Integrated stress equalization during extrusion of a filament for medical applications

Abstract

The present invention discloses a method for filament extrusion suitable for medical implant applications. The filament comprising a thermoplastic polymer and a pharmaceutical active ingredient for controlled drug release. The filament is immersed in a cooling liquid in a cooling bath. Post-extrusion processes is required for stress equalization within the filament. By an controlled elevated cooling liquid temperature, stress equalization occurs simultaneously with solidification of the extruded filament in the cooling bath, hence multiple stress equalization processes are eliminated. The temperature of the cooling liquid in the cooling bath is controlled and linked to extrusion rate and thermal properties of matrix component of the filament and the active ingredient.

Description

[0001] INTEGRATED STRESS EQUALIZATION DURING EXTRUSION OF A FILAMENT FOR MEDICAL APPLICATIONS

[0002] TECHNICAL FIELD

[0003] The present invention relates to a method for filament extrusion suitable for medical implant applications. The filament comprising a thermoplastic polymer and a pharmaceutical active ingredient for controlled drug release. The filament is immersed in a cooling liquid in a cooling bath. Post-extrusion processes are required for stress equalization within the filament. By controlled elevated cooling liquid temperature and solidification of the extruded filament in the cooling bath, multiple stress equalization processes are eliminated. The temperature of the cooling liquid in the cooling bath is controlled and linked to extrusion rate and thermal properties of a matrix component of the filament, which is preferably an EVA, and the active ingredient.

[0004] BACKGROUND

[0005] A variety of medical implants can be made with EVA copolymers, they have emerged as versatile materials in the field of drug delivery systems via extrusion. EVA is a copolymer of ethylene and vinyl acetate, known for its biocompatibility, flexibility, and unique properties that make it well-suited and known for pharmaceutical applications. In drug delivery systems, EVA is used as a matrix material for controlled-release drug formulations. Through extrusion processes, EVA can be combined with pharmaceutical active ingredients to create a range of drug delivery devices, including implants, films, and pellets. The flexibility of EVA allows for precise control over drug release rates, enabling sustained and targeted delivery of medications. One of the key advantages of EVA in drug delivery is its ability to tailor drug release profiles to specific therapeutic needs. By adjusting the ratio of vinyl acetate in the copolymer, the release kinetics of the incorporated drug can be customized, ensuring optimal therapeutic efficacy and patient compliance. EVA-based drug delivery systems have found applications in various medical fields, including pain management, contraception, and the treatment of chronic diseases.

[0006] Moreover, EVA's compatibility with various manufacturing techniques, such as extrusion, has made it a popular choice for pharmaceutical formulation scientists. The extrusion process enables the efficient incorporation of pharmaceutical active ingredients into EVA matrices, ensuring uniform drug distribution and consistent release. Processing EVA via extrusion for filament production causes stress within the filament during the solidification step. It is important for comfort reasons that the implant does not coil in the eye of the patient due to the stresses present in the implant. Hence, post-extrusion processes are required in order to create stress- equalized filaments. Thus, a need remains to reduce the number of stress equalization processes after extrusion.

[0007] The solidification step via a cooling bath is a vital component in the field of polymer extrusion processes, serving to rapidly and effectively cool down polymers as they exit the extruder. The use of a cooling bath in extrusion has several key benefits. Firstly, it helps to maintain the desired shape and dimensions of the extruded material. As materials exit the extruder, they are often at high temperatures, making them susceptible to deformation and warping. The cooling bath rapidly reduces their temperature, ensuring that they solidify in the intended form. Secondly, a cooling bath enhances the material's physical properties. In polymer extrusion, it improves the material's strength, durability, and optical quality during the cooling process. Furthermore, the cooling bath plays a crucial role in increasing production speeds. By rapidly cooling the extruded material, manufacturers can achieve higher throughput and efficiency, reducing the overall production time. However, fast solidification has the downside to induce stresses within the filament as the polymer chains do not have the time to align or crystallize properly, especially for polymers having a cold crystallisation temperature close to their operating temperature.

[0008] In light of the disadvantages of stresses within a filament, it is understandable that a variety of stress equalization processes post-extrusion have been proposed. All are variations on placing the filament at elevated temperature in an oven, in a mould or on a heated wheel for a period of time, having the filament fixed in order to obtain the requested shape and slow cool down the filament after the treatment. These post-extrusion processes, lead to long production times and multiple additional steps before the final product can be made.

[0009] In view of the above, there is an ongoing demand in the field for an enhanced stress equalization method that achieves sustained release in a process for extruded filaments intended for medical implants. The extrusion of medical implants is often produced from hot-melt extrusion. US20050031668 Al, US20230233375 Al, US20050048099 Al and US20100303883 Al disclose typical devices and methods for medical implants. The methods comprise only the mentioning of cooling the extruded filament without specifically detailing the settings, nor mentioning the post-extrusion processes for stress equalisation.

[0010] US20050031668 Al discloses compositions, methods, and kits for administration of nalmefene for treatment of alcoholism, nicotine dependence, or another condition for which treatment with nalmefene is therapeutically beneficial. The invention provides a biocompatible non-erodible polymeric device which releases nalmefene continuously with generally linear release kinetics for extended periods of time. In some embodiments, an implantable device of the invention includes EVA as a biocompatible, non-erodible polymer for formation of the polymeric matrix. Implantable devices of the invention are produced using an extrusion process to produce devices with dimensions of about 2 to about 3 mm in diameter and about 2 to about 3 cm in length. In order to test the effect of the polymer for a human body temperature, the implant is tested in a water bath at 37°C for pharmaceutical active ingredient release. The disadvantage is that there is no mentioning of stress equalisation before the test at 37°C, nor the settings of the solidification step.

[0011] US20230233375 Al discloses an implantable device for delivery of a tyrosine kinase inhibitor is provided. The device comprises a core defining an outer peripheral surface. The core comprises a core polymer matrix within which is dispersed a tyrosine kinase inhibitor. The polymer matrix contains an EVA copolymer. The core may be formed through a hot-melt extrusion technique is and it is generally a solvent- free process in which the components of the core (e.g., EVA copolymer(s), tyrosine kinase inhibitor(s), optional excipients, etc.) may be melt blended and optionally shaped in a continuous filament manufacturing process to enable consistent output quality at high throughput rates. This technique is particularly well suited to EVA copolymers as they typically exhibit a relatively high degree of long chain branching with a broad molecular weight distribution. This combination of traits can lead to shear thinning of the copolymer during the extrusion process, which help facilitates hot-melt extrusion. Furthermore, the polar vinyl acetate monomer units can serve as an "internal" plasticizer by inhibiting crystallization of the polyethylene chain segments. This may lead to a lower melting point of the copolymer, which further enhances its ability to be processed with the tyrosine kinase inhibitor. This invention uses extrusion for blending ingredients of the core, they do not mention the specific settings for solidification, nor is the effect of stress, originating from rapid cooling of the implantable device, discussed.

[0012] US20050048099 Al discloses a biodegradable implant sized for implantation in an ocular region and methods for treating medical conditions of the eye. The implants are formed from a mixture of hydrophilic end and hydrophobic end a poly(lactic-co- glycolic)acid (PLGA) copolymer, and deliver pharmaceutical active ingredients into an ocular region without a high burst release. The invention encompasses a method for making a bio-erodible implant for treating a medical condition of the eye, the method comprising a plurality of extrusions of a biodegradable polymer. A first extrusion is carrying out of blended mixture of feedstocks, to thereby obtain a first extrusion product; pelletizing the first extrusion product and carrying out a second extrusion of the pelletized first extrusion product, thereby, obtaining a bio-erodible implant for an ocular condition. Cooling settings after extrusion are a circulation water bath at 10°C for fast cooling. For most extrusion applications for small filaments, low temperatures equal or below room temperature are used for fast solidification.

[0013] US20100303883 Al discloses a method for the production of implants for delivery of therapeutic agents such as opioids and the manufacture and uses of such implants. A high vinyl acetate content for an EVA is a feedstock for making uniformly dry blended feedstock which is introduced into the hopper of a twin-screw extruder where it is melt compounded into a liquid mass which upon cooling is pelletized and in turn used as a feedstock for an injection moulding process which produces the three- dimensional implant device. There is only mention of a cooling equipment for production of EVA blends for pelletization, not stating its use beyond cooling for solidification before pelletization.

[0014] CA1109218 discloses A fiber which will perform in pile fabrics, WO2023139220 discloses a relates to a core-mantle drug delivery system with a 5 mm diameter, EP3395335 discloses a vaginal ring with a 4 mm axial cross sectional diameter.

[0015] One of the current goals in the method for the extrusion of filaments for medical implants is that it shall i) obtain homogeneous stress equalization in the thin filaments, ii) obtain filaments with a narrow variation in diameter, iii) maintain smooth surface and good visual aspect of the filament, iv) making the production of the thin filaments more energy efficient and v) reduce the number of processing steps. The applicant notes that the above issue of stresses in the extruded filaments are especially problematic when the implant itself is thinner, and thus more fragile. A thinner implant is needed in certain parts of the body, such as the eye.. Thus, there is a need to improve the solidification process to solve one or more above addressed problems.

[0016] SUMMARY OF THE INVENTION

[0017] Accordingly, it is the object of the present method to provide an improved stress equalization method of an extruded filament by using a controlled elevated temperature of a cooling liquid in a cooling bath used for solidification of the filament after extrusion. This solves at least some of the problems mentioned above.

[0018] The present invention comprises a method for filament extrusion suitable for medical implant applications according to claim 1. A thin filament is extruded by said method comprises an EVA as matrix component and a pharmaceutical active ingredient for controlled release. The method comprises the steps of extruding a filament and introducing said extruded filament into a cooling bath containing a cooling liquid. The filament is immersed in the cooling liquid for a predetermined period to facilitate cooling and solidification of the extruded filament by controlling a temperature of the cooling liquid in the cooling bath.

[0019] Said method is advantageous as the elevated controlled cooling liquid temperature allows slow cooling of a filament for a gradual reduction in temperature, which helps to minimize residual stresses within the filament. Controlled cooling promotes uniform cooling of the filament and reduces internal stresses and hence deformation and dimensional instabilities of the filament can be avoided. The filament has more time for the polymer to solidify uniformly, reducing the likelihood of distortion or dimensional instability in the final filament. Thus, using a controlled elevated cooling liquid temperature helps mitigate issues such as warping and shrinking.

[0020] A controlled elevated temperature of the cooling liquid is also advantageous as it allows for better control of the cooling process of the filament, enabling operators to fine-tune the specific material and product requirements such as a narrow distribution of the variation in filament diameter. Even more advantageous is that controlled cooling at elevated temperature also allows the polymer chains to align properly and achieve a more thermodynamically stable crystalline structure, hence decreasing cold crystallization during use giving rise to better control over release of the pharmaceutical active ingredient of the filament. Even so, it minimizes molecular orientation which results in a thermodynamically more stable material.

[0021] Additionally advantageous is that even if a controlled elevated cooling liquid temperature requires longer processing times, it can result in reduced energy consumption compared to rapid cooling methods, making it a more environmentally friendly option.

[0022] And also advantageous is that by using controlled elevated cooling liquid temperature an additional post-extrusion step for stress equalization of internal stresses, can be avoided and thereby promoting overall shorter processing time.

[0023] The present invention discloses a method for pulling and simultaneously immersing a filament in a cooling liquid for a predetermined period to facilitate controlled cooling and solidification of the extruded filament. In order to have controlled cooling and solidification at elevated temperature, a temperature of the cooling liquid in a cooling bath is controlled and linked to extrusion rate and thermal properties of the filament. In the present invention the filament comprises of a matrix component EVA and an active ingredient.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0026] As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise. The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms "comprising", "comprises" and "comprised of" also include the term "consisting of".

[0027] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints. When a numerical value is used, said value encompasses the exact numerical value as such, as well as all numerical values that would be rounded up to said exact numerical value according to standard mathematical and / or statistical regulations.

[0028] Similarly, when a period of time is indicated using a numerical value such as "about 30 minutes", said value encompasses the exact time indicated as well as periods that deviate therefrom by e.g., less than one minute, half a minute, or 1, 2, 3, 4 or 5 minutes. Analogously, the term "about 30 seconds" encompasses about 20, 25 seconds to about 35, 40 seconds, as well as any time in between.

[0029] As used throughout the present disclosure, the terms "concentration" and "content" are used interchangeably and refer to the weight concentration or mass fraction of a constituent, i.e., the mass of a constituent divided by the total mass of all constituents and is expressed in % by weight or wt%.

[0030] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present application. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may refer to the same embodiment. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments.

[0031] By means of further guidance, definitions for the terms used in the description are included to better appreciate the teachings of the present application.

[0032] As used herein, the term "thermoplastic polymer" refers to a molecule whose structure is composed of multiple repeating units. Said molecule, present in bulk, become pliable or mouldable at a certain elevated temperature and solidifies upon cooling. A "thermoplastic polymer for medical implant applications" is thus a biocompatible thermoplastic polymer that is tolerated by living organisms.

[0033] "Thermal properties of EVA matrix component of the filament" refers amongst others and relevant in context of this invention to: crystallisation temperature and crystallisation speed at a given temperature, temperature range of crystallisation, melting temperature and melting temperature range, glass transition temperature, degradation temperature and processing temperature of thermoplastic polymer EVA.

[0034] The thermal properties listed in the definition of the "Thermal properties of EVA matrix component of the filament" also apply for other matrix components of the filament comprising thermoplastic polymers which can either crystalize or form fringed micelles, such as TPUs. Wherein fringed micelles have a lower level of molecular order than crystalline structures and loose solid-state arrangements during heating about a melt temperature range and rearrangement of the solid-state structure is obtained after cooling about the crystallisation temperature range.

[0035] "Thermal properties of the pharmaceutical active ingredient" refers amongst others and relevant in context of this invention to: crystallisation temperature, the melting temperature, the glass transition temperature, degradation temperature and the processing temperature.

[0036] A "core" is defined as a layer or inner part of a filament for medical implant applications. The core comprises of a matrix component EVA and one or more pharmaceutical active ingredients. Alternatively, a core comprises of a matrix component TPU and one or more pharmaceutical active ingredients. Optionally the core comprises of a non-limitative list of: plasticizers, surfactants, stabilizers, crosslinking agents, fillers or a combination thereof.

[0037] A "shell" is synonym to "mantle" and is defined as a layer or outer part of a filament for medical implant applications. The shell acts as a membrane for slow drug release and comprises of a matrix component EVA. Alternatively, a shell comprises of a matrix component TPU. Optionally the shell comprises of a non-limitative list of: plasticizers, surfactants, stabilizers, crosslinking agents, fillers or a combination thereof.

[0038] A "cooling bath" is defined as a temperature-controlled liquid bath or tank used to rapidly and uniformly cool down an extruded filament immediately after it has been extruded through a die head. Purpose of a cooling bath is to efficiently reduce temperature of an extruded material to a level where the extruded material solidifies and maintains its desired shape. The cooling bath has a balk shape volume with a length of the volume defined as the distance between a die head and a device pulling the filament through the cooling liquid in the cooling bath. A "die head" is a specialized component of an extrusion machine and is designed to control the flow in this invention of molten polymer from the extruder's barrel and shape the molten polymer into a specific cross-sectional profile.

[0039] In a first aspect the invention relates to a method for extrusion, preferably filament extrusion. The method for filament extrusion is preferably suitable for medical implant applications comprising a thermoplastic polymer as matrix component of the filament and at least one pharmaceutical active ingredient.

[0040] In an embodiment, the invention relates to a method for filament extrusion suitable for medical implant applications, said filament comprising a thermoplastic polymer as matrix component and at least one pharmaceutical active ingredient for controlled release.

[0041] In an embodiment the filament has a diameter smaller than 2.0 mm, preferably smaller than 1.0 mm and more preferably smaller than 0.5 mm.

[0042] In an embodiment the method comprises the steps of: extruding a filament, and introducing said extruded filament into a cooling bath containing a cooling liquid.

[0043] In a further step the filament can be maintained within said cooling bath, immersed in the cooling liquid, for a predetermined period to facilitate controlled cooling and solidification of the extruded filament.

[0044] Preferably, the temperature of the cooling liquid in the cooling bath is controlled and linked to the extrusion rate and the thermal properties of the filament comprising a thermoplastic polymer as matrix component and thermal properties of the at least one pharmaceutical active ingredient.

[0045] It is to be understood that "a pharmaceutical active ingredient" as used herein refers to "at least one pharmaceutical active ingredient".

[0046] In a preferred embodiment, the invention discloses a method for filament extrusion suitable for medical implant applications, said filament comprising a thermoplastic polymer and a pharmaceutical active ingredient for controlled release having a thin diameter smaller than 2.0 mm. Said method comprising the steps of extruding a filament and introducing said extruded filament into a cooling bath containing a cooling liquid. Said filament is immersed in the cooling liquid for a predetermined period to facilitate controlled cooling and solidification of the extruded filament, wherein the temperature of the cooling liquid in the cooling bath is controlled on a temperature higher than room temperature and the temperature of the cooling liquid is linked to extrusion rate and thermal properties of the filament comprising a thermoplastic polymer as matrix component and thermal properties of the pharmaceutical active ingredient. The advantages of elevated controlling temperature of the cooling liquid are that it mitigates warping and shrinking, give better process control for a narrow distribution of the variation in filament diameter, a more stable crystalline structure, reduced energy consumption hence eliminating additional post-extrusion process for stress equalization.

[0047] In an embodiment, matrix component of an extruded filament for medical implant applications comprises one or more thermoplastic polymers selected from the group consisting of ethylene-co-vinylacetate (EVA), polypropylene (PP), polyethylene (PE), preferably low density polyethylene (LDPE), (plasticized) polyethylene terephthalate, poly(methyl methacrylate) (PMMA), polyolefins or polyvinyl chlorides; regenerated insoluble non-erodible cellulose, acylated cellulose, esterified celluloses, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate diethyl-aminoacetate; thermoplastic aliphatic polyurethane, thermoplastic aromatic polyurethane, thermoplastic hydrophobic polyurethane, thermoplastic hydrophilic polyurethane, polycarbonates, and microporous polymers formed by coprecipitation of a polycation, a polyanion modified insoluble collagen, or combinations thereof.

[0048] In an embodiment, a matrix component of an extruded filament for medical implant applications comprises a thermoplastic polymer selected from the group consisting of ethylene-co-vinylacetate (EVA), polypropylene, polyethylene (preferably low density polyethylene), poly(methyl methacrylate) (PMMA), thermoplastic aliphatic polyurethane, thermoplastic aromatic polyurethane, thermoplastic hydrophobic polyurethane, thermoplastic hydrophilic polyurethane, or combinations thereof.

[0049] In a particular embodiment, the matrix component of the extruded filament comprises of an ethylene-co-vinylacetate (EVA), thermoplastic polyurethanes (TPU) such as aliphatic polyurethane, aromatic polyurethane, hydrophobic polyurethane, hydrophilic polyurethane, or a combination thereof.

[0050] In a particular embodiment, the matrix component of the extruded filament comprises of an ethylene-co-vinylacetate (EVA).

[0051] In an embodiment, a method for filament extrusion wherein a filament comprises a thermoplastic polymer and a pharmaceutical active ingredient for controlled release having a thin diameter smaller than 2.0 mm, preferably smaller than 1.0 mm and more preferably smaller than 0.5 mm. This is advantageous as thinner medical implants are less likely to cause foreign body sensation, or restricted movement. Another advantage is that the medical implant is less likely to be visible or palpable, ensuring that the implant remains discreet and less noticeable.

[0052] In a preferred embodiment, an EVA as a thermoplastic polymer as matrix component of an extruded filament comprising a high vinyl acetate content between 18% to 40%. A high vinyl acetate content is advantageous because said high vinyl acetate EVA feels softer and is more flexible, has a good elasticity, good UV resistance and fit for flexible medical implants.

[0053] In an embodiment, EVA as a thermoplastic polymer as matrix component of an extruded filament comprising a medium vinyl acetate content between 9% to 17%. A medium vinyl acetate content is advantageous because said medium vinyl acetate EVA is flexible and kink resistance, said medium vinyl acetate EVA has a good balance between flexibility and rigidity for medical implants.

[0054] In an alternative embodiment, TPU as a thermoplastic polymer matrix component of an extruded filament comprising isocyanates and diols as monomers. A TPU is advantageous as it allows implants to be conform to the body's movements, such as catheters, stents, or joint implants. Even more, TPU withstands wear and tear, which is crucial for long-lasting medical implants.

[0055] In an embodiment, TPU as a thermoplastic polymer matrix component of an extruded filament is a hydrophobic TPU. Hydrophobic TPU contains high amounts of hydrocarbon parts in repeating units. Wherein the hydrophobic TPU comprises of polyether polyols as monomer. Hydrophobic TPU is advantageous as the hydrophobic TPU has a high resistance to water absorption. In an embodiment, TPU as a thermoplastic polymer matrix component of an extruded filament is a aliphatic TPU. Aliphatic TPU contains no aromatic chemical structures in repeating units. Aliphatic TPU is advantageous as the aliphatic TPU has a higher flexibility compared to aromatic chemical structures.

[0056] In an embodiment, TPU as a thermoplastic polymer matrix component of an extruded filament is a hydrophobic aliphatic TPU. Hydrophilic aliphatic TPU is advantageous as the hydrophilic aliphatic TPU has a higher flexibility compared to aromatic chemical structures and has a high resistance to water absorption.

[0057] Preferably, a matrix component for a filament produced by the method according to the invention, is a thermoplastic polymer having preferably a melt flow index between 0.1 g / 10 min to 150.0 g / 10 min. The melt flow index is defined by ISO 1133 at 190°C and a weight of 2.16 kg. More preferably the melt flow index is between 0.5 g / 10 min to 50.0 g / 10 min, even more preferable the melt flow index is between 1.0 g / 10 min and 10.0 g / 10 min. Most preferable the melt flow index is between 2.0 g / 10 min to 5.0 g / 10 min. The lower range of melt flow index is advantageous as the polymer chains are sufficiently long and consequently exhibit good melt strength which is essential for maintaining the shape and integrity of an extruded filament, especially for thin filaments. At the same time the polymer chains are not too long or branched, which causes extreme die swell. Die swell is elastic recovery of polymer materials after passing through a die head. Die swell impacts the dimensional accuracy of extruded products and may require process adjustments or post-processing steps for control difficulties.

[0058] The distance between a die head of an extruder and a cooling bath, to produce filaments for medical implants according to the method of the invention, is preferably less than 20.0 mm, more preferably less than 15.0 mm and even more preferably less than 10.0 mm. A close distance of the cooling bath to the die head is advantageous as the filament is solidified shortly after leaving the die head in order to maintain the shape of the filament.

[0059] In a preferred embodiment, the invention discloses a method for filament extrusion whereby controlling a cooling liquid temperature in a cooling bath during extrusion of the filament at a temperature between 35°C to 80°C and more preferably between 37°C to 70°C and even more preferably between 40°C to 60°C. Even more preferred a temperature between 30°C to 80°C and more preferably between 30°C to 50°C and even more preferably between 35°C to 45°C, or even between 38°C and 42°C. The advantage of using controlled elevated cooling liquid is that a filament after extrusion is solidified and stress equalization occur at the same time. During stress equalization the polymer chains are able to rearrange themselves from multiple instable crystalline structures to one stable crystalline structure.

[0060] In an alternative embodiment, the invention discloses a method for filament extrusion whereby controlling a cooling liquid temperature in a cooling bath during extrusion of the filament at a temperature between 50°C to 95°C and more preferably between 55°C to 90°C and even more preferably between 60°C to 85°C. The advantage of using controlled elevated cooling liquid is that a filament after extrusion is solidified and stress equalization occur at the same time. During stress equalization the polymer chains are able to rearrange themselves from multiple smaller solid- state structures to bigger stable solid-state structures.

[0061] In an embodiment, a cooling bath is equipped with both an inlet and an overflow aperture to ensure a continuous flow of a cooling liquid. A temperature of the cooling liquid is monitored with a temperature sensor in close surrounding of the cooling liquid flowing into the cooling bath. Controlled temperature of the cooling liquid is obtained by a heat exchange element which is connected to the temperature sensor, giving a signal to the heat exchange element in order to automatically adjust the settings of the heat exchange element.

[0062] In an embodiment, a cooling bath is equipped with both an inlet and an overflow aperture to ensure a continuous flow of a cooling liquid. Temperature of the cooling liquid does not exceed 60°C at the inlet of the cooling bath and temperature of the cooling liquid does not exceed 80°C at the outlet. More preferably the temperature at the outlet of the cooling bath does not exceed 60°C. The advantage of using controlled elevated cooling liquid at the outlet of the cooling bath is that a filament after extrusion is a balance between sufficient fast solidification of the filament and stress equalization of the filament.

[0063] In an alternative embodiment, a cooling bath is equipped with both an inlet and an overflow aperture to ensure a continuous flow of a cooling liquid. Temperature of the cooling liquid does not exceed 90°C at the inlet of the cooling bath and temperature of the cooling liquid does not exceed 95°C at the outlet. More preferably the temperature at the outlet of the cooling bath does not exceed 90°C. The advantage of using controlled elevated cooling liquid at the outlet of the cooling bath is that a filament after extrusion is a balance between sufficient fast solidification of the filament and stress equalization of the filament.

[0064] In an embodiment, the invention discloses a method for filament extrusion wherein a cooling liquid is selected from a non-limitative list of: recirculated water, tap water, salted water or a combination thereof.

[0065] In an embodiment, recirculated water flows from the cooling bath into a reservoir connected to said cooling bath in order to assist temperature control of the cooling liquid by a heat transfer element. Said heat transfer element has the capability to either cool or heat the cooling liquid within the reservoir, which receives the liquid from the cooling bath. Within the reservoir, a temperature sensor is strategically positioned near the inlet of a pump that aids in returning the cooled liquid to the cooling bath. Recirculated water as a cooling liquid is advantageous for ecological reasons.

[0066] In a preferred embodiment, the invention discloses a method for filament extrusion comprising continuously transporting said extruded filament through the cooling bath using a conveyor system at a controlled speed. The controlled speed of the conveyer system is based on a stretch ratio, wherein said stretch ratio is defined as the ratio of a diameter of a die head of the extruder, to a final diameter of the filament after solidification of the stretched filament. The diameter of the extruded filament is measured as the diameter of the die head of the extruder. The stretch ratio is smaller than 3.0, preferably smaller than 2.0 and more preferably not less than minimum 0.5.

[0067] In an embodiment, a stretch ratio is between 0.3 to 3.0, preferably the stretch ratio is between 0.5 to 2.5 and more preferably the stretch ratio is between 0.7 to 1.5 or even between 0.9 and 1.1, wherein said stretch ratio is defined as the ratio of a diameter of a die head of the extruder, to a final diameter of the filament after solidification of the stretched filament. The advantage of the stretch ratio being close to 1.0, more preferably the stretch ratio is between 0.75 and 1.0, is that a minimal stretched filament results in reduced residual stress within the extruded filaments as polymer chains are less strong orientated in the stretch direction. Reduced residual stress is important in applications where material stability and long-term performance are critical.

[0068] In a preferred embodiment, the invention discloses a method for filament extrusion providing an extruder having a die head with a diameter within a range of up to a maximum of 1.5 mm; preferably up to a maximum of 0.8 mm and even more preferably up to a maximum of 0.4 mm. Preferably, an extruded filament is produced from a die head having a round shape.

[0069] In an alternative embodiment, the invention discloses a method for filament extrusion providing an extruder having a die head with a diameter within a range of up to a maximum of 1.5 mm; preferably up to a maximum of 0.8 mm and even more preferably up to a maximum of 0.4 mm. An extruded filament is produced from a die head having a shape selected from a non-limitative list of: a round; an oval or a rectangular.

[0070] In a preferred embodiment, a method for filament extrusion comprises of immersing a filament in a cooling liquid in a cooling bath, wherein said cooling bath has a length of at least 0.5 m, more preferably the cooling bath has a length of at least 1.0 m and even more preferably the cooling bath has a length of at least 1.5 m but not above 2.0 m.

[0071] In an embodiment the time of immersion of a filament in a cooling liquid is proportional to the diameter of the filament. The time of immersion for filaments having a diameter below 1.5 mm is below 90 seconds, more preferably below 60 seconds and even more preferable below 20 seconds. The short immersion time is advantageous to ensuring sufficient cooling, stress equalization and solidification of the extruded filament.

[0072] In an embodiment the time of immersion of a filament in a cooling liquid is proportional to the diameter of the filament. The time of immersion for filaments having a diameter below 0.8 mm is below 75 seconds, more preferably below 45 seconds and even more preferable below 15 seconds. The short immersion time is advantageous to ensuring sufficient cooling, stress equalization and solidification of the extruded filament. In an embodiment the time of immersion of a filament in a cooling liquid is proportional to the diameter of the filament. The time of immersion for filaments having a diameter below 0.4 mm is below 60 seconds, more preferably below 30 seconds and even more preferable below 10 seconds. The short immersion time is advantageous to ensuring sufficient cooling, stress equalization and solidification of the extruded filament.

[0073] In a preferred embodiment, a method for filament extrusion comprises the steps of: extruding a feedstock, wherein said feedstock comprises a thermoplastic polymer, through a die head to form a filament at a specific extruder pressure. Said specific extruder pressure is to maintain stable throughput of the extruded filament resulting in a stable shape of the filament at the die head. Extruder pressure in an extruder to produce thin filaments is preferably between 5 MPa to 45 MPa, more preferably between 10 MPa to 35 MPa, even more preferably between 15 MPa to 25 MPa. Subjecting said extruded filament to a stretching process, wherein the stretch ratio is defined as the ratio of a diameter of a die head of the extruder, to a final diameter of the filament, after solidification of the stretched filament and adjusting the extruder pressure, by adjusting screw speed of the extruder, in relation to the stretch ratio of the filament to control and minimize die swell, thereby achieving a stretched filament with reduced diameter variation. Preferably the feedstock comprises of an EVA. In another embodiment the feedstock is a TPU. A higher extruder pressure induces a higher exit pressure, hence increase die swell. By minimizing die swell, a stretched filament with reduced diameter variation is achieved. This is advantageous as less stretching induces less stresses in the filament.

[0074] In a preferred embodiment, a method for filament coextrusion; providing a coextrusion apparatus having multiple extruder units each configured to extrude a feedstock comprising a thermoplastic polymer as matrix component; comprises of the steps: extruding a feedstock through their respective extruder units and converging said individual feedstock melts into a coextrusion die head within a coextrusion die to form a coextruded filament with distinct layers, wherein said filament with distinct layers comprises of one or more cores and one or more shells. The advantage of distinct layers is to control release of said pharmaceutical active ingredient(s). Preferably, the thermoplastic polymer is an EVA. In another embodiment the thermoplastic polymer is a TPU. In an embodiment, a method for filament coextrusion for medical implants requires a coextrusion apparatus having multiple extruder units each configured to extrude a feedstock comprising a thermoplastic polymer suitable for medical applications as matrix component and all feedstocks comprise of at least two different thermoplastic polymers suitable for medical applications. The method for filament coextrusion comprises of the steps: extruding a feedstock through their respective extruder units and converging said individual feedstock melts into a coextrusion die head within a coextrusion die to form a coextruded filament with distinct layers, wherein said filament with distinct layers comprises of one or more cores and one or more shells. Preferably one or more cores differ from one or more shells, as cores and shells comprise of different thermoplastic polymers suited for medical applications. This is beneficial as release of a pharmaceutic active ingredient can be tailored according to the required dose of active ingredient. Or even more, different types of active ingredient are released at different stages during the use of the medical implant.

[0075] In a preferred embodiment, a method for coextruded filament comprising of coextruding a feedstock, comprising a thermoplastic polymer for medical implant applications as matrix component, in distinct layers comprising a core and a shell, wherein said core comprises of the same thermoplastic polymer as the shell, and the core also comprises a pharmaceutical active ingredient. Using the same thermoplastic polymer is advantageous as the pharmaceutical active ingredient is dosed at a slow rate. Even more, by using the same thermoplastic polymer as matrix component for the core and the shell, the extrusion temperature is comparable for both extruder units, hence when both extrudates are fed to the coextruder die head, good alignment and covering of the core by the shell is obtained. Preferably the thermoplastic polymer suited for medical implants is an EVA. In another embodiment the thermoplastic polymer suited for medical implants is a TPU.

[0076] In an embodiment, a method for coextruded filament comprising of coextruding a feedstock, comprising a thermoplastic polymer suitable for medical implants as matrix component, in distinct layers comprising a core and a shell. Said core comprises of a thermoplastic polymer for medical implants and differs merely with the matrix component of the shell in polymer architecture, copolymer composition or a combination thereof. The core also comprises a pharmaceutical active ingredient. The use of the same thermoplastic polymer but with different architecture, copolymer composition or a combination thereof is advantageous as the pharmaceutical active ingredient is dosed at tailored rates and at the same time the same thermoplastic polymer as matrix component but with different architecture, copolymer composition or a combination thereof allows good adhesion between the core and shell.

[0077] In an embodiment, a method for coextruded filament comprising of coextruding a feedstock, wherein said feedstock comprises different thermoplastic polymers suitable for medical implants as matrix component, in distinct layers comprising a core and a shell. Said core and shell comprise of different thermoplastic polymers for medical implants and the core also comprises a pharmaceutical active ingredient. This is advantageous as the pharmaceutical active ingredient is dosed at tailored rates. Even more, by using different thermoplastic polymers for medical implants, the flow behaviour of the matrixes is customized in such way that customized covering in thickness by the shell of the core is obtained.

[0078] In a preferred embodiment, filament coextrusion providing a coextrusion apparatus having multiple extruder units, each equipped with an extruder screw. Coextruding feedstock materials comprises of a thermoplastic polymer as matrix component, through a coextrusion die to form a filament with distinct layers. By adjusting the screw speed ratio, control of layer thickness and distribution within the coextruded filament is obtained. Screw speeds of the individual extruder units define the speed ratio. In an embodiment with a single core and single shell, the screw speed ratio is defined by screw speed which dose the core to the screw speed which dose the shell and the screw speed ratio is preferably below 5.0, more preferably below 1.5 and even more preferable above 0.2 This is beneficial in order to assist control of the slow release property of the extruded filament for medical implant applications as it controls thickness of the core to the shell towards higher core percentages relative to the overall composition of the filament for high doses of an pharmaceutical active ingredient.

[0079] In an embodiment, filament coextrusion providing a coextrusion apparatus having multiple extruder units, each equipped with an extruder screw. Coextruding feedstock materials comprises of a thermoplastic polymer as matrix component, through a coextrusion die to form a filament with distinct layers. By adjusting the screw speed ratio, control of layer thickness and distribution within the coextruded filament is obtained. Screw speeds of the individual extruder units define the speed ratio. In an embodiment with a single core and single shell, the screw speed ratio is defined by screw speed which dose the core, to the screw speed which dose the shell. The screw speed ratio is preferably above 0.2, more preferably above 0.5 and even more preferable above 0.8. This is beneficial in order to assist control of the slow release property of the extruded filament for medical implant applications as it controls thickness of the core to the shell towards lower core percentages relative to the overall composition of the filament for low doses of an pharmaceutical active ingredient.

[0080] In a preferred embodiment, a thermoplastic polymer blend is compounded as a prior step to extrusion or coextrusion of a filament for medical applications. A compounding apparatus comprises of twin screws, a die head and granulator. One or more feedstock materials are introduced into the compounding apparatus, wherein said feedstock material comprising a first feedstock material a thermoplastic polymer, preferably an EVA, and a second feedstock material a pharmaceutical active ingredient. Compounded pellets are feedstock for one or more extruder units, producing the core of the filament. Utilizing compounded pellets as feedstock materials for extrusion or coextrusion offers advantages of achieving a more homogeneous blend of materials for the extrusion process. In another embodiment the thermoplastic polymer as a first feedstock material is a TPU.

[0081] In an embodiment, a thermoplastic polymer is compounded as a prior step to extrusion or coextrusion of a filament for medical implant applications. Preferably the thermoplastic polymer is an EVA. A compounding apparatus comprises of twin screws, a die head and a granulator. One or more feedstock materials are introduced into the compounding apparatus. Said feedstock material comprising a first feedstock material a thermoplastic polymer as matrix component and a third feedstock material comprises at least one plasticizer. Plasticizers are added in percentages between 0.05% to 1.00%, more preferably between 0.10% to 0.75% and even more preferably between 0.15% to 0.50%. Wherein the percentage is relative to overall feedstock weight. The addition of plasticizer to the matrix component is advantageous as the plasticizer improves the flexibility and impact resistance of a thermoplastic polymer. In another embodiment the thermoplastic polymer is a TPU.

[0082] In an embodiment, a thermoplastic polymer is compounded as a prior step to extrusion or coextrusion of a filament for medical implant applications. A compounding apparatus comprises of twin screws, a die head, and a granulator. One or more feedstock materials are introduced into the compounding apparatus. Said feedstock material comprising a first feedstock material a thermoplastic polymer as matrix component and a fourth feedstock material comprises at least one additive, wherein said additive is selected from a list of: anti-microbial agents, stabilizers, fillers or combinations thereof. Addition of additives to support final product properties is beneficial.

[0083] The twin screws convey and mix said feedstock materials within the apparatus, discharging the compounded material through a die head to form a continuous compound. The continuous compound is transported to a granulator and granulates the continuous compound into discrete pellets.

[0084] In an embodiment, overall weight percentage of one or more pharmaceutical active ingredients is preferably between 1% to 49%, more preferably 10% to 45% and more preferably between 20% to 40%. Balanced amounts of pharmaceutical active ingredients are advantageous as it allows ease of extrusion of a filament for medical implant applications and at the same time provides sufficient pharmaceutical active ingredient for slow release to be possible.

[0085] In an embodiment, filament extrusion comprises of extruding a feedstock, wherein a matrix component of the feedstock comprises of a thermoplastic polymer and a pharmaceutical active ingredient through an die head to form a filament at a processing temperature. The processing temperature is the processing temperature of a matrix component with a highest processing temperature.

[0086] In a preferred embodiment, an EVA is a matrix component of the feedstock, wherein the processing temperature for EVA is above 50°C and below 200°C, more preferably between 100°C to 150°C. A medium processing temperature is beneficial for a good flow behaviour of the filament at exit of a die head without initiating degradation of the matrix component.

[0087] In an embodiment, TPU is a matrix component of the feedstock, wherein the processing temperature for TPU is above 100°C and below 220°C, more preferably between 135°C to 205°C. A medium processing temperature is beneficial for a good flow behaviour of the filament at exit of a die head without initiating degradation of the matrix component.

[0088] In a preferred embodiment, a method for stress equalization for an extruded filament comprises of the additional steps: cutting the filament into segments, placing a segment of extruded filament into a mould at a equalization temperature higher than room temperature but below liquidization temperature of a matrix component of the filament, maintaining the segment of extruded filament within the mould at said elevated equalization temperature for a predetermined period of time to facilitate stress equalization within the filament and removing the filament segment from the mould after the stress equalization period. The liquidization temperature is a temperature at which the filament loses its solidified shape. The advantages of additional stress equalization step is to fully remove all remaining residual stresses if said residual stresses were not fully removed during immersion of the filament in a cooling bath with a cooling liquid at controlled elevated temperature.

[0089] Preferably, the matrix component of the filament segment is EVA, hence the mould temperature is preferably between 20°C to 95°C, more preferably between 25°C to 80°C and even more preferably between 30°C to 65°C.

[0090] Alternatively, the matrix component of the filament segment is TPU, hence the mould temperature is preferably between 40°C to 120°C, more preferably between 50°C to 110°C and even more preferably between 60°C to 100°C.

[0091] In a preferred embodiment, a method for connecting an additional polymeric part to a filament segment is an additional step during filament stress equalization and comprising of: applying a clamping force to the moulded filament segment within the mould, wherein the clamping force is the force required to keep the mould closed without causing any leaks of polymer. Injection and shaping molten thermoplastic polymer in the mould and adhering the molten thermoplastic polymer to the filament segment allowing the molten thermoplastic polymer to become an integrated part with the filament segment wherein the clamping force is maintained. And thereafter removing the integrated part adhering to the filament segment from the mould after release of the clamping force. Preferably the thermoplastic polymer and the filament segment is an EVA. In another embodiment the thermoplastic polymer and the filament segment is a TPU.

[0092] In an embodiment, a molten thermoplastic polymer for injection and shaping an additional polymeric part to a filament segment is of the same thermoplastic polymer for medical implant applications as the filament segment. The use of the same thermoplastic polymer is beneficial as a good adhesion between both filament segment and additional polymeric part is obtained. Preferably the thermoplastic polymer is an EVA. In another embodiment the thermoplastic polymer is a TPU. In an embodiment, a molten thermoplastic polymer for injection and shaping an additional polymeric part to a filament segment is of a different thermoplastic polymer for medical implant applications as the filament segment. Preferably the thermoplastic polymer for the filament segment is an EVA. The use of different thermoplastic polymers is beneficial as diverse properties of the filament segment and the additional polymeric part is required. In another embodiment the thermoplastic polymer for the filament segment is a TPU.

[0093] In an embodiment, a molten thermoplastic polymer for injection and shaping an additional polymeric part to a filament segment is of the same thermoplastic polymer for medical implant applications as the filament segment, but with a different flow behaviour. Preferably the thermoplastic polymer for the filament segment is an EVA. The use of different thermoplastic polymers is beneficial as diverse properties of the filament segment and the additional polymeric part is required. Additionally, shorter cycle time are obtained. In another embodiment the thermoplastic polymer for the filament segment is a TPU.

[0094] In a preferred embodiment, a method for connecting one or more additional polymeric part to a filament segment is an additional step during filament stress equalization and comprises of: introducing one or more additional polymeric parts adjacent to a moulded filament segment within a mould, applying a clamping force to the additional polymeric part and the moulded filament segment within the mould and introducing molten thermoplastic polymer in the area between the filament segment and the additional polymeric part, allowing the additional polymeric part to adhere to and become an integrated part of the moulded polymer filament and removing additional polymeric part adhering to the filament segment from the mould after release of the clamping force. The clamping force is the pressure required to keep the mould closed without causing any leaks of polymer. The clamping force is maintained during the connection steps of the additional polymeric part, starting from closing the mould with the filament segment and additional polymeric part inside until the introduced molten thermoplastic polymer is solidified.

[0095] In an embodiment, an additional polymeric part comprises of a thermoplastic polymers for medical implant applications and is of the same thermoplastic polymer as the filament segment. The use of the same thermoplastic polymer is beneficial as a good adhesion between both filament segment and additional polymeric part is obtained. Preferably the thermoplastic polymer is an EVA. In another embodiment the thermoplastic polymer is a TPU.

[0096] In an embodiment, an additional polymeric part comprises of a thermoplastic polymers for medical implant applications and is of a different thermoplastic polymer for medical applications as the filament segment. Preferably the thermoplastic polymer for the filament segment is an EVA. The use of different thermoplastic polymers is beneficial as diverse properties of the filament segment and the additional polymeric part is required. In another embodiment the thermoplastic polymer for the filament segment is a TPU.

[0097] In an embodiment, an additional polymeric part comprises of a thermoplastic polymers for medical implant applications and is of the same thermoplastic polymer for medical applications as the filament segment, but with a different flow behaviour. Preferably the thermoplastic polymer for the filament segment is an EVA. The use of different thermoplastic polymers is beneficial as diverse properties of the filament segment and the additional polymeric part is required. Additionally, shorter cycle time are obtained. In another embodiment the thermoplastic polymer for the filament segment is a TPU.

[0098] In a preferred embodiment, a method for capping filament segments, wherein the filament segments originate from an extruded filament comprising of a matrix component comprising a thermoplastic polymer for medical applications, capping filament segments with thermoplastic polymer caps. Preferably the filament segments and the caps are of the same thermoplastic polymer for medical applications, more preferably of an EVA. In another embodiment the filament segments and the caps are a TPU.

[0099] In an embodiment, a method for capping filament segments, wherein the filament segments originate from an extruded filament comprising of a matrix component comprising a thermoplastic polymer for medical applications, capping filament segments with thermoplastic polymer caps. the caps are of a different thermoplastic polymer for medical applications than the filament segment.

[0100] The pharmaceutical active ingredients that can be present in the filament of the present application include, for example: antibiotic agents such as fumagillin analogs, minocycline, fluoroquinolone, cephalosporin antibiotics, herbimycon A, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamicin and erythromycin; antibacterial agents such as sulfonamides, sulfacetamide, sulfamethizole, sulfoxazole, nitrofurazone, and sodium propionate; antiviral agents such as idoxuridine, famvir, trisodium phosphonoformate, trifluorothymidine, acyclovir, ganciclovir, DDI and AZT, protease and integrase inhibitors; prostaglandin analogues such as latanoprost, travoprost, unoprostone and bimatoprost; anti-glaucoma agents such as beta blockers (timolol, betaxolol, atenolol), prostaglandin analogues, hypotensive lipids, and carbonic anhydrase inhibitors; antiallergenic agents such as antazoline, methapyriline, chlorpheniramine, pyrilamine and prophenpyridamine; antiinflammatory agents such as hydrocortisone, leflunomide, dexamethasone phosphate, fluocinolone acetonide, medrysone, methylprednisolone, prednisolone phosphate, prednisolone acetate, fluoromethalone, betamethasone, triamcinolone acetonide, adrenalcortical steroids and their synthetic analogues, and 6-mannose phosphate; anti-angiogenesis agents including those that can be potential anti- choroidal neovascularization agents such as 2-methoxyestradiol and its analogues (e.g., 2-propynl-estradiol, 2-propenyl-estradiol, 2-ethoxy-6-oxime-estradiol, 2- hydroxyestrone, 4-methoxyestradiol), VEGF antagonists such as VEGF antibodies (such as bevacizumab, ranibizumab, aflibercept) and VEGF antisense, angiostatic steroids (e.g., anecortave acetate and its analogues, 17-ethynylestradiol, norethynodrel, medroxyprogesterone, mestranol, androgens with angiostatic activity such as ethisterone); immune system modifying agents such as cyclosporine A, Prograf (tacrolimus), macrolide immunosuppressants, mycophenolate mofetil, rapamycin, and muramyl dipeptide, and vaccines; anti-cancer agents such as 5- fluoroucil, platinum coordination complexes such as cisplatin and carboplatin, adriamycin, antimetabolites such as methotrexate, anthracycline antibiotics; antisense agents such as fomivirsen; antifungal agents such as fluconazole, amphotericin B, liposomal amphotericin B, voriconazole, imidazole- based antifungals, triazole antifungals, echinocandin-like lipopeptide antibiotics; myotic and anticholinesterase agents such as pilocarpine, eserine salicylate, carbachol, diisopropyl fluorophosphate, phospholine iodine, and demecarium bromide; mydriatic agents such as atropine sulfate, cyclopentane, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; differentiation modulator agents; sympathomimetic agents such as epinephrine; anesthetic agents such as lidocaine and benzodiazepam; vasoconstrictive agents such as pseudoephedrine and phenylephrine; vasodillatory agents such as tolazoline, nicotinic acid, nicotinyl alcohol and nylidrin; decongestants such as naphazoline, phenylephrine, tetrahydrozoline and exymetazoline; polypeptides and protein agents such as angiostatin, endostatin, matrix metalloproteinase inhibitors, platelet factor 4, interferon-gamma, insulin, growth hormones, insulin related growth factor, heat shock proteins, humanized anti-IL-2 receptor mAb (daclizumab), etanercept, mono and polyclonal antibodies, cytokines, antibody to cytokines; steroidal agents such as triamcinolone, dexamethasone, clobetasol, betamethasone, and halometasone; cell transport / mobility impending agents such as colchicine, vincristine, cytochalasin B; carbonic anhydrase inhibitor agents such as acetazolamide, brinzolamide, dorzolamide and methazolamide; polycations and polyanions such as suramine and protamine; and lubricating agents.

[0101] In a preferred embodiment, the at least one pharmaceutical active ingredient is selected from the group consisting of bevacizumab, ranibizumab, aflibrcept, timolol, latanoprost, bimatoprost, travoprost, dorzolamide, triamcinolone, dexamethasone or cyclosporin. In a particularly preferred embodiment, the at least one pharmaceutical active ingredient is chosen from bimatoprost, travoprost and timolol, preferably timolol.

[0102] The present invention will be now described in more details, referring to examples that are not limitative.

[0103] EXAMPLES

[0104] Example 1

[0105] The objective of this experiment was to identify the process parameters of the coextrusion process, and material attribute (EVA MFI) having an influence on the shrinking of EVA filaments to limit it or even eliminate it to obtain a filament which would be stable under normal temperature condition (encountered during its use as well as during its storage).

[0106] The experimental setup involved a coextrusion process to produce EVA filaments with variations in several key parameters to determine their impact on shrinkage behavior. The die sizes used were 0.4 mm, 0.6 mm, and 0.8 mm, and the coextrusion temperatures tested were 100°C, 125°C, and 150°C. The bath temperatures ranged from 15°C to 40°C, and the degree of stretching (stretching factor) varied between 1 and 3 to determine its effect on filament stability. The materials used included EVA with three different Melt Flow Indices (3, 25, and 43). A Design of Experiment (DoE) approach was implemented to systematically test the different combinations of these parameters. The filaments were either directly tested after production or put through a shrinking process in an oven at 57.5°C for 30 minutes before being gamma sterilized. The produced filaments were monitored for stability at elevated temperatures over several months, allowing for the identification of optimal production parameters to minimize shrinkage post-production.

[0107] Filaments of 30cm were cut directly after production then filament length was measured after sterilization. The evolution of filament length was then monitored after being placed in a climatic chamber at 45"C for 48h, 1 week, 1 month, 3 months and 6 months after sterilization.

[0108] It was shown that the length of filaments does evolve post-production if not shrunk. Regarding shrunk filaments, it shows that the length does not evolve after sterilization nor overtime, meaning that the stabilization through shrinking process was efficient and allows obtain filaments that are less sensitive to gamma sterilization and subsequent evolutions during storage.

[0109] The behavior observed on non-shrunk filaments confirmed the results obtained with shrunk filaments. The results on non-shrunk filaments demonstrated the instability of the polymer postproduction and especially post gamma irradiation, which would result in instability during storage if the stabilization of the polymer is not complete after shrinking step for example.

[0110] The results of this experiment show that the parameter having the most significant impact on shrinking behavior is the stretching of the filament during coextrusion process followed by die size, coextrusion temperature and bath temperature. Moreover, cross effects between parameters such as die size and stretching and die size and bath temperature were also identified. The model, which matched the data with a R2 of 0.95, identified optimum parameters that would lead to no shrinking of the filaments post processing. The identified optimum parameters are the following:

[0111] Die size:0.4 mm,

[0112] Coextrusion temperature: 150°C,

[0113] Bath temperature: 40°C,

[0114] Stretching factor: 1 (= no stretching),

[0115] Screw speed: 1.15 rpm (no effect),

[0116] - EVA MFI: 3 g / 10 min Example 2

[0117] The goal of this experiment is to verify the optimum process parameters which would minimize shrinking behavior of EVA. The shrinking behavior was evaluated on timolol loaded EVA coextruded filaments produced using optimized material attribute and coextrusion process parameters based on preliminary data available from study.

[0118] The experimental setup involved producing timolol-loaded EVA filaments using a coextrusion process, with different configurations to evaluate shrinking behavior. Filaments were made with die size 0.4 mm, varying bath temperatures (ranging between 38-42°C), and pulling speeds (between 0-20 m / min). Both stretched and non-stretched configurations were tested using EVA from two different batches. Process parameters such as the inner and outer screw speeds (ranging from 0.77 to 7 rpm) and extrusion pressures were systematically adjusted. Ten filaments of 30 cm in length were placed in an oven at 57.5°C for 30 minutes, and their final length was measured to determine the degree of shrinkage, aiming to identify the most effective process parameters to minimize filament shrinking.

[0119] The shrinking behavior evaluated on timolol loaded EVA coextruded filaments, produced using optimized material attribute and coextrusion process parameters, demonstrated that the non-stretched filaments shrunk very slightly (1 to 2 %).

[0120] The study also showed that filament swelling as the product exits the 0.4 mm die can results in stretching needed to achieve 330 pm on-line. Therefore, to obtain 330 pm filament (on-line measurement) without stretching the filament, a smaller die could be used. The dimension of the die that would apply a minimum stretching to reach a stable 330 pm filament is estimated to be between 0.25 mm and 0.30 mm.

[0121] The invention may thus be described according to the following embodiments:

[0122] 1. A method for filament extrusion suitable for medical implant applications, said filament comprising a thermoplastic polymer as matrix component, preferably an ethylene vinyl acetate (EVA) copolymer, and at least one pharmaceutical active ingredient for controlled release and having a diameter smaller than 2.0 mm, preferably smaller than 1.0 mm and more preferably smaller than 0.5 mm, comprising the steps of: extruding a filament, introducing said extruded filament into a cooling bath containing a cooling liquid.

[0123] 2. The method according to embodiment 1, wherein the cooling liquid has a temperature between 35°C to 80°C, more preferably between 35°C to 65°C and even more preferably between 35°C to 45°C, or even between 38 and 42°C.

[0124] A higher bath temperature in view of known techniques has been found to help stabilize the filaments after extrusion by reducing internal stresses, ultimately contributing to reduced shrinkage.

[0125] 3. The method according embodiment 1 or 2, wherein the filament has a diameter of smaller than 0.5 mm, and wherein during extrusion an extruder die size of at most 0.4 mm is used, preferably at most 0.35 mm or even at most 0.3 mm.

[0126] Using a die size of 0.4 mm resulted in least shrinkage, if the diameter of the filament is even smaller, an even smaller die size of between 0.25 mm and 0.30 mm could reduce the need for stretching, thereby minimizing post-production shrinkage.

[0127] 4. The method according to any of the preceding embodiments, wherein the coextrusion temperature is between 100 and 200°C, preferably between 125 and 175°C.

[0128] Higher coextrusion temperatures, particularly at around 150°C, resulted in better material curing and filament quality with a lower tendency to shrink. Higher temperatures during extrusion enhanced material flow and stability, which ultimately led to reduced shrinkage.

[0129] 5. The method according to any of the preceding embodiments, wherein the filament is pulled with a pulling speed of at most 20 m / min.

[0130] Pulling speeds between 0 and 20 m / min are preferably used. Higher pulling speeds led to more stretching, which in turn resulted in greater shrinkage when heated. By reducing the pulling speed, less tension was applied to the filaments, which helped to significantly reduce shrinkage.

[0131] 6. The method according to any of the preceding embodiments, wherein the screw speed is between 0.5 rpm and 10 rpm, preferably between 0.5 and 5 rpm, or even between 0.5 and 2 rpm.

[0132] Screw speeds between 0.77 rpm and 7 rpm are preferably used, with lower screw speeds resulting in a more stable extrusion process. Lower speeds helped to avoid excessive pressure buildup, leading to a more consistent material flow and reduced filament shrinkage after production.

[0133] 7. The method for filament extrusion according to any of the preceding embodiments, wherein the pressure is kept between 150 and 300 bar, preferably between 165 and 175 bar.

[0134] Lower extrusion pressures (for example 172 - 269 bar) reduced the likelihood of excessive material stretching during the extrusion process. Lower pressures resulted in less internal stress, contributing to reduced shrinkage in the final product.

[0135] 8. The method according any of the preceding embodiments wherein said extruding comprises the steps of: extruding said ethylene vinyl acetate (EVA) copolymer, and / or a combination of ethylene vinyl acetate (EVA) copolymer and said pharmaceutical active ingredient in separate extruder units to obtain individual ethylene vinyl acetate (EVA) copolymer melts, at least one thereof comprising said pharmaceutical active ingredient; and converging said individual ethylene vinyl acetate (EVA) copolymer melts into a coextrusion die head within a coextrusion die to form a coextruded filament, having one or more cores and one or more mantles (shells).

[0136] 9. The method according embodiment 8, wherein the filament has a diameter of smaller than 0.5 mm, and wherein said coextrusion die has a die size of at most 0.4 mm, preferably at most 0.35 mm or even at most 0.3 mm.

[0137] 10. The method according any of the preceding embodiments, wherein the stretch ratio is smaller than 3.0, preferably smaller than 2.0 and more preferably at most 1.1, wherein said stretch ratio is defined as the ratio of a diameter of a die head of the extruder, to a final diameter of the filament, after solidification of the stretched filament.

[0138] 11. The method according any of the preceding embodiments, wherein no stretching is carried out.

[0139] Filaments produced under tension showed significantly more shrinkage during the heat test. Stretching introduced internal stresses, leading to instability and greater shrinkage. Non-stretched filaments showed minimal shrinkage (1-2%). Limiting stretching has been found to be the most effective way to reduce shrinkage. The method according to embodiment 4, wherein said one or more cores comprise the same type of EVA as the one or more shells, and wherein the one or more cores comprise the pharmaceutical active ingredient. The method according to any of the preceding embodiments, wherein the at least one pharmaceutical active ingredient is selected from the group consisting of bevacizumab, ranibizumab, aflibrcept, timolol, latanoprost, bimatoprost, travoprost, dorzolamide, triamcinolone, dexamethasone or cyclosporin, preferably chosen from: bimatoprost, travoprost, and timolol, more preferably timolol.

Claims

CLAIMS1. A method for filament extrusion suitable for medical implant applications, said filament comprising an ethylene vinyl acetate (EVA) copolymer and a pharmaceutical active ingredient for controlled release and having a diameter smaller than 2.0 mm, preferably smaller than 1.0 mm and more preferably smaller than 0.5 mm; comprising the steps of: extruding a filament, introducing said extruded filament into a cooling bath containing a cooling liquid; and maintaining said filament within said cooling bath, immersed in the cooling liquid, for a predetermined period, the temperature of the cooling liquid being between 35°C to 80°C .

2. The method for filament extrusion according claim 1, wherein the cooling liquid has a temperature between 35°C to 65°C and even more preferably between 35°C to 45°C.

3. The method for filament extrusion according any of the preceding claims 1 or 2, further comprising: continuously transporting said extruded filament through the cooling bath using a conveyor system at a controlled speed, wherein the controlled speed of the conveyer system is based on a stretch ratio, wherein said stretch ratio is defined as the ratio of a diameter of a die head of the extruder, to a final diameter of the filament, after solidification of the stretched filament; wherein said ratio is smaller than 3.0, preferably smaller than 2.0 and more preferably smaller than 1.1.

4. The method for filament extrusion according to any of the preceding claims 1, 2 or 3, further comprising of: providing an extruder die having a die head with a diameter, wherein said diameter is within a range of up to a maximum of 1.5 mm; preferably up to a maximum of 0.8 mm and even more preferably up to a maximum of 0.4 mm.

5. The method for filament extrusion according to any of the preceding claims 1-4, comprising of: immersing said filament in a cooling liquid in a cooling bath,wherein said cooling bath has a length of at least 0.5 m, more preferably below 2.0 m and wherein the immersing cooling time of said filament is proportional to the diameter of the filament, ensuring cooling, stress equalization and solidification of the extruded filament.

6. The method for filament extrusion according to any of the preceding claims 1-5, comprises the steps of: extruding a feedstock, wherein said feedstock comprises an EVA, through a die head to form a filament at a specific extruder pressure; subjecting said extruded filament to a stretching process, wherein the stretch ratio is defined as the ratio of a diameter of a die head of the extruder, to a final diameter of the filament, after solidification of the stretched filament; adjusting the extruder pressure, by adjusting screw speed of the extruder, in relation to the stretch ratio of the filament to control and minimize die swell, thereby achieving a stretched filament with reduced diameter variation7. The method for filament coextrusion according to any of the preceding claims 1- 6, providing a coextrusion apparatus having multiple extruder units, each configured to extrude a feedstock comprising an EVA as matrix component, comprising the steps of: extruding said feedstock through their respective extruder units; and converging said individual feedstock melts into a coextrusion die head within a coextrusion die to form a coextruded filament with distinct layers, wherein said filament with distinct layers comprises of one or more cores and one or more shells.

8. The method for coextruded filament produced according to claim 7, comprising of: coextruding a feedstock comprising an EVA as matrix component in distinct layers comprising a core and a shell, wherein said core comprises of the same EVA as the shell, and the core also comprises a pharmaceutical active ingredient.

9. The method for filament extrusion according to any of the preceding claims 7 or 8, providing a coextrusion apparatus having multiple extruder units, each equipped with an extruder screw, comprises of:coextruding feedstock materials, wherein said feedstock material comprises of an EVA as matrix component, through a coextrusion die to form a filament with distinct layers, adjusting the screw speed ratio to control the layer thickness and distribution within the coextruded filament, wherein screw speeds of the individual extruder units define the speed ratio which is below 5.0, more preferably below 1.5 and above 0.2 to assist control of the slow release property of the extruded filament for medical implant applications.

10. The method for filament extrusion according to claim 1, wherein the pharmaceutical active ingredient is selected from the group consisting of bevacizumab, ranibizumab, aflibrcept, timolol, latanoprost, bimatoprost, travoprost, dorzolamide, triamcinolone, dexamethasone or cyclosporin,11. The method for filament extrusion according to claim 10, wherein the pharmaceutical active ingredient is timolol.

12. The method for filament extrusion according to any of claims 10 or 11, wherein the filament has a diameter smaller than 0.5 mm, and wherein during extrusion an extruder die size of at most 0.4 mm is used, preferably at most 0.35 mm or even at most 0.3 mm.

13. The method for filament extrusion according to any of claims 10-12, wherein the filament is stretched with a stretch ratio of at most 1.1, wherein said stretch ratio is defined as the ratio of a diameter of a die head of the extruder, to a final diameter of the filament, after solidification of the filament.

14. A method for compounding EVA as a prior step for any of the preceding claims 1-13, providing a compounding apparatus comprising twin screws, a die head and granulator; introducing one or more feedstock materials into the compounding apparatus, wherein said feedstock material comprising a first feedstock material EVA as matrix component, wherein a second feedstock material comprises at least a pharmaceutical active ingredient operating the twin screws to convey and mix said feedstock materials within the apparatus; discharging the compounded material through a die head to form a continuous compound;transporting said continuous compound to a granulator; and granulating the continuous extrudate into discrete pellets.

15. A method for stress equalization for an extruded filament, wherein the extruded filament is produced by any of the preceding claims 1-13, comprises of the additional steps: cutting the filament into segments; placing a segment of extruded filament into a mould at a temperature higher than room temperature but below liquidization temperature of matrix material EVA of the filament, the liquidization temperature of EVA is the temperature at which the filament loses its solidified shape; maintaining the segment of extruded filament within the mould at said elevated temperature for a predetermined period of time to facilitate stress equalization within the filament; removing the filament segment from the mould after the stress equalization period.

16. A method for connecting an additional polymeric part to a filament segment, wherein the EVA filament is extruded by any of the preceding claims 1-13 and the method is an additional step during filament stress equalization by a method according to claim 14, comprising of: applying a clamping force to the moulded filament segment within the mould, wherein the clamping force is the pressure required to keep the mould closed without causing any leaks of polymer; and injection and shaping molten EVA in the mould and adhering the molten EVA to the filament segment, allowing the molten EVA to become an integrated part with the filament segment, wherein the clamping force is maintained; removing integrated part adhering to the filament segment from the mould after release of the clamping force.

17. A method for connecting an additional polymeric part to a filament segment, wherein the EVA filament is extruded by any of the preceding claims 1-13 and the method is an additional step during filament stress equalization by a method according to claim 14, comprising of: introducing an additional polymeric part adjacent to a moulded filament segment within a mould;applying a clamping force to the additional polymeric part and the moulded filament segment within the mould, wherein the clamping force is the pressure required to keep the mould closed without causing any leaks of polymer; and introducing molten EVA in the area between the filament segment and the additional polymeric part, allowing the additional polymeric part to adhere to and become integrated with the moulded polymer filament, wherein the clamping force is maintained; removing additional polymeric part adhering to the filament segment from the mould after release of the clamping force.

18. A method for capping filament segments, wherein the segments originate from EVA filaments extruded by any of the preceding claims 1-13, and the method is an additional step after filament stress equalization by a method according to claim 14, comprising of, capping filament segments with EVA caps.