° C, to the point where the agitator rotation was changed to the downward direction. When the batch temperature reached 90 ° C, the oil temperature was adjusted to 95 ° C. These conditions were maintained and samples were taken from the container to be measured
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41/65 by Brookfield viscosity. When the viscosity of the polymer batch reached at least 110 centipoise, the batch was ready for unloading. The agitator speed was reduced to 5 RPM, and a preheated filter was attached to the container discharge port. The polymer was discharged from the container into suitable containers, under a nitrogen purging, covered, and transferred to a nitrogen curing oven set at 80 ° C. A solid state polymerization was initiated over a period of approximately 96 hours; During this stage, the nitrogen flow inside the oven was maintained to minimize degradation due to moisture.
[000123] Once this solid state curing cycle has been completed, the polymer containers were removed from the oven and allowed to cool to room temperature. The crystallized polymer was removed from the containers and placed in a freezer adjusted to approximately -20 ° C for a minimum of 24 hours. The polymer was removed from the freezer and ground in a Cumberland granulator fitted with an ironing screen to reduce the polymer granules to approximately 0.48 cm (3/16 inches) in size. The granules were then sieved to remove any fine solids and then placed in a 566.3 L (20 cubic foot) Patterson - Kelley dryer.
[000124] The dryer was closed and the pressure was reduced to less than 2 mm Hg. When the pressure was below 2 mm Hg, the rotation of the dryer was activated at a rotation speed of 6 RPM, without heat for 10 hours. After the 10 hour period, the oil temperature was adjusted to 95 ° C at a heating rate of 120 ° C per hour. The oil temperature was maintained at approximately 95 ° C for a period of 32 hours. At the end of this heating period, the batch was cooled naturally for a period of at least 4 hours, while rotation and high vacuum were maintained. The polymer
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42/65 was discharged from the dryer by pressurizing the container with nitrogen, opening the discharge valve, and allowing the polymer granules to descend into the containers for long-term storage. The containers for long-term storage were airtight and equipped with valves, allowing evacuation so that the resin was stored under vacuum.
[000125] The resin was characterized. It showed an inherent viscosity of 1.99 dL / g, as measured in hexafluoroisopropanol at 25 ° C and at a concentration of 0.10 g / dL. Gel permeation chromatography analysis showed an average molecular weight of approximately 85,000 Daltons. Differential scanning calorimetry revealed a glass transition temperature of about -15 ° C and a melting transition of about 105 ° C. Nuclear magnetic resonance analysis confirmed that the resin was the poly homopolymer (pdioxanone) with a residual monomer content of less than 2 percent. The X-ray diffraction analysis demonstrated a crystallinity level of approximately 40 percent. For polymers with a different molecular weight than the target, the initiator (dodecanol) can be adjusted to achieve the required I.V. In addition, if the surgical application does not require a colored article, the addition of dye can be eliminated from the process steps, thereby producing a polymer that is natural or not colored.
Example 5
Dry Mixing [000126] When the lactide / glycolide and poly (p-dioxanone) polymers were produced by the methods described above, adequate amounts of these components, in split (ground) form were combined in a dry mixture. These dry mixes are produced based on weight, depending on the specific application and the surgical need. In the present example, 20% poly (p-dioxanone), in
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43/65 weight, and an 80 wt% lactide / glycolide copolymer were mixed dry.
[000127] In a clean Patterson-Kelley dryer of 85.0 L (3-cubic feet), 36.0 kg of granules of the 85/15 lactide / glycolide molar copolymer of EXAMPLE 2 were weighed and added to the dryer. In the same 85.0 L (3-cubic foot) dryer, 9.0 kg of poly (p-dioxanone) polymer granules from EXAMPLE 4 were weighed and added to the dryer. The dryer was closed, and the vessel pressure was reduced to less than 26.7 Pa (200 MTorr). The rotation started to
7.5 RPM and continued for a minimum of one hour. The dry mixture was then discharged into the portable vacuum storage containers, and these containers were vacuum-treated, until it was ready for the next step.
[000128] In accordance with the purposes of this invention, mixtures of this type can be produced in a similar way with different compositions. Other compositions of the invention that have been made are summarized in Table I. In addition, some mixtures of the prior art, specifically Smith mixtures, were made for comparison purposes. Three mixtures that were made contained 30% by weight of poly (p-dioxanone) and 70% by weight of a lactide / glycolide copolymer with 80, 85 and 90 mol% of polymerized L (-) - lactide, respectively. Again, for some demanding situations, these mixtures containing more than about 24% by weight of poly (pdioxanone) are very soft.
Example 6
Casting Mixture [000129] When dry mixtures have been produced and have been vacuum-conditioned for at least three days, the casting stage of the mix can begin. A twin-screw ZSK-30 extruder was fitted with threads created for the molten state mix using
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44/65 double vacuum ports for the purpose of volatilization of the residual monomer. The thread design contained several different types of elements, including conveying, compacting, mixing and sealing elements. The extruder was fitted with a three-hole matrix plate, and an ice water bath with the water temperature adjusted between 4.4 and 21.1 ° C (between 40 and 70 ° F) was placed close to the extruder outlet. A pelletizing cord and a pelletizer were placed at the end of the water bath. The temperature zones of the extruder were heated to a temperature of 160 to 180 ° C, and the cold vacuum traps were set to -20 ° C. The preconditioned dry mix granules were removed from the vacuum and placed in a double screw metering hopper under nitrogen purging. The threads of the extruder were adjusted at a speed of 175 to 225 RPM, and the doser was turned on, allowing the dry mixture to be introduced into the extruder.
[000130] The melted polymeric mixture was left to purge through the extruder until the mixture was consistent, to the point where the vacuum was applied to the two vacuum ports. The extruded strands of the polymeric mixture were introduced through the water bath and into the strand pelletizer. The pelletizer cuts the strings into suitably sized pellets; pellets with a diameter of 1 mm and an approximate length of 3 mm have been found to be sufficient. The pellets were then fed into the classifier. The classifier separated larger and smaller pellets of the desired size, usually a weight of about 10 to 15 mg per pellet. This process continued until the dry polymer mixture was mixed in a molten state in the extruder, and formed into substantially uniform pellets. Samples were taken through the entire extrusion process and the characteristics of the polymer such as inherent viscosity, molecular weight and composition were measured. When the
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45/65 The melting process of the mixture was completed, the pelleted polymer was placed in polyethylene bags, weighed, and stored in a freezer below -20 ° C to wait for the devolution of the residual monomer.
[000131] The melted polymer mixture was placed in a Patterson-Kelley dryer of 85.0 L (3-cubic feet), which was placed under vacuum. The dryer was closed and the pressure was reduced to less than 26.7 Pa (200 mTorr). When the pressure was below 26.7 Pa (200 mTorr), the dryer rotation was activated at a rotation speed of 10 RPM, without heat for 6 hours. After the 6 hour period, the oil temperature was adjusted to 120 ° C, at a heating rate of 85 ° C per hour. The oil temperature was maintained at approximately 85 ° C for a period of 12 hours. At the end of this heating period, the batch was cooled naturally for a period of at least 4 hours, while rotation and high vacuum were maintained. The pellets of the molten polymeric mixture were discharged from the dryer by pressurizing the container with nitrogen, opening the discharge valve, and allowing the polymer pellets to descend into the containers for long-term storage. The containers for long-term storage were airtight and equipped with valves, allowing evacuation so that the resin was stored under vacuum. The resin was characterized.
[000132] The dry mixture of EXAMPLE 5 was mixed in a molten state by the process described above. The resulting molten mixture showed an inherent viscosity of 1.70 dL / g, as measured in hexafluoroisopropanol at 25 ° C and at a concentration of 0.10 g / dL. Gel permeation chromatography analysis demonstrated an average molecular weight of approximately 88,000 Daltons. Differential scanning calorimetry revealed two glass transition temperatures of about -15 ° C and 55 ° C, and two glass transition temperatures
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46/65 melting at about 105 and 150 ° C. Nuclear magnetic resonance analysis confirmed that the resin was a mixture of poly (p-dioxanone) and 85/15 lactide / glycolide copolymer (mol%), with a composition of approximately 64 percent polymerized lactide, 24 percent poly (p-dioxanone), and 11 percent polymerized glycolide, as measured on a molar basis. The total residual monomer content was less than 2 percent. X-ray diffraction analysis showed a crystallinity level of approximately 40 percent.
[000133] As previously mentioned in EXAMPLE 5, mixtures of various compositions comprising poly (p-dioxanone), polylactide homopolymers, and lactide-rich lactide / glycolide copolymers were produced by the method described above. For the purposes of this invention, the polymers and melt mixtures described below in Table I were produced using these methods. The polymer of EXAMPLES 1 and the molten mixtures of EXAMPLE 6 were injection molded into the surgical articles described in EXAMPLE 7, and were analyzed for their physical, biological and chemical characteristics. Table I
Molten Mixtures of Poly (p-dioxanone) and a Lactide / Lactide Rich Glycolide Copolymer
Exemplo Mixture Composition Based on%, Poly Weight (p-dioxanone) / L / G Copolymer Percent in Poly Weight (pdioxanone) Mol% of Lactide in L / G Copolymer 6 A 0% Poly (p-dioxanone) /100% APL 0.0 100.0 6 B 5% Poly (p-dioxanone) / 95%APL 5.0 100.0 6 C 7.5% Poly (p-dioxanone) /92.5% APL 7.5 100.0
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Example Mixture Composition Based on%, Poly Weight (p-dioxanone) / L / G Copolymer Percent in Poly Weight (pdioxanone) Mol% of Lactide in L / G Copolymer 6 D 9% Poly (p-dioxanone) / 91%APL 9.0 100.0 6 H 9% Poly (p-dioxanone) / 91%APL / APG 90/10 9.0 90.0 6 E 10% Poly (p-dioxanone) / 90%APL 10.0 100.0 6 L 10% Poly (p-dioxanone) / 90%APL / APG 85/15 10.0 85.0 6 J 12% Poly (p-dioxanone) / 88%APL / APG 90/10 12.0 90.0 6 P 13% Poly (p-dioxanone) / 87%APL / APG 80/20 13.0 80.0 6K 15% Poly (p-dioxanone) / 85%APL / APG 90/10 15.0 90.0 6 M 15% Poly (p-dioxanone) / 85%APL / APG 85/15 15.0 85.0 6 S 15% Poly (p-dioxanone) / 85%APL / APG 75/25 15.0 75.0 6 Q 17% Poly (p-dioxanone) / 83%APL / APG 80/20 17.0 80.0 6 T 17.5% Poly (p-dioxanone) /82.5% APL / APG 75/25 17.5 75.0 6 G 20% Poly (p-dioxanone) / 80%APL / APG 95/5 20.0 95.0 6 N 20% Poly (p-dioxanone) / 80%APL / APG 85/15 20.0 85.0
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Exemplo Mixture Composition Based on%, Poly Weight (p-dioxanone) / L / G Copolymer Percent in Poly Weight (pdioxanone) Mol% of Lactide in L / G Copolymer 6 R 20% Poly (p-dioxanone) / 80%APL / APG 80/20 20.0 80.0 6 W 20% Poly (p-dioxanone) / 80%APL / APG 75/25 20.0 75.0 6 F 24% Poly (p-dioxanone) / 76%APL 24.0 100.0 6 X 24% Poly (p-dioxanone) / 76%APL / APG 75/25 24.0 75.0 Exemp the 7
Test Article Description [000134] The article chosen for evaluation was a 5 mm laparoscopic device for hernia repair; it was in the form of a clamp or belt with teeth and means of retaining tissue to the end of the teeth. The device is illustrated in Figure 2. The article was geometrically complex and was sterilized using conventional ethylene oxide gas sterilization processes after being subjected to an annealing process. The device was used to fix the prosthetic mesh mesh to the soft tissue in both laparoscopic and open procedures.
Example 8
Injection Molding [000135] Injection molding is a process well known in the plastic industry. It is designed to produce parts of various shapes and sizes by melting the plastic, mixing and then injecting the molten resin into a suitable shaped mold. After the resin is solidified, the part is usually expelled from the
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49/65 mold and the process continues.
[000136] For the purposes of this invention, a conventional electrically controlled injection molding machine of
27,215.5 kg (30 ton) was used. The polymer of EXAMPLE 1 and the polymeric mixtures of EXAMPLE 6 were processed in the following general manner. The polymer and polymeric mixtures were introduced by gravity from a hopper, under nitrogen purging inside a heated cylinder. The polymer was moved forward in the cylinder by the threaded plunger in a heated chamber. As the thread advanced forward, the melted polymer and polymer mixtures were forced through a nozzle that rests against a mold, allowing the polymer and polymer mixtures to enter a specially designed mold cavity, through a door and the sprue system. The mixture was formed inside the part in the mold cavity, and naturally cooled to a certain temperature over a period of time. It was then removed from the mold, or expelled, and separated from the door and sprue. The injection molding cycle consisted of entire series of events during the process. It started when the mold closed, and was followed by the injection of polymers and polymeric mixtures into the mold cavity. When the cavity was filled, the support pressure was maintained to compensate for the shrinkage of the material. Then, the threaded plunger was threaded, feeding the next dose in front of the thread. The thread retracted as the next dose was prepared. The part was cooled in the mold to a sufficient temperature, the mold opened and the part was expelled. The closing and ejection times lasted from a fraction of a second to a few seconds. Cooling times were based on a number of factors, including the size and composition of the part material.
Example 9
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Annealing of Molded Part [000137] When the articles in EXAMPLE 8 were injection molded, they were then subjected to an annealing cycle to mature the polymer's morphology. As noted earlier, this often increases the level of crystallinity in the part. The articles in EXAMPLE 8 were annealed using an annealing accessory that supported the distortion parts in the horizontal plane of the part. Although this annealing accessory is intended to assist in resisting distortion at elevated temperatures during annealing, it will not prevent dimensionally unstable parts from the warp.
[000138] The annealing cycle used for the articles in EXAMPLE 8 was composed of three stages: 60 ° C for 8 hours, 70 ° C for 4 hours, and then 80 ° C for 4 hours. The purpose of the 60 ° C step is to crystallize the poly (p-dioxanone) phase in the mixture before reaching the crystallization temperatures for the poly (lactide-coglycolide) phase. The 70 ° C step begins to crystallize the poly (lactide-coglycolide) phase before reaching the last step in the cycle. Finally, the 80 ° C step further crystallizes the poly (lactide-coglycolide) phase.
[000139] It should be noted that for a given device and certain conditions mentioned in the annealing composition, certain important characteristics that optimize performance can be discovered. These advantageous annealing conditions can be developed through experimentation, changing the temperature and duration of the annealing, and measuring the response.
Example 10
Analytical Characterization of Molded Parts [000140] In general, the molded parts were characterized by chemical composition by nuclear magnetic resonance (NMR); molecular weight by the viscosity inherent in hexafluoroisopropanol at
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0.1 g / dL at 25 ° C, and / or gel permeation chromatography (GPC); by morphology through X-ray diffraction, differential scanning calorimetry (CVD), and etching by chemical corrosion. The analysis was performed on the parts before annealing, after annealing, and often after sterilization with EtO.
[000141] The crystallinity levels of the selected batches of the injection molded annealed articles can be found in the Table below.
Table II
Crystallinity Levels of Selected Batches of Annealed Injection Molded Items
Poly (p-dioxanone)%, by weight, in the mixture Molar% of Glycolide Content in Lactide / Glycolide Copolymer % of Crystallinity Level as Measured by X-Ray Diffraction 20 10 45.0 20 10 45.9 20 12 46.4 20 15 38.4 20 15 39.9 20 15 38.2 20 15 42.6 20 20 38.9 30 15 36.3 30 20 45.6
Example 11
In Vitro Tests; Mechanical Properties [000142] Selected batches of the annealed molded articles from EXAMPLE 9 were tested for their mechanical properties using an INSTRON tensile testing machine, model 5544
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52/65 fitted with a suitable load cell. The articles were placed in an accessory designed to catch the barbed teeth at one end and the crown at the other. The breaking force was recorded as Day Zero Breaking Strength.
Example 12
In Vitro Tests; RRR tests [000143] Selected batches of the annealed molded articles from EXAMPLE 9 were placed in containers filled with an adequate amount of pH 7.27 phosphate buffer. The containers were then incubated at 37 ° C and a representative sample size, typically ten, was recovered periodically for mechanical testing. The incubated articles were tested for their mechanical properties using an INSTRON tensile testing machine, in a manner similar to the method of EXAMPLE 11. The breaking strength was recorded as Breaking Strength. The ratio between Break Resistance and Day Zero Break Resistance was calculated and recorded as Break Resistance Retention for each period of time. The test results are graphically presented in Figure 4. Figure 4 is a graph showing the effects of compositional changes to the injection molded device, when related to the retention of rupture resistance or RRR, after being subjected to the in vitro test.
Example 13
Penetration [000144] The test articles in EXAMPLE 9N were tested for their ability to penetrate body tissue and fix the surgical mesh. Using an INSTRON machine, the force required to attach a commercially available surgical mesh to the porcine belly was measured. The penetration test used customized accessories above and below. The top accessory was a strength
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53/65 laying keel to push the tack through the mesh, while the bottom accessory was a claw to hold the belly of the pig in place.
[000145] The test articles in EXAMPLE 9N worked properly. This means that they had a suitably sharp tip, dimensional stability, and had adequate stiffness and column strength. Depending on the functional need of the article, this stiffness can be increased by lowering the level of poly (p-dioxanone), as for orthopedic applications. Similarly, stiffness can be decreased by increasing the level of poly (pdioxanone), as for soft tissue applications.
Example 14
Retention Strength [000146] The ability to attach the surgical mesh to body tissue is an important function, especially during the critical wound healing period. The fixed surgical mesh was subjected to mechanical forces to determine the force required to loosen the mesh mesh from the tissue; this force is called Retention Resistance. More specifically, the surgical mesh was attached to the porcine belly by inserting three articles from EXAMPLE 9N together with one side of the mesh. The mesh was then secured with claws attached to a forced gauge and pushed in a shear direction (parallel to the plane of the fabric) until the mesh was released from the fabric. The maximum force was recorded as the Retention Strength. EXAMPLE 9N articles generated values of clamping force of about 10 to 11 pounds. Depending on the medical application, the requirement for retention strength will vary and the composition of the article used may be adjusted to meet this requirement.
[000147] Retention strength data for articles produced
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54/65 from mixtures of various weights of the average molecular weight in the 20% by weight of poly (p-dioxanone) / 80% by weight of the composition of poly (L (-) - lactide-coglycolide ) 85/15 were obtained. The data are provided in Table III below:
Table III
Retention Strength Data on Various Molecular Weights
Average Pond Molecular Weight Retention Resistance (N (Gives) (lbs)) 91,200 49.2 (11.06) 85,100 46.0 (10.34) 74,200 46.0 (10.34) 66,600 48.7 (10.95) 58,000 45.2 (10.16) 53,400 48.0 (10.80)
Example 15
Dimensional Stability [000148] The unheated articles of EXAMPLE 8N were subjected to X-ray diffraction analysis, and showed levels of crystallinity of about 11 to 12 percent total. Most of the crystallinity was attributed by X-ray diffraction (XRD) techniques to the poly (p-dioxanone) phase. When annealed, the molded parts had superior dimensional stability. The EXAMPLE 9 articles demonstrated higher levels of crystallinity than their counterparts in EXAMPLE 8. In fact, the annealed articles of EXAMPLE 9N were also analyzed by X-ray diffraction (XRD) and demonstrated higher levels of crystallinity, around 38 to 41 percent.
[000149] The molded articles of EXAMPLE 9 were tested for dimensional stability. The dimensions of the molded articles were measured before annealing and after annealing; additional photographic images were taken. Although it is not expected to have
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55/65 exact corresponding dimensions, it is clear that unacceptable levels of distortion exist. In some cases, excessive distortion results in decreased functionality.
[000150] The test articles in EXAMPLE 9 are geometrically complex and have numerous critical dimensions. For example, if the teeth of the molded article distort excessively, the ability of the device to penetrate and trap the tissue will be reduced. Similarly, if the barbs of the molded article have significantly shrunk, functionality would be reduced due to the decreased ability to hold the fabric. Each drawing will have its own critical dimensions. It is believed that the design of EXAMPLE 7 is representative of a demanding device with respect to dimensional stability; this is felt in part because of the geometric complexity. Additionally, the size of the thin part tends to increase the molecular orientation during injection molding leading to an increased propulsion force for the distortion of the part expelled at elevated temperatures, as seen in annealing, and / or sterilization, and / or storage.
[000151] The parts were evaluated and characterized in a way to pass / fail. The layout of the molded articles was based on raw warp effects, to which an article is considered to have been approved if excessive distortion is not evident. Similarly, if excessive distortion is evident, the part is considered to have failed. Inherently, all injection molded articles have some degree of residual stress after molding, so that parts with tolerable levels of distortion are considered to have passed the dimensional stability test.
[000152] For the articles in EXAMPLE 9, the end-to-end distance is a critical dimension; see Figure 3. Figure 3 is a drawing of the device in Figure 2 showing the critical dimensions of said device.
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56/65 vo. These dimensions, if altered due to lack of dimensional stability, can lead to poor performance and / or device failure. A tip-to-tip distance of less than 0.29 cm (0.115 inches) for the items in EXAMPLE 9 was considered acceptable, while a tip-to-top distance greater than or equal to 0.29 cm (0.115 inches) was considered unacceptable and denoted as failure mode one or mf1. Similarly, the length of the barb elements in EXAMPLE 9 was also considered to be of critical dimensions. A splinter length less than or equal to 0.35 cm (0.136 inches) was considered unacceptable and denoted as failure mode 2 or mf2.
[000153] The photographic images and dimensions were captured using a Keyence digital microscope, model VHX-600, with a magnification of 20 times. The test results are shown in Table IV.
Table IV
Results of Dimensional Stability in Injection Molded Articles of Examples 8 and 9 produced from Lactide / Glycolide Copolymer Rich in Lactide with Poly (o-dioxanone) Melted Mixtures of Example 6
Molded Device EXAMPLE No. * Before Annealing FIGURE No. After Annealing FIGURE No. Degree of StabilityDimensional / Reason for Failure ** 8 and 9 A (0.100) Failed: mf1, mf2 8 and 9 B (5,100) Failed: mf1 8 and 9 C (7.5,100) 6th 6b Failed: mf1 8 and 9 D (9,100) 7th 7b Approved 8 and 9 E (10,100) Approved 8 and 9 F (24,100) Approved
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Molded Device EXAMPLE No. * Before Annealing FIGURE No. After Annealing FIGURE No. Degree of StabilityDimensional / Reason for Failure ** 8 and 9 G (20.95) Approved 8 and 9 H (9.90) Failed: mf1, mf2 8 and 9 J (12.90) Approved 8 and 9 K (15.90) Approved 8 and 9 L (10.85) Failed: mf1 8 and 9 M (15.85) Approved 8 and 9 N (20.85) 8th 8b Approved 8 and 9 P (13.80) Failed: mf2 8 and 9 Q (17.80) Approved 8 and 9 R (20.80) Approved 8 and 9 S (15.75) 9a 9b Failed: mf1 8 and 9 T (17.5.75) 10th 10b Approved 8 and 9 W (20.75) Approved 8 and 9 X (24.75) 11a 11b Approved
* EXAMPLE 8 refers to articles molded prior to annealing, while EXAMPLE 9 is after annealing ** Failure modes:
mf1 = Increase in end-to-end distance;
mf2 = Shrinkage of one or both splinters [000154] Figure 6a is a photograph of an injection molded tack in EXAMPLE 8C (ie, prior to annealing) produced from the polymer composition of EXAMPLE 6C that provided tacks molded by injection showing unacceptable warp after annealing. Figure 6b is a photograph of an injection molded tack in EXAMPLE 9C (similar to the tack in Figure 6a, but after annealing) produced from the polymer composition of EXEMPetição 870190087583, from 09/05/2019, pg. 61/81
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PLO 6C which supplied injection molded tacks with unacceptable warp after annealing.
[000155] Figure 7a is a photograph of an injection molded tack in EXAMPLE 8D (that is, prior to annealing) produced from the polymer composition of EXAMPLE 6D that provided injection molded tacks with superior dimensional stability and a level acceptable warp after annealing. Figure 7b is a photograph of an injection molded tack in EXAMPLE 9D (similar to the tack of Figure 7a, but after annealing) produced from the polymer composition of EXAMPLE 6D that provided the injection molded tack that has superior dimensional stability and an acceptable level of warp after annealing.
[000156] Figure 8a is a photograph of an injection molded tack in EXAMPLE 8N (that is, prior to annealing) produced from the polymer composition of EXAMPLE 6N that provided injection molded tacks with superior dimensional stability and a level acceptable warp after annealing. Figure 8b is a photograph of an injection molded tack in EXAMPLE 9N (similar to the tack in Figure 8a, but after annealing) produced from the polymer composition of EXAMPLE 6N that provided injection molded articles that exhibit superior dimensional stability and an acceptable level of warp after annealing.
[000157] Figure 9a is a photograph of an injection molded tack in EXAMPLE 8S (ie, prior to annealing) produced from the polymer composition of EXAMPLE 6S that supplied the injection molded studs showing unacceptable warping after annealing. Figure 9b is a photograph of an injection molded tack in EXAMPLE 9S (similar to the tack of Figure 9a, but after annealing) produced from the polymer composition of EXAMPLE 6S, which provided the injection molded studs presented
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59/65 making warp unacceptable after annealing.
[000158] Figure 10a is a photograph of an injection molded tack in EXAMPLE 8T (ie, prior to annealing) produced from the polymer composition of EXAMPLE 6T that provided injection molded tacks with superior dimensional stability and a level acceptable warp after annealing. Figure 10b is a photograph of an injection molded tack in EXAMPLE 9T (similar to the tack in Figure 10a, but after annealing) produced from the polymer composition of EXAMPLE 6T that provided the injection molded tack that has superior dimensional stability and an acceptable level of warp after annealing.
[000159] Figure 11a is a photograph of an injection molded tack in EXAMPLE 8X (that is, prior to annealing) produced from the polymer composition of EXAMPLE 6X that provided injection molded tacks with superior dimensional stability and a level acceptable warp after annealing. Figure 11b is a photograph of an injection molded tack in EXAMPLE 9X (similar to the tack in Figure 11a, but after annealing) produced from the polymer composition of EXAMPLE 6X that provided the injection molded tack that has superior dimensional stability and an acceptable level of warp after annealing. Example 16
Absorption Profile [000160] The articles of the present invention are absorbable in body tissue. In general, the greater the amount of glycolide in the lactide-rich poly (lactide-coglycolide) copolymer, the faster the article will absorb. In addition, the greater the amount of poly (pdioxanone) in the polymer mixture, the faster the article will absorb.
[000161] Annealed molded articles substantially similar in design to Figure 2, produced from polymeric mixtures of
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60/65 poly (lactide-coglycolide) rich in lactide and poly (p-dioxanone) were tested for the hydrolysis time at a pH of 7.27 and a temperature of 70 ° C. The data in Table V summarize the results of this accelerated hydrolysis test.
Table V
Accelerated Hydrolysis Values
Mole% Polymerized Lactide in Lactid-Based Copolymer Percent Weight Poly (p-dioxanone) Polymer in Mixture Time to Complete Hydrolysis (Hours) 90 20 360 85 30 260 80 20 220 80 30 200 Example 17
Determination of Mixture Morphology [000162] The determination was made of the morphology of the secondary component of the injection molded articles of the polymeric mixture of 20% by weight of poly (p-dioxanone) and 80% by weight of poly (lactideocoglycolide) ), in which the poly (lactide-colactide) is 85 mol% of lactide and 15 mol% of glycolide. The photomicrograph was obtained according to the procedure set out below: an injection molded device was cut into 8 small pieces to expose all the internal structures; the small pieces were immersed in chloroform (5 ml) overnight to dissolve the poly (lactideocoglycolide) component of the mixture. The chloroform solution was then stirred to break the intertwined fibrous structure; the solution was then passed through a polypropylene filter with a pore size of 0.3 pm; the filter was then rinsed with chloroform to remove any possible lactide / glycolide copolymer deposited on the filter; at
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61/65 poly (p-dioxanone) structures left on the surface of the filter were then analyzed with scanning electron microscopy (SEM). [000163] Figure 1 is a photomicrograph obtained under scanning electron microscopy (SEM) of the poly (p-dioxanone) structures collected from the injection molded articles of the polymer mixture at 20% by weight of poly (p-dioxanone) and 80% by weight of poly (lactide-glycolide), where poly (lactide-cholactide) is 85% by mol of polymerized lactide and 15% by mol of polymerized glycolide. The aspect ratio of the poly (p-dioxanone) phase is well above that indicating a high level of shear during the manufacturing process that typically leads to high levels of residual stress, increasing the propulsion force for subsequent shrinkage and warp.
Example 18
Applicability of the Mixture of the Invention to Medical Devices [000164] It is to be understood that the mixture of the present invention can be used to manufacture medical devices using various melt processing techniques. As shown in some of the examples above, injection molding is one of the techniques that are applicable. It is further understood that a variety of designs can be applied using the mixtures of the invention.
[000165] One of the devices that was produced was in the form of a 0.89 cm (0.35 inch) long dumbbell with substantially disk-like endings of 0.51 cm (0.20 inch) in diameter and 0.13 cm (0.05 inch) thick. The connection between the two discs had a substantially circular cross section of 0.157 cm (0.062 inches) in diameter. Figure 12 provides engineering drawings of this dumbbell device. This design was injection molded using a 90/10 lactide / glycolide copolymer as a control and polymer blend of the present invention.
Petition 870190087583, of 9/5/2019, p. 65/81
62/65 tion, specifically a molten mixture of 20% by weight of poly (pdioxanone) and 80% by weight of 90/10 lactide / glycolide copolymer. The articles thus produced were thermally annealed without restriction at 60, 70, and 80 ° C for 8, 4 and 4 hours, respectively. The devices molded from the 90/10 lactide / glycolide copolymer showed substantial shrinkage and warp after this annealing process. The devices molded from the blend of the invention were substantially free from shrinkage and warp after annealing.
[000166] It is expected that the mixtures of the present invention would be useful in manufacturing, via injection molding, a very broad set of devices including, but not limited to, clamps, pins, threads, plates, clips, supports, scaffolds for engineering of tissue, and devices for closing wounds. In addition, it is also expected that other processing methods can be applied to form useful articles using the mixtures of the present invention. These processes include, but are not limited to, fiber extrusion, profile extrusion, film extrusion, tube extrusion, and blow molding. The person skilled in the art can, for example, cut or clamp specific shapes to manufacture blade stock devices formed by extrusion methodologies. It will be evident to those skilled in the art to select an appropriate training methodology.
Example 19
Fused-State Mixing During Medical Device Manufacturing [000167] As mentioned earlier, an alternative method of forming the fused mixture of the present invention was to add the properly sized components of the mixture directly into the hopper of the injection molding machine. The mixture
Petition 870190087583, of 9/5/2019, p. 66/81
63/65 in molten state occurred within the cylinder limits of the injection molding machine producing acceptable parts as described in EXAMPLE 7.
Example 20
Calculation of the Minimum Percentage, by Weight, of Poly (p-dioxanone) in the Invention [000168] As stated previously, the minimum level of poly (pdioxanone) was dependent on the molar amount of the polymerized lactide present in the lactide-based polymer present in the mixture and was calculated using the equation found below.
%, by Weight, Poly (p-dioxanone) = (215.6212 /% in mol Polymerized Lactide) ² ' ⁷⁰²⁷ [000169] For example, when the composition of the lactide-glycolide copolymer was 82/8 (on a mol basis), the minimum percentage by weight of poly (p-dioxanone) in the mixture was calculated to be 10 percent and the maximum amount was approximately 24. Similarly, if the composition of the lactide-coglycolide copolymer was 86/14 (in a mol base), the minimum percentage by weight of poly (p-dioxanone) in the mixture was calculated to be 12 percent and the maximum amount was approximately 24. Table VI contains a table of the poly (p-dioxanone range) ), expressed as a percentage, by weight, minimum and maximum in the mixture of the present invention. Table VI
Compositions of the Lactide / Glycolide Copolymer Invention Mixture with Poly (p-dioxanone)
Mol% of Lactide Polymerized in Lactid-Based Copolymer MinimumPercent Weight Poly (p-dioxanone) Polymer in Mixture Maximum Percent by Weight Poly (p-dioxanone) Polymer in Mixture 100 8.0 Approximately 24
Petition 870190087583, of 9/5/2019, p. 67/81
64/65
Mol% of Lactide Polymerized in Lactid-Based Copolymer MinimumPercent Weight Poly (p-dioxanone) Polymer in Mixture Maximum Percent by Weight Poly (p-dioxanone) Polymer in Mixture 99 8.2 Approximately 24 98 8.4 Approximately 24 97 8.7 Approximately 24 96 8.9 Approximately 24 95 9.2 Approximately 24 94 9.4 Approximately 24 93 9.7 Approximately 24 92 10.0 Approximately 24 91 10.3 Approximately 24 90 10.6 Approximately 24 89 10.9 Approximately 24 88 11.3 Approximately 24 87 11.6 Approximately 24 86 12.0 Approximately 24 85 12.4 Approximately 24 84 12.8 Approximately 24 83 13.2 Approximately 24 82 13.6 Approximately 24 81 14.1 Approximately 24 80 14.6 Approximately 24 79 15.1 Approximately 24 78 15.6 Approximately 24 77 16.2 Approximately 24 76 16.7 Approximately 24 75 17.4 Approximately 24
Petition 870190087583, of 9/5/2019, p. 68/81
65/65
Mol% of Lactide Polymerized in Lactid-Based Copolymer MinimumPercent Weight Poly (p-dioxanone) Polymer in Mixture MaximumPercent Weight Poly (p-dioxanone) Polymer in Mixture 74 18.0 Approximately 24 73 18.7 Approximately 24 72 19.4 Approximately 24 71 20.1 Approximately 24 70 20.9 Approximately 24
[000170] Figure 5 is a graph of mol% of the polymerized lactide in the lactide / glycolide copolymer component versus the%, by weight, of poly (p-dioxanone); the area bounded by the curves shows the innovative polymer compositions of the present invention.
[000171] Although this invention has been shown and described in relation to the detailed modalities thereof, those skilled in the art will understand that various changes in the form and detail of the same can be made without deviating from the character and scope of the claimed invention.

权利要求:
Claims (37)
[1]
1. Bioabsorbable polymeric mixture, characterized by the fact that it comprises:
a first bioabsorbable polymer and a second bioabsorbable polymer, the first polymer comprising from 76% by weight to 92% by weight of a mixture of a lactide-rich polymer comprising from 100 mol% to 70 mol% of lactide polymerized and from 0 mol% to 30 mol% of polymerized glycolide, and the second polymer comprising poly (p-dioxanone), wherein the maximum% by weight of poly (p-dioxanone) in the mixture is 24% by weight and the% by weight of minimum poly (p-dioxanone) in the mixture depends on the molar amount of polymerized lactide in the lactide-rich polymer and is calculated by the expression:
%, by Weight, of Poly (p-dioxanone) = (215.6212 / mol% of Polymerized Lactide) ² , ⁷⁰²⁷ and in which the polymeric mixture provides dimensional stability to a manufactured article.
[2]
Polymeric mixture according to claim 1, characterized in that the lactide-rich polymer comprises from 76% by weight to 84% by weight of the mixture and the poly (p-dioxanone) comprises from 16% by weight to 24% % by weight of the mixture.
[3]
Polymeric mixture according to claim 1, characterized by the fact that the lactide-rich polymer comprises from 80 mol% to 90 mol% of polymerized lactide and 10 mol% to 20 mol% of polymerized glycolide.
[4]
Polymeric mixture according to claim 1, characterized in that the lactide-rich polymer comprises from 76% by weight to 84% by weight of the mixture and the poly (p-dioxanone) comprises from 16% by weight to 24 % by weight of the mixture and the
Petition 870190106994, of 10/22/2019, p. 5/14
2/7 lactide-rich polymer comprises 80 mol% to 90 mol% of polymerized lactide and 10 mol% to 20 mol% of polymerized glycolide.
[5]
Polymeric mixture according to claim 2, characterized in that the lactide-rich polymer comprises from 78% by weight to 82%, by weight, of the mixture, and the poly (p-dioxanone) comprises from 18% by weight. weight to 22% by weight of the mixture.
[6]
Polymeric mixture according to claim 3, characterized by the fact that the lactide-rich polymer comprises from 83 mol% to 87 mol% of polymerized lactide and 13 mol% to 17 mol% of polymerized glycolide.
[7]
Polymeric mixture according to claim 4, characterized in that the lactide-rich polymer comprises from 78% by weight to 82% by weight of the mixture and the poly (p-dioxanone) comprises from 18% by weight to 22 % by weight of the mixture and the lactide-rich polymer comprises from 83 mol% to 87 mol% of polymerized lactide and 13 mol% to 17 mol% of polymerized glycolide.
[8]
Polymeric mixture according to any one of claims 1 to 7, characterized by the fact that it has an inherent viscosity of at least 0.8 dL / g when measured in hexafluoroisopropanol at 25 degrees Centigrade at a concentration of 0.1 g / dL.
[9]
Polymeric mixture according to any one of claims 1 to 8, characterized in that the first polymer has an inherent viscosity of at least 0.8 dL / g when measured in hexafluoroisopropanol at 25 degrees Centigrade at a concentration of 0, 1 g / dL.
[10]
Polymeric mixture according to any one of claims 1 to 9, characterized in that the second polymer
Petition 870190106994, of 10/22/2019, p. 6/14
3/7 has an inherent viscosity of at least 0.8 dL / g as when in hexafluoroisopropanol at 25 degrees Centigrade at a concentration of 0.1 g / dL.
[11]
Polymeric mixture according to any one of claims 1 to 10, characterized by the fact that it has a crystallinity of at least 15% when measured by X-ray diffraction.
[12]
Polymeric mixture according to any one of claims 1 to 11, characterized in that it additionally comprises an antimicrobial agent.
[13]
Polymeric mixture according to claim 12, characterized by the fact that the antimicrobial agent is a phenolic polyphenol phenol.
[14]
Polymeric mixture according to any one of claims 1 to 13, characterized in that it additionally comprises a bioglass.
[15]
15. Polymeric mixture according to claim 14, characterized by the fact that the bioglass is selected from the group consisting of apatite hydroxy, tricalcium phosphate, carbonates, sulfate, calcium and magnesium oxides.
[16]
Polymeric mixture according to any one of claims 1 to 15, characterized in that it additionally comprises a therapeutic agent.
[17]
17. Polymeric mixture according to claim 16, characterized by the fact that the therapeutic agent is selected from the group consisting of antibiotics, antivirals, adhesion preventives, contraceptives, and analgesics.
[18]
Polymeric mixture according to any one of claims 1 to 17, characterized in that the polymeric mixture additionally comprises an additional polymer.
Petition 870190106994, of 10/22/2019, p. 7/14
4/7
[19]
19. Polymeric mixture according to claim 18, characterized in that the additional polymer is selected from the group consisting of an absorbable synthetic polymer, and an absorbable natural polymer.
[20]
20. Polymeric mixture according to claim 18, characterized in that the additional polymer is a non-absorbable polymer.
[21]
21. Polymeric mixture according to any one of claims 1 to 20, characterized in that it additionally comprises a dye.
[22]
22. Polymeric mixture according to claim 21, characterized by the fact that the dye is selected from the group consisting of Violet D&C n ° 2 and Blue D&C n ° 6, in an amount in the range of 0.01% by weight at 0.3% by weight of the polymer mixture.
[23]
23. Polymeric mixture according to any one of claims 1 to 22, characterized in that said mixture is a thermally processed mixture.
[24]
24. Bioabsorbable medical device, characterized in that it comprises a polymeric mixture as defined in any one of claims 1 to 23.
[25]
25. Medical device according to claim 24, characterized in that the device is selected from the group consisting of staples, tacks, loops, sutures, tissue fixation devices, mesh net fixation devices, anastomosis devices , bone suture and supports, tissue and bone screws, prostheses, support structures, tissue augmentation devices, tissue ligation devices, patches, substrates, mesh netting, tissue engineering frameworks, drug delivery devices , and stents.
[26]
26. Medical device according to claim 24,
Petition 870190106994, of 10/22/2019, p. 8/14
5/7 characterized by the fact that the medical device is a mesh mesh fixture that is selected from the group consisting of tacks and staples.
[27]
27. Medical device according to claim 24, characterized in that the device is supplied in a sterile manner.
[28]
28. Medical device according to claim 24, characterized in that the aspect ratio of the second polymer is greater than 3, preferably greater than 5, more preferably greater than 20.
[29]
29. The medical device according to claim 24, characterized in that the medical device remains dimensionally stable when subjected to immersion in water at an elevated temperature, preferably at an elevated temperature of 49 degrees centigrade, more preferably at an elevated temperature of 70 degrees centigrade.
[30]
30. Method of manufacturing a bioabsorbable medical device, characterized in that it comprises the steps of processing a mixture of a first bioabsorbable polymer and a second bioabsorbable polymer as defined in any one of claims 1 to 22.
[31]
31. Method according to claim 30, characterized in that the mixture is supplied by means of thermal processing.
[32]
32. Method according to claim 31, characterized by the fact that the means of thermal processing are selected from the group consisting of polymerization, melt mixing, and removal of residual monomer by solvent extraction or devolatilization.
[33]
33. The method of claim 32, characterized
Petition 870190106994, of 10/22/2019, p. 9/14
6/7 due to the fact that the molten state mixture occurs directly in a process selected from the group consisting of injection molding, compression modeling, blow molding, blown film, thermoforming, film extrusion, fiber extrusion, fiber extrusion blade, profile extrusion, non-woven meltblown extrusion, coextrusion, tube extrusion, foaming, rotation molding, calendering and extrusion.
[34]
34. Method according to claim 31, characterized in that the processing comprises one or more stages of the process selected from the group consisting of polymerization, pelletizing, grinding, particle sizing, dry mixing, melt mixing, mixing double-screw, single-screw extrusion, coextrusion, double-screw mixture with vacuum thread devolatilization with simultaneous opening, removal of residual monomer by solvent extraction, drying in a vacuum dryer, devolatilization, and resin annealing.
[35]
35. Method according to claim 31, characterized by the fact that the device is formed by a process selected from the group consisting of injection molding, compression molding, blow molding, blown film, thermoforming, film extrusion, extrusion fiber, sheet extrusion, profile extrusion, nonwoven meltblown extrusion, coextrusion, tube extrusion, foaming, rotation molding, calendering, and extrusion.
[36]
36. The method of claim 31, characterized in that it further comprises the step in which the device is thermally annealed at a temperature of at least 45 degrees Celsius for at least one minute.
[37]
37. Method according to claim 36, characterized by the fact that the device is thermally annealed at a temperature of 60 degrees Celsius for 8 hours, followed by
Petition 870190106994, of 10/22/2019, p. 10/14
7/7 annealing at a temperature of 70 degrees Celsius for 4 hours, followed by annealing at a temperature of 80 degrees Celsius for 4 hours.

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法律状态:
2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2019-08-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2019-10-15| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|

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2019-12-10| B09A| Decision: intention to grant|

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2020-02-11| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 21/09/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US12/887,995|2010-09-22|

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US12/887,995|US9173978B2|2010-09-22|2010-09-22|Bioabsorbable polymeric compositions, processing methods, and medical devices therefrom|

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PCT/US2011/052536|WO2012040316A1|2010-09-22|2011-09-21|Bioabsorbable polymeric compositions, processing methods, and medical devices therefrom|

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