Method and device for removing aggregates from viscous materials

Abstract

A method for filtering or removing agglomerates of individual particles from a viscous substance, such as a dermal filler formulation, is provided. The method involves loading the viscous substance into an extrusion system with a sieve or filter located inside, outside, or adjacent to the system, or external thereto. The substance is extruded through the filter / sieve, which filters / removes agglomerates present in the viscous substance due to their larger size. Alternatively, pressure-based filtration causes the separation of individual particles, which causes the agglomerates to break down, allowing the viscous substance to pass through the extrusion system without clogging issues. The filtered viscous substance is suitable for administration to a patient. The present invention also describes a device for implementing the proposed pressure-based filtration technique.

Description

[Technical Field]

[0001] The present invention relates generally to filtering aggregates from viscous injectable materials. More specifically, the present invention relates to methods and devices for removing aggregates from viscous injectable materials, such as dermal fillers. [Background technology]

[0002] Certain drug formulations may be inherently highly viscous, which can cause problems when administered as an injection. Problems inherent in this densification include the formation of aggregates. These aggregates form heterogeneous zones within the hydrogel, sol, or colloid, leading to inconsistencies in the final injectable material. In many cases, the rheological properties of the viscous material change, resulting in poor performance in the syringe upon administration.

[0003] Agglomerates within viscous materials can cause two major problems: clogging and uneven extrusion forces. Importantly, agglomerates of individual particles can clog the needle and prevent proper delivery of the pharmaceutical formulation. Similarly, partial clogging can require excessive force, potentially resulting in the delivery or injection of a larger amount of material than desired when the clog is cleared. This can have a significant impact on the final outcome, as the material will not be delivered precisely as desired.

[0004] Furthermore, there are several secondary problems associated with uneven particle size distribution. For example, heterogeneous materials may have different mechanical properties and elicit different immune and host cell responses in the body. For example, a more homogeneous material may be expected to provide more uniform deposition of extracellular matrix than a conglomerate of individual particles, which limits the surface area over which matrix deposition can occur.

[0005] An example of such a viscous substance is a dermal filler. Certain viscous substances prepared using powders can be diluted or reconstituted to adjust the viscosity; however, dilution or reconstitution does not effectively address viscous substances, as the problem recurs when the substance thickens. For some viscous substances, such as dermal fillers described by the applicant in International Patent Application WO 2021 / 248,236, it is desirable to adjust the viscosity of the filler substance. For example, a lower viscosity allows for easier injection, while a higher viscosity allows for more uniform particle placement and / or maintains volume, for example, over a longer period of time. Therefore, in the manufacture of dermal fillers, the particles produced must be concentrated to achieve the desired viscosity. For use as an injectable, the substance must be able to pass through a needle or cannula for effective delivery. Furthermore, certain applications may require certain viscous substances to have a specific particle size or a substantially uniform or controlled particle size distribution. A common solution involves the use of large-bore needles or cannulas, however, large needles are painful and inconvenient for the patient. Another common approach to overcoming the problems associated with agglomerates involves sizing and sorting individual particles, however, this can result in a final material with different, undesirable mechanical properties. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Patent Application WO 2021 / 248,236 Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, methods and / or devices that can help overcome the above-mentioned drawbacks are desirable. [Means for solving the problem]

[0008] Provided herein are methods for removing agglomerates of individual particles from a viscous substance. The methods can also be used to filter and size individual particles of a viscous substance to achieve a uniform mixture of components and a substantially uniform matrix suitable for administration of the viscous substance. In one embodiment, the method includes removing or filtering agglomerates of individual particles from the viscous substance by loading the substance into an extrusion system or a first injection device comprising at least one filter / sieve. In some embodiments, the extrusion system can comprise a series of filters / sieves. The viscous substance is then passed through filters / sieves located inside, outside, adjacent to, or external to the extrusion system or first injection device, causing the removal or filtering of agglomerates and making the substance suitable for administration to a patient. The passing step can further involve extruding the substance through a filter / sieve under pressure. These methods are suitable for removing / filtering agglomerates of individual particles from a wide variety of viscous substances, including dermal fillers.

[0009] In some instances, the method may be performed differently, in which the viscous material is first loaded or collected into a first collection container. The material then passes through at least one filter / sieve attached to the interior of the first collection container, and the filtered material is collected in a second collection container, where it is stored before being administered to a patient. The filtered material stored in the second collection container can be transferred to individual administration / transfer syringes prior to direct administration to a patient. Uses of the method for aggregate removal / filtration, and other purposes, are also described.

[0010] Devices for removing aggregates are also provided. The devices for removing aggregates may comprise an extrusion system or a first injection device having at least one filter / sieve attached thereto. The extrusion system may be connected to a loading container / transfer syringe or a second injection device, which may be employed to store the filtered viscous material or to administer the material directly to a patient(s). Different versions of the device are also provided, in which the material is collected in a first collection container having a filter / sieve within its body. In some embodiments, the first collection container may comprise an extrusion system as previously defined herein. The first collection container may be connected to a second collection container, which allows the filtered material to be stored therein before being administered to a patient(s). [Brief explanation of the drawings]

[0011] [Figure 1] Figure 1 shows the results of needle occlusion tests using mercerized viscous materials. Figure 1(A) shows the 27G needle and syringe used in extrusion. Figure 1(B) shows the extrusion of the mercerized viscous material. Figure 1(C) provides an example of 3D printing or controlled dispensing / extrusion. [Figure 2] FIG. 1 shows the results of a sieving test (individual particles / agglomerates too large to pass through the sieve are collected in a separate container). [Figure 3] Figure 1 shows the results of the sliding surface modification test, showing the extrusion force for a 0% gelatin formulation (red) and a 5% gelatin formulation (blue). An extrusion speed of 1 mm / sec was used. The material was extruded from a 1 cc syringe through a 27G needle. [Figure 4] FIG. 1 shows the mesh employed in the pressure-driven sieving protocol. [Figure 5] FIG. 1 shows a microscopic image (magnification ×10) of the mesh employed in pressure-driven sieving. [Figure 6]Figure 1 shows the results of particle size and morphology investigated / checked after pressure-driven sieving. Particles were stained using Congo Red and imaged at 10x magnification on an SZ16 stereo microscope (scale = 500 μm). [Figure 7] FIG. 1 shows the particle size distribution of a viscous injectable material passed through a mesh in a pressure-driven sieving process. [Figure 8] 1 is a diagram showing an in-line pressure filtration device of the present invention. [Figure 9] FIG. 1 shows an in-syringe pressure filtration device of the present invention, in which the mesh is located at the base inside the syringe. [Figure 10] FIG. 1 shows an in-line syringe pressure filtration device in which the mesh is housed within a custom Luer lock connector connected between the syringe and needle. [Figure 11] FIG. 1 shows a block diagram of a filtration process. [Figure 12] FIG. 1 shows a block diagram of small, medium, and large scale filtration processes. DETAILED DESCRIPTION OF THE INVENTION

[0012] The following description is of preferred embodiments for illustrative purposes only, but without limitation, the combination of attributes required to effectuate the invention.

[0013] All terms are intended to be understood as understood by one of ordinary skill in the art. Unless otherwise defined, 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 disclosure pertains. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0014] While various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may, for clarity, be described herein in the context of separate embodiments, the present disclosure may also be implemented in a single embodiment.

[0015] The following definitions supplement those in the art and are relevant to the present application. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0016] The terms "first injection device," "extrusion system," and "first collection vessel" refer to a container in which the material to be deagglomerated or filtered is collected prior to the filtration step.

[0017] The terms "secondary injection device," "loading vessel," "transfer syringe," or "secondary collection vessel" refer to a container in which the filtered or deaggregated material is stored after the filtration step or before administration to a patient.

[0018] To overcome the issues / problems associated with the prior art, the inventors sought to identify a solution that would limit the number of blockages or eliminate blockage events altogether. Apart from removing aggregates present in the viscous material, the claimed technology sizes individual particles of the viscous material without affecting their characteristics and / or morphology. It is related to the importance of preventing potential blockage events and having a substantially uniform or controlled extrusion profile, which is crucial to accurately delivering a drug formulation. To prevent pressure buildup and uneven extrusion pressure, the applicants conducted experiments using known techniques and devices to determine whether any prior art or device could be adapted to resolve the problems associated with injecting viscous materials. It is important to note that the inventors identified and defined a blockage event as a clogged needle or a clogged extrusion or ejection system, where the material cannot flow through the needle, thereby clogging the extrusion / ejection system. Various embodiments of the present invention are described in detail below.

[0019] Provided herein is a method for removing agglomerates of individual particles from a viscous substance for administration to a patient. The method includes loading the viscous substance into an extrusion system including at least one filter / sieve, and passing the viscous substance through the at least one filter / sieve to cause removal of agglomerates of individual particles from the viscous substance. The filtered viscous substance produced by the method is suitable for administration to a patient.

[0020] In certain embodiments, the method does not alter the characteristics or morphology of at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the viscous material.

[0021] In further embodiments, the passing step further comprises forcing the viscous substance through at least one filter / sieve under / by applying pressure. In certain embodiments, the viscous substance is forced through at least one filter / sieve by applying pressure using a device such as a plunger, an extruder, manual compression, a syringe pump, platen compression, rollers for flexible tubing, a compressor, or similar mechanism.

[0022] In some embodiments, the agglomerates are removed from the viscous substance by breaking / disintegrating the agglomerates. The agglomerates are removed from the viscous substance by filtering / sieving out the agglomerates that cannot pass through at least one filter / sieve.

[0023] In some further embodiments, the viscous material is pre-filtered through multiple pre-filtration devices, with the pre-filtration step occurring before the passing step. In some embodiments, the viscous material is pre-filtered through a first pre-filtration device followed by a second pre-filtration device. In some alternative embodiments, the multiple pre-filtration devices are a series of injection devices, injection syringes, evacuation systems, injection devices with luer-lock connectors, compressible tubing, non-compressible tubing, cylinders, or large-scale syringes.

[0024] In some embodiments, the first and second pre-filtration devices are a series of injection devices, injection syringes, or large-scale syringes, and the first pre-filtration device has a larger opening size than the second pre-filtration device. The opening sizes of the first and second pre-filtration devices can be in the range of 18G to 34G.

[0025] In some embodiments, the viscous substance is passed through at least one filter / sieve having a pore size / opening size smaller than the individual particle sizes of the viscous substance, and the pore size of the at least one filter / sieve can be in the range of 1-1000 μm and the individual particle sizes can be in the range of 20-1000 μm. In some alternative embodiments, the pore size of the at least one filter / sieve can be in the range of 25-500 μm and the individual particle sizes can be in the range of 40-500 μm. In some other embodiments, the pore size of the at least one filter / sieve can be in the range of 50-200 μm and the individual particle sizes can be in the range of 75-200 μm.

[0026] In some embodiments, the filtered viscous material is collected in a loading vessel / transfer syringe and, when expelled out of the loading vessel / transfer syringe, does not clog the loading vessel / transfer syringe. In some embodiments, when expelled out of the loading vessel / transfer syringe, the filtered viscous material achieves a substantially uniform or controlled extrusion profile and, after an initial characteristic burst / break force, is expelled out of the loading vessel / transfer syringe without pressure buildup.

[0027] In certain embodiments, the individual particles of the viscous substance have an intact morphology. The filtered viscous substance, when administered, elicits the desired immune response in a patient. The extrusion system can be an injection syringe, a discharge system, a Luer lock connector device, or a compressible tube. In some embodiments, the extrusion system can be a syringe, the syringe having a needle size ranging from 18G to 34G.

[0028] In some embodiments, the loading vessel / transfer syringe is an injection syringe, a discharge system, a luer lock connector device, or a compressible tube. In some embodiments, the loading vessel / transfer syringe can be a syringe, the syringe having a needle size of 18G to 34G. In some of the previous embodiments, the volume of the extrusion system exceeds the volume of the loading vessel / transfer syringe, or the extrusion system has a smaller cross-sectional area compared to the loading vessel / transfer syringe.

[0029] In some of the previous embodiments, the at least one filter / sieve may be a nylon mesh, a stainless steel mesh, a polytetrafluoroethylene mesh, or a nitrocellulose mesh. The at least one filter / sieve may be located inside, outside, or adjacent to the extrusion system, or screwed onto the extrusion system, and may be replaced by an in-line filter, a gated impeller, a static mixer, a high shear mixer, a viscous mixer, or a sieving channel.

[0030] A related note is that the passing step sizes individual particles of the viscous substance to create a substantially uniform or controlled particulate matrix for administration. In some embodiments, the extrusion system is a luer lock connector device, and at least one filter / sieve is attached / located inside the luer lock connector portion of the device.

[0031] The viscous substance is forced under / by pressure through at least one filter / sieve attached / disposed inside the luer lock connector portion. Pressure can be applied using a plunger, extruder, manual compression, syringe pump, platen compression, rollers for flexible tubing, compressor, or similar device. In some embodiments, pressure is applied using a plunger or extruder.

[0032] In certain embodiments, the passing step can be repeated using multiple filters / sieves. In some embodiments, the multiple filters / sieves are the same size or have different sizes. In some embodiments, the pore size of at least one filter / sieve is in the range of 1 to 1000 μm.

[0033] In some of the previous embodiments, passing the material through multiple filters / sieves reduces the viscosity of the viscous material or adjusts its particle size distribution to a desired level, preferably within the range of 50-750 μm. The proposed method may also reduce the extrusion force required to eject the viscous material from the extrusion system.

[0034] In certain embodiments, the viscous substance is a dermal filler; a sealant; an adhesive; a composite mixture of mammalian cells; a scaffolding material; a bone paste; a bone cement; a cartilage biomaterial; an injectable solution, including for venous stasis applications; a protein hydrogel; a carbohydrate hydrogel comprising cellulose, pectin, and lignin; a cellular material mixture; a thickener; a gelling agent; and a stabilizer.

[0035] Also provided is a method for removing agglomerates of individual particles from a viscous dermal filler material for administration to a patient, the method comprising: loading the dermal filler material into an extrusion system comprising at least one filter / sieve; and passing the dermal filler material through the at least one filter / sieve to cause removal of agglomerates of individual particles from the dermal filler material. The filtered dermal filler material is suitable for administration to a patient.

[0036] In certain embodiments, the method does not alter the characteristics or morphology of at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the dermal filler material.

[0037] In a further embodiment, the passing step further comprises forcing the dermal filler material through at least one filter / sieve under / by applying pressure.

[0038] In certain embodiments, the dermal filler material is forced through at least one filter / sieve by applying pressure using a device that can utilize a plunger, extruder, manual compression, syringe pump, platen compression, rollers for flexible tubing, compressor, or similar mechanism.

[0039] In some embodiments, the agglomerates are removed from the dermal filler material by breaking / disintegrating the agglomerates. The agglomerates are removed from the dermal filler material by filtering / sieving out the agglomerates that cannot pass through at least one filter / sieve.

[0040] In some further embodiments, the dermal filler material is pre-filtered through multiple pre-filtration devices, and the pre-filtration step occurs before the passing step. In some embodiments, the dermal filler material is pre-filtered through a first pre-filtration device followed by a second pre-filtration device. In some alternative embodiments, the multiple pre-filtration devices are a series of injection devices, injection syringes, evacuation systems, injection devices with luer lock connectors, compressible tubing, non-compressible tubing, cylinders, or large scale syringes.

[0041] In some embodiments, the first and second pre-filtration devices are a series of injection devices, injection syringes, or large-scale syringes, and the first pre-filtration device has a larger opening size than the second pre-filtration device. The opening sizes of the first and second pre-filtration devices can be in the range of 18G to 34G.

[0042] In some embodiments, the dermal filler material is passed through at least one filter / sieve having a pore size / opening size smaller than the individual particle sizes of the dermal filler material, and the pore size of the at least one filter / sieve can be in the range of 1-1000 μm, and the individual particle sizes can be in the range of 20-1000 μm. In some alternative embodiments, the pore size of the at least one filter / sieve can be in the range of 25-500 μm, and the individual particle sizes can be in the range of 40-500 μm. In some other embodiments, the pore size of the at least one filter / sieve can be in the range of 50-200 μm, and the individual particle sizes can be in the range of 75-200 μm.

[0043] In some embodiments, the filtered dermal filler material is collected in a loading container / transfer syringe and, when expelled out of the loading container / transfer syringe, the filtered dermal filler material does not clog the loading container / transfer syringe. In some embodiments, when expelled out of the loading container / transfer syringe, the filtered dermal filler material achieves a substantially uniform or controlled extrusion profile and is expelled out of the loading container / transfer syringe without a buildup of pressure after an initial characteristic burst / break force.

[0044] In certain embodiments, the individual particles of the dermal filler have an intact morphology. Upon administration, the filtered dermal filler elicits the desired immune response in the patient. The extrusion system can be an injection syringe, a drainage system, a Luer lock connector device, or a compressible tube. In some embodiments, the extrusion system can be a syringe, the syringe having a needle size ranging from 18G to 34G.

[0045] In some embodiments, the loading vessel / transfer syringe is an injection syringe, a discharge system, a luer lock connector device, or a compressible tube. In some embodiments, the loading vessel / transfer syringe can be a syringe, the syringe having a needle size of 18G to 34G. In some of the previous embodiments, the volume of the extrusion system exceeds the volume of the loading vessel / transfer syringe, or the extrusion system has a smaller cross-sectional area compared to the loading vessel / transfer syringe.

[0046] In some of the previous embodiments, the at least one filter / sieve may be a nylon mesh, a stainless steel mesh, a polytetrafluoroethylene mesh, or a nitrocellulose mesh. The at least one filter / sieve may be located inside, outside, or adjacent to the extrusion system, or may be screwed onto the extrusion system, but may also be replaced by an in-line filter, a gated impeller, a static mixer, a high shear mixer, a viscous mixer, or a sieving channel.

[0047] A related note is that the passing step may size individual particles of the dermal filler material to create a substantially uniform or controlled particulate matrix for administration. In some embodiments, the extrusion system is a luer lock connector device, and at least one filter / sieve is attached / located inside the luer lock connector portion of the device.

[0048] The dermal filler material is forced under / by pressure through at least one filter / sieve attached / disposed inside the luer lock connector portion. Pressure can be applied using a plunger, extruder, manual compression, syringe pump, platen compression, rollers for flexible tubing, compressor, or similar device. In some embodiments, pressure is applied using a plunger or extruder.

[0049] In certain embodiments, the passing step can be repeated using multiple filters / sieves. In some embodiments, the multiple filters / sieves are the same size or have different sizes. In some embodiments, the pore size of at least one filter / sieve is in the range of 1 to 1000 μm.

[0050] In some of the previous embodiments, passing the material through multiple filters / sieves reduces the viscosity of the dermal filler material or adjusts its particle size distribution to a desired level, preferably within the range of 50-750 μm. The proposed method may also reduce the extrusion force required to eject the dermal filler material from the extrusion system.

[0051] In certain embodiments, the dermal filler material is a dermal filler; a sealant; an adhesive; a composite mixture of mammalian cells; a scaffolding material; a bone paste; a bone cement; a cartilage biomaterial; an injectable solution, including for venous stasis applications; a protein hydrogel; a carbohydrate hydrogel comprising cellulose, pectin, and lignin; a cellular material mixture; a thickener; a gelling agent; and a stabilizer.

[0052] A method of removing agglomerates of individual particles from a viscous substance for administration to a patient is provided, the method comprising the steps of loading the viscous substance into a first collection vessel comprising at least one filter / sieve, passing the viscous substance through the at least one filter / sieve to cause removal of agglomerates of individual particles from the viscous substance, and collecting the viscous substance in a second collection vessel, wherein the filtered viscous substance collected in the second collection vessel is suitable for administration to the patient.

[0053] The first collection vessel comprises an extrusion system, the extrusion system comprising at least one filter / sieve. In some embodiments, the method does not alter the characteristics or morphology of at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the viscous substance.

[0054] In certain embodiments, the passing step further comprises forcing the viscous substance through at least one filter / sieve under / by applying pressure. The viscous substance can be forced through at least one filter / sieve by applying pressure using a device such as a plunger, an extruder, manual compression, a syringe pump, a platen compression, a roller for flexible tubing, a compressor, or a similar mechanism.

[0055] In some embodiments, the agglomerates are removed from the viscous substance by breaking / disintegrating the agglomerates. The agglomerates are removed from the viscous substance by filtering / sieving out the agglomerates that cannot pass through at least one filter / sieve.

[0056] In some alternative embodiments, the viscous material is pre-filtered through multiple pre-filtration devices, with the pre-filtration step occurring before the passing step. In some further embodiments, the viscous material is pre-filtered through a first pre-filtration device followed by a second pre-filtration device. The multiple pre-filtration devices may be selected from a series of injection devices, injection syringes, evacuation systems, injection devices with luer lock connectors, compressible tubing, non-compressible tubing, cylinders, or large-scale syringes. The multiple pre-filtration devices may be a series of injection devices, injection syringes, or large-scale syringes, with the first pre-filtration device having a larger opening size than the second pre-filtration device.

[0057] In some embodiments, the opening size of the first pre-filtration device may be selected from 18 G to 34 G. In some further embodiments, the opening size of the second pre-filtration device is selected from 18 G to 34 G.

[0058] In certain embodiments, the viscous substance is passed through at least one filter / sieve having a pore size / opening size smaller than the individual particle sizes of the viscous substance. In some embodiments, the pore size of the at least one filter / sieve can be in the range of 1-1000 μm, and the individual particle sizes can be in the range of 20-1000 μm. In some embodiments, the pore size of the at least one filter / sieve can be in the range of 25-500 μm, and the individual particle sizes can be in the range of 40-500 μm. In some alternative embodiments, the pore size of the at least one filter / sieve can be in the range of 50-200 μm, and the individual particle sizes can be in the range of 75-200 μm.

[0059] The filtered viscous material is collected in a second collection container and can be dispensed / dispensed using a dispensing device. In some embodiments, when dispensed / dispensed from the dispensing device, the filtered viscous material does not clog the dispensing device. In some embodiments, when dispensed / dispensed from the dispensing device, the filtered viscous material has a substantially uniform or controlled extrusion profile.

[0060] In some embodiments, the filtered viscous material is dispensed / expelled from the dispensing device without pressure buildup after a characteristic initial burst / rupture force. Individual particles of the viscous material retain their morphology, i.e., have an intact morphology. The filtered viscous material, when administered, has the ability to elicit the desired immune response in a patient.

[0061] In some embodiments, the dispensing device can be a series of injection devices, injection syringes, evacuation systems, injection devices with luer lock connectors, compressible tubing, non-compressible tubing, cylinders, or large scale syringes. In some other embodiments, the dispensing device is a syringe, and the syringe has a needle size of 18G to 34G.

[0062] In some embodiments, the at least one filter / sieve is a nylon mesh, a stainless steel mesh, a polytetrafluoroethylene mesh, or a nitrocellulose mesh. The at least one filter / sieve may be located inside, outside, or adjacent to the first collection vessel, or may be screwed onto the extrusion system. The at least one filter / sieve may be replaced with an in-line filter, a gated impeller, a static mixer, a high-shear mixer, a viscous mixer, or a sieving channel. In some embodiments, the passing step sizes individual particles of the viscous substance to create a substantially uniform or controlled particulate matrix for administration.

[0063] In some embodiments, at least one filter / sieve is disposed inside a luer lock connector attached to the inside of the first collection container / the luer lock connector portion of the first collection container. The viscous substance can be forced through the at least one filter / sieve disposed inside the luer lock connector portion under / by applying pressure. The pressure can be applied using a plunger, extruder, manual compression, syringe pump, platen compression, rollers for flexible tubing, compressor, or similar device. In some alternative embodiments, the pressure is applied using a plunger or extruder.

[0064] In certain embodiments, the passing step is repeated using multiple filters / sieves, preferably of the same size or different sizes. The size of at least one filter / sieve can be in the range of 1-1000 μm. In some other embodiments, passing the material through multiple filters / sieves reduces the viscosity of the viscous material or adjusts its particle size distribution to a desired level, preferably within the range of 50-750 μm. In some embodiments, the proposed method reduces the extrusion force required to eject the viscous material from the extrusion system.

[0065] In some embodiments, the viscous substance can be a dermal filler; a sealant; an adhesive; a composite mixture of mammalian cells; a scaffolding material; a bone paste; a bone cement; a cartilage biomaterial; an injectable solution, including for venous stasis applications; a protein hydrogel; a carbohydrate hydrogel comprising cellulose, pectin, and lignin; a cellular material mixture; a thickener; a gelling agent; and a stabilizer.

[0066] In certain embodiments, the first collection vessel is a series of containers of different sizes, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, an injection syringe, a large injection syringe, a luer lock connector device, an evacuation system, or a compressible tubing. In some embodiments, the second collection vessel is selected from at least one of a transfer container, a storage bottle, an injection syringe, a filler cartridge, a series of containers of different sizes, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, a large injection syringe, a luer lock connector device, an evacuation system, or a compressible tubing.

[0067] In some further embodiments, the second collection container is used to dispense / expel the filtered viscous material for administration to the patient. The first collection container may have a greater volume than the second collection container.

[0068] Also provided is the use of any of the above method embodiments to reduce the viscosity of a viscous substance or dermal filler material or adjust its particle size distribution to a desired level, preferably within the range of 50 to 750 μm.Also provided is the use of any of the above method embodiments to break down clumps / aggregates within a viscous substance or dermal filler material.

[0069] Further provided is a use of any of the above method embodiments for preventing needle blockage in an injection or dispensing device during delivery of the viscous or dermal filler material. Further provided is a use of any of the above method embodiments for sizing individual particles of a viscous or dermal filler material such that the viscous or dermal filler material has an approximately / substantially uniform individual particle size.

[0070] Further provided is the use of any of the above method embodiments for reducing the individual particle size of a viscous or dermal filler material without affecting / impacting its rheological properties. Further provided is the use of any of the above method embodiments for reducing the individual particle size of a viscous or dermal filler material without affecting / impacting its rheological properties or without affecting / impacting / changing the characteristics or morphology of the individual particles of the viscous or dermal filler material.

[0071] Further provided is the use of any of the above method embodiments for filtering a viscous or dermal filler material so that the viscous or dermal filler material has a uniform or controlled particulate matrix for administration. The viscous material may be selected from the group consisting of dermal fillers, sealants, adhesives, complex mixtures of mammalian cells, scaffolding materials, bone pastes, bone cements, cartilage biomaterials, injectables including for venous stasis applications, protein hydrogels, carbohydrate hydrogels including cellulose, pectin, and lignin, cellular material mixtures, thickeners, gelling agents, and stabilizers.

[0072] There is further provided a use of any of the above method embodiments to reduce the individual particle size of a viscous or dermal filler material, thereby reducing the extrusion force required to expel the viscous or dermal filler material from an extrusion system.

[0073] There is further provided a device for removing agglomerates of individual particles from a viscous substance, comprising an extrusion system and at least one filter / sieve located inside, outside or adjacent to the extrusion system or screw-mounted onto the extrusion system, wherein passing the viscous substance through the at least one filter / sieve causes removal of agglomerates of individual particles from the viscous substance.

[0074] In some embodiments, the device further comprises an extruder for extruding the viscous material through at least one filter / sieve under / by application of pressure. In some embodiments, the extruder pressure can be controlled by electronic means. The at least one filter / sieve of the device can be nylon, stainless steel, polytetrafluoroethylene, or nitrocellulose. In some embodiments, the at least one filter / sieve can be nylon mesh or stainless steel mesh. In some further embodiments, the at least one filter / sieve can be replaced with an in-line filter, a gated impeller, a static mixer, a high-shear mixer, a viscous mixer, or a sieving channel. The dimensions of the in-line filter or sieving channel can be in the range of 0.5 mm to 2540 mm.

[0075] In some embodiments, the extrusion system is connected to a plurality of pre-filtration devices for pre-filtering the viscous material before passing the material through at least one filter / sieve. The extrusion system may be connected to at least one pre-filtration device and a loading vessel / transfer syringe, where at least one pre-filtration device is connected to the loading vessel / transfer syringe.

[0076] In some embodiments, the extrusion system is coupled to a loading vessel / transfer syringe for collecting the filtered viscous material. At least one filter / sieve can have an opening size smaller than the individual particle sizes of the viscous material. In some embodiments, at least one filter / sieve can have an opening size in the range of 1-1000 μm, and the individual particle sizes are in the range of 20-1000 μm. In some alternative embodiments, at least one filter / sieve has an opening size in the range of 25-500 μm, and the individual particle sizes are in the range of 40-500 μm. In some alternative embodiments, at least one filter / sieve has an opening size in the range of 50-200 μm, and the individual particle sizes are in the range of 75-200 μm.

[0077] In some embodiments, the extrusion system can be an injection syringe, a drainage system, a luer lock connector device, or a compressible tube. In some other embodiments, the extrusion system can be a syringe, the syringe having a needle size of 18G to 34G.

[0078] In some embodiments, the loading vessel / transfer syringe is selected from the group of an injection syringe, a discharge system, a luer lock connector device, or a compressible tube. In some embodiments, the loading vessel / transfer syringe can be a syringe, the syringe having a needle size of 18G to 34G.

[0079] In some other embodiments, the extrusion system has a volume that exceeds the volume of the loading vessel / transfer syringe, or the extrusion system has a smaller cross-sectional area compared to the loading vessel / transfer syringe. In some further embodiments, the extrusion system is a luer lock connector injection device and the at least one filter / sieve is disposed inside the luer lock connector.

[0080] There is also provided a device for removing agglomerates of individual particles from a viscous substance, comprising a first collection vessel, at least one filter / sieve attached to the interior, exterior or adjacent to the first collection vessel or screw-mounted thereto, and a second collection vessel coupled to the first collection vessel for collecting the filtered viscous substance, wherein passing the viscous substance through the at least one filter / sieve causes removal of agglomerates of individual particles from the viscous substance.

[0081] In some embodiments, the first collection vessel comprises an extrusion system as defined hereinbefore. The device of claim 169, wherein the first collection vessel is selected from the group of a series of containers having different dimensions, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, an injection syringe, a large injection syringe, a luer lock connector device, a discharge system, or a compressible tube.

[0082] In some embodiments, the second collection vessel may be selected from the group of a transfer container, a storage bottle, an injection syringe, a filler cartridge, a series of containers of different sizes, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, a large injection syringe, a luer lock connector device, a drainage system, or a compressible tubing. In some further embodiments, an additional filter / sieve may be attached inside the second collection vessel. The second collection vessel may be a collection chamber disposed inside the first collection vessel.

[0083] In certain embodiments, the device further comprises an extruder for extruding the viscous substance through at least one filter / sieve under / by applying pressure, wherein the extruder pressure is controlled by electronic means.

[0084] In some embodiments, at least one filter / sieve may have an opening size in the range of 1-1000 μm, and the individual particle sizes may be in the range of 20-1000 μm. In some alternative embodiments, at least one filter / sieve has an opening size in the range of 25-500 μm, and the individual particle sizes are in the range of 40-500 μm. In some embodiments, at least one filter / sieve has an opening size in the range of 50-200 μm, and the individual particle sizes are in the range of 75-200 μm.

[0085] In some embodiments, the at least one filter / sieve may be selected from a nylon mesh, a stainless steel mesh, a polytetrafluoroethylene mesh, or a nitrocellulose mesh. In some further embodiments, the at least one filter / sieve may be replaced with an in-line filter, a gated impeller, a static mixer, a high shear mixer, a viscous mixer, or a sieving channel.

[0086] In some embodiments, the first collection vessel may be connected to multiple pre-filtration devices for pre-filtering the viscous material before passing the material through at least one filter / sieve, but preferably the first collection vessel is connected to multiple pre-filtration devices, and the pre-filtration devices are connected to a second collection vessel. In some embodiments, the first collection vessel is connected to a first pre-filtration device and a second pre-filtration device, and each of the pre-filtration devices is connected to a second collection vessel.

[0087] In some embodiments, the at least one filter / sieve has an opening size smaller than the individual particle sizes of the viscous substance. In some embodiments, a luer lock connector can be attached to the inside of the first collection container. In certain embodiments, the at least one filter / sieve can be disposed within a luer lock connector attached to the inside of the first collection container.

[0088] The experimental data is discussed in detail below.

[0089] Experimental data Experiment A: Occlusion test In the occlusion test, the viscous material was able to pass through 27G and 30G needles. It was found that although some material passed through the needles, periodic clogging was visible, which is not ideal when a viscous drug formulation is to be injected / administered to a patient.

[0090] Figure 1 shows the needle occlusion test results. As shown in Figure 1(A), the viscous injectable material passes through a 27G needle and syringe. Figure 1(B) shows the mercerized viscous material after extrusion, and Figure 1(C) provides an example of 3D printing using a controlled injection / extrusion technique. While some of the viscous material passed through the needle, periodic clogging occurred, making this technique unsuitable for drug delivery applications.

[0091] Conclusions: When material was passed through a 27G needle, 10 mL of material resulted in 10 blockages. When material was passed through a 30G needle, 10.5 mL of material resulted in 39 blockages. As is evident from the results, both the 27G and 30G needles continued to experience periodic clogging and blockages, suggesting that the blockage test was unsuccessful.

[0092] Experiment B: Sieving test The inventors initially hypothesized that needle clogging was due to the presence of large individual particles in the viscous injectable material. Therefore, the highly viscous viscous material was diluted so that it could be filtered on a vibrating sieve. The material was passed through large and small sieves arranged in a serial configuration in an attempt to narrow the particle size distribution. This technique is similar to differential centrifugation, which is known to limit particle sizes to a desired range. It should be noted that clogging did not occur initially; however, as the material became more concentrated, the clogging problem persisted. Figure 2 shows the results of the sieving test. The figure shows a container in which particles / agglomerates too large to pass through a 425 μm sieve were collected.

[0093] The sieving protocol was as follows: 35 mL of viscous injectable material (e.g., MerAA or CelluJuve, Ross, blended and extruded sample) was diluted to 1 L with distilled water and stirred on a magnetic stirrer plate for 15 minutes. The diluted sample was sieved by placing a 425 μm sieve on top of a 45 μm sieve. 500 mL of the diluted sample was transferred to the 425 μm sieve, and the vibrator was activated for 15 seconds. The 425 μm sieve was then rinsed with 250 mL of distilled water, and the vibrator was activated for 15 seconds. This step was repeated two more times. The material remaining on the surface of the 425 μm sieve was discarded.

[0094] Extrusion process: 1 mL of material was loaded into a syringe and a 30 G needle was attached. The material was manually extruded and the number of occlusions was recorded for each 1 mL set.

[0095] The table below (Table I) shows the results of the sieving tests: [Table 1]

[0096] Conclusion: The size-limiting sieving test did not prevent needle clogging. Furthermore, pressure changes were observed during the extrusion process. Therefore, sieving alone did not solve the above problem.

[0097] Experiment C: Mixed Test A mixing device was prepared using an interlocked syringe connected to a Luer lock adapter, and then special mixers (planetary and static mixers) for viscous materials were used, aiming to create a substantially homogenous material that would not clog the needle.

[0098] Protocol: Again, 1 mL of material was loaded into a syringe and a 30G needle was attached. The material was manually extruded and the number of blockages recorded for each 1 mL set. Note that a blockage event was defined as a clogging of the needle such that material could no longer flow through the needle.

[0099] The table below (Table II) shows the results of the mixed tests: [Table 2] JPEG2025536867000004.jpg176121

[0100] Conclusion: As can be seen from the table, industrial planetary and static mixers were unable to prevent needle clogging.

[0101] Experiment D: Pre-filtration A "brute force" method of extruding the material was attempted. The viscous material was passed through the needle until it clogged. After a clogging event occurred, the needle was replaced with a new needle to remove the blockage. The material that successfully passed through the needle was then used in a clogging test using a needle of the same size as that used in screening. Nevertheless, periodic clogging of the needle occurred.

[0102] Conclusion: Pre-filtration by extrusion through a targeted needle did not prevent needle clogging.

[0103] Experiment E: Pre-filtration of mixed samples followed by sieving A combined method to remove blockages was employed. Experiments A, B, and C were tried together to evaluate whether an additive approach would solve the blockage problem. Samples mixed using an industrial mixer were pre-filtered by extruding the material until the needle clogged, then replacing the needle with a new one, followed by dilution and sieving to remove any large agglomerates. The material was then collected, loaded into a syringe, and passed through a needle size identical to that used in screening. While the blockage events were reduced, significant clogging still occurred, and the extrusion did not provide a sufficiently uniform pressure. The results of the combined method are presented in Table III below. [Table 3]

[0104] Conclusion: Based on the above results, the inventors concluded that the combined method did not provide the needed solution because it failed to prevent needle clogging.

[0105] summary statistics A summary table of statistics (Table IV) was prepared to assess the success of the experiments conducted so far. One-way ANOVA showed that the mixed samples (samples from Experiment B) were significantly different from the samples that were mixed and then pre-filtered / sieved (samples from Experiment E) (P = 1.2 × 10 -5 ) was found. No significant differences were observed at the 0.05 level between the samples in other experiments. [Table 4]

[0106] Conclusion: These results show that the above method is not sufficient to prevent the occurrence of blockages. The blockage rate is clearly too high. The risks associated with needle blockage far exceed the mere necessity of needle replacement. Apart from product loss during extrusion, it can lead to undesirable amounts of product delivered subcutaneously, excessive forces, and tissue damage.

[0107] Experiment F: Modification by sliding surface It was then hypothesized that the problem of needle clogging and agglomeration could be solved by adding a lubricant to create a sliding surface between particle interfaces. This tribological approach involved mixing the viscous injectable material with different concentrations of gelatin. However, clogging still occurred, and this method was not successful in removing agglomerates of individual particles from the viscous sample.

[0108] As shown in Figure 3, it is clear from the repeated extrusion force curves and the sudden force increase (no decrease in the curve) that overloads the system that the addition of lubricant (gelatin) did not prevent the occurrence of blockages. It is worth noting that the graph presents overlaid force curves for repeated extrusions.

[0109] Conclusion: Addition of lubricants in an attempt to create sliding surfaces between the individual particles of the viscous material failed to remove the blockage.

[0110] Experiment G: Pressure-driven sieving The inventors designed a solution to break down agglomerates without fragmentation by using carefully selected filters / sieves (e.g., small-diameter channels or mesh screens). Such a method effectively separates individual particles without affecting their desired rheological properties, thereby breaking down or disintegrating the agglomerates. The channels and mesh screens can be constructed from a variety of different materials and sizes. While many combinations and prototypes are possible, the original prototype included a pre-filtration step in which the material was passed through a 27- to 30-gauge needle. In some embodiments, the orifice size of the pre-filtration injection device ranged from 18 to 34 g. After pre-filtration, the material that passed through the needle was collected and then extruded using a needle in the 18- to 34-gauge range for the final extrusion. The needle used in the final extrusion step had a lower gauge size compared to the needle used in the pre-filtration step. In its final, highly viscous form, the material was extruded through a filter / sieve with openings or pore sizes smaller than the average size of the individual particles of the material (e.g., approximately 220-250 μm for the individual particles, or 75-150 μm for the sieve, although mesh sizes can range from 1-1000 μm depending on the particle size of the viscous material). In some embodiments, the individual particle size can be in the range of 20-1000 μm. Notably, the mercerized individual particles were able to bend and slip through without breaking or damaging their morphology or affecting their rheological properties. Surprisingly, the small pore sizes effectively removed and broke down the agglomerates, thereby proving successful removal of individual particle agglomerates from the viscous material. After small pore size filtration (i.e., filtering the material through a filter with opening sizes smaller than the individual particles), no needle blockage was observed, and a highly uniform extrusion profile was achieved with no observable intermittent pressure buildup and release.

[0111] Protocol: In an exemplary embodiment, the material was preloaded into an injection device or extrusion system, such as a syringe. As shown in FIG. 4, the syringe was pressed firmly against a filter / sieve (intended to be used as a Falcon tube filter). FIG. 5 shows a 10x magnified microscope image of the mesh used in the exemplary embodiment. The material that passed through the syringe was then loaded into a 1 cc syringe and passed through needles of various sizes (ranging from 27G to 33G), ultimately extruding a 1 mL volume, and the number of occlusion events was recorded (shown in Table V below). [Table 5]

[0112] To analyze the effectiveness of the designed process, we performed a one-way ANOVA, which revealed that the samples extruded through nylon mesh were significantly different from the samples extruded using an industrial mixer and from the samples extruded after sieving, respectively (P = 4 × 10 -8 and P = 0.0126).

[0113] Although the results of the occlusion tests were promising, the inventors recognized that it was important to examine the size and morphology of the particles to ensure that the individual particles did not fragment or become damaged, which would elicit an undesirable immune response in patients when administered.

[0114] The particles were stained with 0.1% Congo Red and imaged on an SZ16 stereomicroscope equipped with a BV filter, as shown in Figure 6, and plotted on a 500 μm scale. The particle size distribution of particles that passed through the mesh is shown in Figure 7. As can be seen, no damage was observed to the individual particles, and only 0.86% of the individual particles were found to be smaller than 20 μm. N=1282 individual particles were analyzed, and the average particle size was 246.64 ± 2.52 μm (mean ± standard error of the mean). However, this distribution was within the expected range.

[0115] Based on the results from Table V, the one-way ANOVA, and the dyeing test, the inventors concluded that passing the material through a filter / sieve (e.g., a mesh screen) separates the individual particles, sufficiently breaking down particle agglomerates and preventing blockages. No blockage events occurred when the material was extruded through an injection device or extrusion system (e.g., a 27G, 30G, or 33G needle). Qualitatively, the extrusions had a very uniform pressure after a characteristic initial burst force. Additionally, while pressure variations and pressure buildup have been observed in previous extrusion experiments, they were not observed in this experiment. Indeed, no blockage events were recorded, and a substantially uniform extrusion was achieved.

[0116] One issue that may be of concern is that the proposed method for filtering and sizing individual particles of a viscous injectable material involves the combined use of pressure and sieving, rather than the independent use of sieving or pressure. As those skilled in the art will appreciate, none of the other "obvious" approaches were able to achieve the desired extrusion profile. Additionally, the initial assumption that high-pressure sieving would simply "push" large agglomerates through the mesh, resulting in a filler material that exhibited increased clogging, was proven incorrect. Furthermore, it was thought that high pressure would cause undesirable shearing of the individual particles, leading to particle ripping and fragmentation. Surprisingly, the small, flexible individual particles remained intact even after exposure to high-intensity localized shearing. Furthermore, the agglomerates remained separate throughout the extrusion period, rather than simply clogging the pores of the filter / sieve.

[0117] The claimed technology not only allows for the size control of individual particles in viscous injectable materials (e.g., dermal fillers), but also offers a promising solution for removing aggregates while maintaining the morphological characteristics and properties of the individual particles. As previously discussed, formulations with non-uniform particle size or altered morphology can provoke undesirable and diverse immune responses. Most importantly, pressure-sieved materials exhibit no occlusion events (meaning that no pressure buildup occurs within the needle, even after the initial characteristic burst / break force), eliciting a predicted or controlled immune response. This also avoids the need to utilize larger needles or cannulas to deliver viscous formulations, which are not only inconvenient but can also result in the unintended delivery of aggregates, which can also provoke a heterogeneous immune response.

[0118] In one embodiment of the present invention, a method for removing agglomerates of individual particles from a viscous substance includes: a) loading the viscous substance into an extrusion system including at least one filter / sieve; and b) passing the viscous substance through a filter / sieve that is internal, external, adjacent, in-line, or screw-mounted to the extrusion system, causing the removal of agglomerates of individual particles from the dermal filler substance. In some embodiments, the viscous substance is filtered by passing the filler substance through an external filter / sieve or by pressing the extrusion system against the filter / sieve, whereby passing the substance through the sieve causes the removal of agglomerates of individual particles from the viscous substance. In some embodiments, the passing step sizes the individual particles of the viscous substance to achieve a substantially uniform or controlled settling of the particle matrix. This achieves particle size reduction of the viscous substance without causing significant damage to the overall morphology of the individual particles. More importantly, the individual particles maintain their characteristics and rheological properties and have an intact morphology.

[0119] In some embodiments, the filter / sieve can be nylon mesh, stainless steel mesh, polytetrafluoroethylene (Teflon) mesh, or nitrocellulose mesh. The filter material is selected based on the type of viscous substance to be filtered. For example, stainless steel mesh can withstand higher pressures than nylon mesh and can therefore be used to filter highly viscous substances, while nylon mesh can be used to filter less viscous substances. In some embodiments, the viscous substance passes through a sieve with pores or openings smaller than the particle size of the substance. The filter material and size can vary depending on the type of viscous substance, the composition and particle size of the substance, and the desired viscosity of the final injectable product. The pore size of the filter / sieve is in the range of 1-1000 μm. In some embodiments, the individual particle sizes are in the range of 20-1000 μm. In preferred embodiments, the pore size of the filter / sieve is in the range of 25-500 μm. In such embodiments, the individual particle sizes can be in the range of 40-500 μm. In a more preferred embodiment, the pore size of the filter / sieve is in the range of 50-200 μm. In such an embodiment, the individual particle sizes are in the range of 75-200 μm. In alternative embodiments, the filter / sieve is replaced with an in-line filter, a gated impeller, a static mixer, a high shear mixer, a viscous mixer, a filter located inside a filtration device or extrusion system, a filter screwed to an extrusion system, or a sieving channel. The sieving channel can be a tubular structure, or a crosshatch mixing device, a screen with a woven mesh, or a plate with perforations, or a bonded (non-woven) mesh with holes that is easy to clean.

[0120] In one embodiment of the invention, immediately after filtration, the filtered viscous material is collected in a loading vessel / transfer syringe or a second injection device. In some embodiments, the loading vessel / transfer syringe is a collection chamber, in which case several batches of filtered material are collected. This is more appropriate for large-scale applications or when large amounts of material are involved.

[0121] In an alternative embodiment, the loading container / transfer syringe or second injection device is an injection syringe and is suitable for direct administration to a patient. The injection syringe can also be used as a collection chamber in which the filtered material is stored and then transferred to a smaller syringe for administration to a patient. The size of the loading container / transfer syringe can vary depending on whether it is used as a collection device or for direct administration.

[0122] The filtered viscous material is suitable for administration to a patient because it does not clog the loading vessel / transfer syringe when expelled out of the loading vessel / transfer syringe. A related note is that the filtered viscous material has a substantially uniform or controlled extrusion profile due to the removal or disruption of agglomerates, since the filtered material is expelled out of the loading vessel / transfer syringe without building up pressure. As previously noted, the method effectively separates individual particles, thereby disrupting or breaking down agglomerates, without affecting their rheological properties. After the extrusion process, a substantial portion of the individual particles of the viscous material remain intact or unfragmented, i.e., have a substantially uniform, undamaged, or minimally damaged morphology, even after passing through the sieve. More specifically, the individual particles go through the extrusion process without causing particle breakdown or damage, i.e., without affecting their characteristics and / or morphology. This is important in order to elicit the expected immune response in the patient when the substance is administered.

[0123] The extrusion system can be an injection syringe, a discharge system, a luer lock connector device, or compressible tubing. If an injection syringe is preferred, the syringe can have a needle size in the range of 18-34G. Similarly, the loading container / transfer syringe can be an injection syringe, a discharge system, a luer lock connector device, or compressible tubing. If an injection syringe is preferred, the syringe of the loading container / transfer syringe can have a needle size in the range of 18-34G. In some embodiments, the volume of the extrusion system is similar to the volume of the loading container / transfer syringe. In alternative embodiments, the volume of the extrusion system exceeds the volume of the loading container / transfer syringe, or the extrusion system has a smaller cross-sectional area compared to the loading container / transfer syringe. In some embodiments, there can be a smaller syringe that dispenses into and fills a larger syringe, or multiple smaller syringes or refills of smaller syringes can be used. Cross-sectional area is usually considered in terms of the amount of force required to force it through the filter / sieve.

[0124] In some embodiments, the passing step is performed using a luer lock connector injection device having at least one filter / sieve disposed within the device. In such instances, the passing step further comprises forcing the viscous material from an external source through the sieve under or by applying pressure. Pressure can be applied using a plunger, extruder, manual compression, syringe pump, platen compression, rollers for flexible tubing, or compressor, or some similar mechanism. It is important to control the pressure to prevent unintended mercerization of individual particles or unnecessary damage to particle morphology.

[0125] In alternative embodiments, the passing step is repeated using a series of filters or sieves of different sizes to adjust or reduce the viscosity of the viscous substance or to adjust its particle size distribution to a desired level, preferably within the range of 50 to 750 μm. In some embodiments, the method reduces the extrusion force required to expel the viscous substance from the extrusion system. This adjustment of viscosity and particle size distribution prepares the viscous substance (e.g., a dermal filler) for administration to a patient. In such embodiments, two or more sieves / filters can be attached to the inside of the extrusion system so that the viscous substance passes through multiple filters of different sizes before being filtered. This may prove useful in embodiments where the viscosity of the substance needs to be adjusted prior to its administration.

[0126] In one embodiment of the present invention, agglomerates present in the viscous material are removed by breaking up the agglomerates or separating the individual particles, thereby breaking up the agglomerates, without affecting their characteristics or morphology. In an alternative embodiment, the agglomerates are removed by filtering out agglomerates that are unable to pass through a filter or sieve.

[0127] In some embodiments, the viscous material is pre-filtered through a series of pre-filtration devices prior to the passing step. The pre-filtration step can be performed using a series of injection devices, injection syringes, discharge systems, injection devices with Luer lock connectors, compressible or non-compressible tubing, cylinders, or large-scale syringes. In a preferred embodiment, the pre-filtration devices are syringes with different opening sizes, in which case the opening sizes can range from 18 to 34G. The pre-filtration devices can be selected to be identically sized devices or to have decreasing opening sizes, depending on the material, experimental design, expected / required results, and the amount of aggregates present in the material. If decreasing sizes are preferred, the first pre-filtration device has a larger opening size than the second pre-filtration device. Thus, the opening sizes of the first and second pre-filtration devices can be selected from 18 to 34G.

[0128] In some embodiments, the viscous material is pre-filtered through a first pre-filtration device followed by a second pre-filtration device prior to the passing step, i.e., before the material is forced through the sieve.

[0129] Dermal fillers are materials commonly employed for cosmetic and / or aesthetic applications, such as filling wrinkles, altering appearance, or addressing soft tissue damage caused by disease or injury. In certain embodiments, dermal filler products can be considered "permanent" in that they provide a long-term, natural, and biocompatible solution for such applications. Many dermal fillers in the field have been temporary. After a certain period of time, traditional dermal fillers are resorbed by the body. Other dermal fillers may use synthetic particles, such as PMMA, to provide a more long-term solution. In certain embodiments, dermal fillers are cellulose-based materials processed to fall within a target size range for dermal fillers. These can be derived from natural plant polymers and can be permanent due to the fact that humans lack the enzymes to break down cellulose. Therefore, the individual particles of a dermal filler must fall within a desired target size range. The individual particles must have a desirable SA:V ratio, particle size, and viscosity to effectively promote vascularization and contribute to biocompatibility; therefore, fillers can be employed to provide tissue composed of the patient's own tissue rather than synthetic materials.

[0130] In one embodiment of the present invention, a method for removing agglomerates of individual particles from a dermal filler material for administration to a patient is described, comprising: a) loading the dermal filler material into an extrusion system including at least one filter / sieve; and b) passing the dermal filler material through a filter / sieve located inside, outside, adjacent to, in-line with, or screwed onto the extrusion system, causing removal of agglomerates of individual particles from the dermal filler material. In some embodiments, a viscous material is filtered by passing the filler material through an external filter / sieve or by pressing the extrusion system against the filter / sieve. The filtered dermal filler material is suitable for administration to a patient.

[0131] In some embodiments, the passing step sizes the individual particles of the viscous dermal filler material to achieve a substantially uniform or controlled settling of the particle matrix, thus reducing the particle size of the viscous dermal filler material without seriously damaging the overall morphology of the individual particles.

[0132] In some embodiments, the filter / sieve can be a nylon mesh, a stainless steel mesh, a polytetrafluoroethylene (Teflon) mesh, or a nitrocellulose mesh. In some embodiments, the viscous dermal filler material is passed through a sieve having a pore size or opening size smaller than the particle size of the viscous dermal filler material. In other embodiments, the pore size of the filter / sieve is in the range of 1 to 1000 μm. In such embodiments, the individual particle sizes are in the range of 20 to 1000 μm. In preferred embodiments, the pore size of the filter / sieve is in the range of 25 to 500 μm. In such embodiments, the individual particle sizes are in the range of 40 to 500 μm. In even more preferred embodiments, the pore size of the filter / sieve is in the range of 50 to 200 μm. In such embodiments, the individual particle sizes are in the range of 75 to 200 μm. The sieving channel may be a tubular structure, or a cross-hatch mixing device, a screen with a woven mesh, or a plate with through holes, or a mesh with bonded (non-woven) holes that is easy to clean.

[0133] In one embodiment of the present invention, immediately after filtration, the filtered viscous dermal filler material is collected in a loading vessel / transfer syringe. In some embodiments, the loading vessel / transfer syringe is a collection chamber, in which case several batches of filtered filler material are collected. This is more appropriate for large-scale applications or when large amounts of filler material are involved.

[0134] In an alternative embodiment, the loading container / transfer syringe is an injection or withdrawal syringe, suitable for direct administration to a patient. The injection syringe can also be used as a withdrawal chamber, in which the filtered loading substance is stored and then transferred to a smaller syringe for administration to a patient. The size of the loading container / transfer syringe can vary depending on whether it is used as a withdrawal device or for direct administration.

[0135] The filtered viscous dermal filler material is suitable for administration to a patient because it does not clog the loading container / transfer syringe when discharged out of the loading container / transfer syringe. It should be noted that the filtered viscous dermal filler material has a substantially uniform or controlled extrusion profile due to the separation of individual particles, which causes the removal or destruction of agglomerates, because the filtered filler material is discharged out of the loading container / transfer syringe without building up pressure. Agglomerates are broken down by separating the individual particles without affecting their morphological characteristics. After the extrusion process, a substantial portion of the individual particles of the viscous dermal filler material remain intact or unfragmented, i.e., have a uniform, undamaged, or minimally damaged morphology even after passing through a sieve. In some embodiments, at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the viscous substance pass through the filter / sieve without their characteristics or morphology being affected, i.e., the method does not alter the characteristics or morphology of at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the viscous substance, which is important for eliciting the expected immune response in a patient when the loading substance is administered.

[0136] The extrusion system can be an injection syringe, an ejection system, a luer lock connector device, or compressible tubing. If an injection syringe is preferred, the syringe can have a needle size in the range of 18-34G. Similarly, the loading container / transfer syringe can be an injection syringe, an ejection system, a luer lock connector device, or compressible tubing. If an injection syringe is preferred, the syringe of the loading container / transfer syringe can have a needle size in the range of 18-34G. In some embodiments, the volume of the extrusion system is similar to the volume of the loading container / transfer syringe. In alternative embodiments, the volume of the extrusion system exceeds the volume of the loading container / transfer syringe, or the extrusion system has a smaller cross-sectional area compared to the loading container / transfer syringe. In some embodiments, there can be a smaller syringe that dispenses into and fills a larger syringe, or multiple smaller syringes or refills of smaller syringes can be used. Cross-sectional area is usually considered in terms of the amount of force required to force it through the filter / sieve.

[0137] In some embodiments, the passing step is performed using a luer lock connector injection device having at least one filter / sieve disposed within the device. In such examples, the passing step further includes forcing the viscous dermal filler material from an external source through the sieve under or by applying pressure. The pressure can be applied using a plunger, an extruder, manual compression, a syringe pump, a platen compression, a roller for flexible tubing, or a compressor, or some similar mechanism. It is important to control the pressure to prevent unexpected fragmentation of individual particles or unnecessary damage to particle morphology.

[0138] In an alternative embodiment, the passing step is repeated using a series of filters or sieves of different sizes to adjust or reduce the viscosity of the viscous dermal filler material or to adjust its particle size distribution to a desired level, preferably within the range of 50 to 750 μm. In such an embodiment, two or more sieves / filters can be attached to the inside of the extrusion system so that the viscous dermal filler material passes through multiple filters of different sizes before being filtered. This may prove useful in embodiments where the viscosity of the filler material needs to be adjusted prior to its administration. This adjustment of viscosity and particle size distribution prepares the viscous material (e.g., dermal filler) for administration to a patient.

[0139] In one embodiment of the present invention, agglomerates present within the viscous dermal filler material are removed by separating the individual particles, which breaks the agglomerates, or by breaking up the agglomerates. In an alternative embodiment, the agglomerates are removed by filtering out agglomerates that cannot pass through a filter or sieve.

[0140] In some embodiments, the viscous dermal filler material is pre-filtered through a series of pre-filtration devices, in which case the pre-filtration step occurs before the passing step. The pre-filtration step can be performed using a series of injection devices, injection syringes, discharge systems, injection devices with Luer lock connectors, compressible or non-compressible tubing, cylinders, or large-scale syringes. In a preferred embodiment, the pre-filtration devices are syringes with different needle sizes, in which case the pre-filtration devices can be selected to be identically sized devices or to have decreasing needle sizes depending on the filler material, experimental design, expected / required results, and the amount of aggregates present in the filler material. If decreasing sizes are preferred, the first pre-filtration device has a larger opening size than the second pre-filtration device. Thus, the opening sizes of the first and second pre-filtration devices can be selected from 18 to 34G.

[0141] In some embodiments, the viscous dermal filler material is pre-filtered through a first pre-filtration device followed by a second pre-filtration device prior to the passing step, i.e., before the filler material is extruded through a sieve.

[0142] In one embodiment of the present invention, a method for removing agglomerates of individual particles from a viscous substance can include: a) loading the viscous substance into a first collection vessel comprising at least one filter / sieve; b) passing the viscous substance through the filter / sieve to cause removal of the agglomerates of individual particles from the viscous substance; and c) collecting the viscous substance in a second collection vessel. In some embodiments, the first collection vessel can comprise an extrusion system as defined hereinbefore, where the extrusion system also comprises a filter / sieve. The filtered viscous substance collected in the second collection vessel is suitable for administration to a patient. The collection vessel can have a mixing capacity in the range of 0.02 gallons to 750 gallons.

[0143] Without wishing to be bound by theory, the chart below provides some examples of mixers and vessels currently offered by Charles Ross & Company that may be employed in large-scale filtration operations. Those skilled in the art will readily appreciate that there may be other vessels that may be used in filtration operations. [Table 6]

[0144] In some embodiments, the first collection vessel is a series of containers having different dimensions, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, an injection syringe, a large injection syringe, a luer lock connector device, an evacuation system, or a compressible tube. The second collection device can be selected from at least one of a transfer container, a storage bottle, an injection syringe, a filler cartridge, a series of containers having different dimensions, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, a large injection syringe, a luer lock connector device, an evacuation system, or a compressible tube.

[0145] The method of removing agglomerates using a collection vessel does not alter the characteristics or morphology of at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the viscous material, i.e., at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the viscous material pass through the filter / sieve without their characteristics or morphology being affected.

[0146] In some embodiments, the viscous substance is forced through the filter / sieve under pressure / by applying pressure using a plunger, extruder, manual compression, syringe pump, platen compression, roller, or compressor, or similar mechanism.

[0147] Without being bound by theory, it is believed that agglomerates are removed from the viscous substance by breaking / disintegrating the agglomerates or by filtering / sieving out agglomerates that cannot pass through a filter / sieve. The method allows for the separation of individual particles (causing the breakdown of agglomerates) without affecting their rheological properties. The passing step sizes the individual particles of the viscous substance to create a substantially uniform or controlled particulate matrix that is suitable for administration to a patient in need thereof.

[0148] In some embodiments, the viscous material is pre-filtered through multiple pre-filtration devices, where the pre-filtration step occurs before the passing step. In alternative embodiments, the viscous material is pre-filtered through a first pre-filtration device followed by a second pre-filtration device, where each of the multiple pre-filtration devices is a syringe with a different opening size. The pre-filtration step can be performed using a series of injection devices, injection syringes, evacuation systems, injection devices with luer lock connectors, compressible or non-compressible tubing, cylinders, or large-scale syringes. In some embodiments, the first pre-filtration device has an opening size larger than the second pre-filtration device. The opening sizes of the first and second pre-filtration devices can be selected from 18 to 34G.

[0149] In some embodiments, the viscous substance is passed through at least one filter / sieve having a pore size / opening size smaller than the particle size of the viscous substance, where the filter / sieve pore size is in the range of 1-1000 μm. In such embodiments, the individual particle sizes can be in the range of 20-1000 μm. In some embodiments, the filter / sieve pore size is in the range of 25-500 μm or in the range of 50-200 μm. In such embodiments, the individual particle sizes can be in the range of 40-500 μm or 75-200 μm.

[0150] The filtered viscous material may be collected in a second collection container and dispensed / dispensed using a dispensing device, where the filtered viscous material does not clog the dispensing device when dispensed / dispensed from the dispensing device. The filtered viscous material has a substantially uniform or controlled extrusion profile when dispensed / dispensed from the dispensing device, where the filtered viscous material dispenses / dispenses from the dispensing device without pressure buildup after an initial characteristic burst / break force.

[0151] In some embodiments, the dispensing device is an industrial filtration unit, a large syringe device, a screw-driven extruder, a hydraulic platen pump, or a discharge system. In a preferred embodiment, the dispensing device is a syringe, where the syringe has a needle size of 18-34G. In some embodiments, the filter / sieve is a nylon mesh, a stainless steel mesh, a polytetrafluoroethylene mesh, or a nitrocellulose mesh. In alternative embodiments, the filter / sieve is replaced by an in-line filter, a gated impeller, a static mixer, a high-shear mixer, a viscous mixer, a filter located inside the filtration device, a filter screwed to the filtration device, or a sieving channel.

[0152] In some embodiments, a filter / sieve is placed inside a luer lock connector attached to the inside of the first collection container / the luer lock connector portion of the first collection container, and the viscous substance is forced under / by pressure through the filter / sieve placed inside the luer lock connector portion. In such embodiments, pressure is applied using a plunger, extruder, manual compression, syringe pump, platen compression, rollers for flexible tubing, or compressor, or some similar mechanism.

[0153] In some embodiments, the passing step can be repeated using multiple filters / sieves, either the same size or different sizes within the range of 1 to 1000 μm, to adjust or reduce the viscosity of the viscous material or to adjust its particle size distribution to a desired level, preferably within the range of 50 to 750 μm. This adjustment of viscosity and particle size distribution prepares the viscous material (e.g., a dermal filler) for administration to a patient. The method reduces the extrusion force required to expel the viscous material from the extrusion system.

[0154] In some embodiments, the second collection container is used to dispense / expel the filtered viscous material for administration to the patient, where the first collection container has a greater volume than the second collection container.

[0155] In some embodiments, the methods described hereinabove can be used to adjust the viscosity of a viscous substance or dermal filler material to a desired level. In some embodiments, the methods described hereinabove can be employed to break down clumps / aggregates within a viscous substance or dermal filler material. The described methods may also prove useful, particularly during the delivery period of a viscous substance or any dermal filler material, when preventing needle blockage within an injection device is essential. Furthermore, the described methods may be useful in sizing individual particles of a viscous substance so that the viscous substance or dermal filler material has a substantially uniform particle size. Additionally, the methods can be applied to reduce the particle size of a viscous substance or dermal filler material without affecting its rheological properties, so that the viscous substance or dermal filler material has a substantially uniform or controlled particle matrix settling. In some embodiments, the methods reduce the extrusion force required to eject the viscous substance from an extrusion system.

[0156] The described method can be used with a wide range of viscous materials. Without limiting its scope, the method can be used to process viscous materials such as dermal fillers, sealants, adhesives, complex mixtures of mammalian cells, scaffolding materials, bone pastes, bone cements, cartilage biomaterials, injectables including those for venous stasis applications, protein hydrogels, carbohydrate hydrogels including cellulose, pectin, and lignin, cellular material mixtures, thickeners, gelling agents, and stabilizers.The method described involves the addition of other substances such as gums and hydrocolloids, such as cassia gum powder, guar gum powder, rapidly hydrating guar gum powder, Cassia Tora powder, tamarind kernel powder, sesbania gum powder, fenugreek gum powder, psyllium husk powder, kappa carrageenan gum powder, locust bean gum powder, date palm mucilage, guar meal, "Erva Baleeira" mucilage, guar gum, kondagogu gum. Kondagogu), Konjac glucomannan, Taro, Gellan gum, Curdlan gum, Starch, Wheat starch, Corn starch, Barley starch, Modified starch, Arrowroot starch, Corn starch, Tapioca powder, Potato starch, Stabilizer, Acacia (Gum Arabic), Agar-agar, Ammonium alginate, Calcium alginate, Carob bean gum (Locust bean gum), Chondrus crispa extract (Carrageenan), Gatti gum, Guar gum, Pectin, Potassium alginate, Sodium alginate, Sterculia gum (Karaya gum), Tragacanth (Tragacanth gum), Thickener, Sodium alginate, Potassium alginate, Ammonium alginate The present invention can also be used to remove aggregates from foods such as gluten, gluten-containing gelling agents ...

[0157] In some embodiments, the method can be used to reduce the particle size of the material, thereby reducing the extrusion force required to eject the viscous material from an extrusion system. In some embodiments, the method can be useful in reducing the viscosity of a viscous material or dermal filler material within the range of 1-99%. In some embodiments, the method can be used to filter and extrude a viscous material using a controlled or uniform extrusion force.

[0158] In some embodiments, a device for removing agglomerates of individual particles from a viscous substance is described, the device comprising the following elements: a) an extrusion system; and b) at least one filter / sieve located inside, outside, adjacent to, in-line with, or screwed onto the extrusion system, causing the removal of agglomerates of individual particles from the dermal filler substance. In some embodiments, the viscous substance is filtered by passing through the external filter / sieve or by pressing the extrusion system against the filter / sieve, thereby allowing the removal of agglomerates in the viscous substance / dermal filler substance as the substance passes through the filter / sieve.

[0159] In some embodiments, the device may further comprise an extruder for extruding the viscous substance / dermal filler substance under pressure through a filter / sieve. The pressure of the extruder may be controlled electronically or mechanically.

[0160] The filter / sieve can be selected from nylon mesh, stainless steel mesh, polytetrafluoroethylene (Teflon) mesh, or nitrocellulose mesh. In some embodiments, the filter / sieve is nylon mesh. The nylon mesh used in the process can be replaced with a more robust solution for large-scale operations. For example, in-line 316 stainless steel mesh (among several different size options) can be used in place of the nylon mesh.

[0161] The filter / sieve may have a pore size in the range of 1-1000 μm. In such embodiments, the individual particle sizes may be in the range of 20-1000 μm. In preferred embodiments, the pore size of the filter / sieve is in the range of 25-500 μm. In such embodiments, the individual particle sizes may be in the range of 40-500 μm. In even more preferred embodiments, the pore size of the filter / sieve is in the range of 50-200 μm. In such embodiments, the individual particle sizes may be in the range of 75-200 μm. In alternative embodiments, the filter / sieve is replaced with an in-line filter, a gated impeller, a static mixer, a high-shear mixer, a viscous mixer, a filter located inside the filtration device, a filter screwed to the filtration device, or a sieving channel. The dimensions of the in-line filter may be in the range of 0.5 mm to 2540 mm. The sieving channel is a tubular structure, or a cross-hatch mixing device, or a screen with a woven mesh, or a plate with through holes, or a mesh with bonded (non-woven) holes that is easy to clean.

[0162] In alternative embodiments, the device design can be modified so that the extrusion system is connected to a series of pre-filtration devices, thereby pre-filtering the viscous dermal filler material at least before passing through the filter / sieve. In such embodiments, the extrusion system is connected to at least one pre-filtration device, and the pre-filtration device(s) are linked to a loading container / transfer syringe. The loading container / transfer syringe can simply be a collection chamber for collecting and storing the filtered material, especially if multiple batches of material are being filtered / pre-filtered. In some additional embodiments, the loading container / transfer syringe can be used to administer the material to a patient.

[0163] The extrusion system can be an injection syringe, a discharge system, a luer lock connector device, or compressible tubing. The loading vessel / transfer syringe can be an injection syringe, a discharge system, a luer lock connector device, or compressible tubing. The at least one pre-filtration device can be a series of injection devices, syringes, discharge systems, injection devices with luer lock connectors, compressible or non-compressible tubing, cylinders, or large-scale syringes. The injection devices can have needle sizes ranging from 18 to 34G. In some embodiments, the extrusion system can have a volume greater than the volume of the loading vessel / transfer syringe, or the extrusion system has a smaller cross-sectional area compared to the loading vessel / transfer syringe. For example, the extrusion system and loading vessel / transfer syringe can be 1 ml syringes, or in an alternative embodiment, the extrusion system can be a 5 ml syringe and the transfer syringe can be a 1 ml syringe. In such cases, the opening size of the extrusion system may exceed the opening size of the charge vessel / transfer syringe. In some embodiments, there may be a smaller syringe that dispenses into and fills a larger syringe, or multiple smaller syringes or refills of smaller syringes may be used. Cross-sectional area is typically considered in terms of the amount of force required to force it through a filter / sieve.

[0164] In some embodiments, the filter / sieve used in the final passing / filtration step has an opening size smaller than the particle size of the viscous material. The smaller size aids in mercerization of the particles to achieve a substantially uniform or controlled particle distribution. The opening size of the filter / sieve can range from 1 to 1000 μm.

[0165] In some embodiments, a luer lock connector can be attached inside the extrusion system. The luer lock connector can accommodate a filter / sieve, i.e., the filter / sieve can be placed within the luer lock connector instead of placing it at the bottom of the first injection device.

[0166] In alternative embodiments, the device may have a slightly different configuration, in which case the device for removing agglomerates may comprise a) a first collection device; b) at least one filter / sieve mounted inside the first collection device (through which the viscous substance / dermal filler substance passes, causing removal of agglomerates of individual particles from the substance); and c) a second collection device coupled to the first collection device for collecting the filtered substance.

[0167] In such embodiments, the first collection device can be a series of containers having different dimensions, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, a luer lock connector device, an injection syringe, a large injection syringe, a discharge system, or a compressible tubing. In alternative embodiments, the second collection device can be a transfer container, a storage bottle, an injection syringe, a filler cartridge, a series of containers having different dimensions, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, a large injection syringe, a luer lock connector device, a discharge system, or a compressible tubing.

[0168] In some embodiments, an additional filter / sieve is attached inside the second collection device. In such embodiments, the opening size of the first and additional filter / sieve(s) may be in the range of 1 to 1000 microns. In such embodiments, the individual particle sizes may be in the range of 20 to 1000 μm. In preferred embodiments, the pore size of the filter / sieve is in the range of 25 to 500 μm. In such embodiments, the individual particle sizes may be in the range of 40 to 500 μm. In even more preferred embodiments, the pore size of the filter / sieve is in the range of 50 to 200 μm. In such embodiments, the individual particle sizes may be in the range of 75 to 200 μm. The filter / sieve(s) may be nylon, stainless steel, Teflon, or nitrocellulose. In some preferred embodiments, the filter / sieve may be nylon mesh or stainless steel mesh. In alternative embodiments, the filter / sieve is replaced by an in-line filter, a gated impeller, a static mixer, a high shear mixer, a viscous mixer, a filter located inside the filtration device, a filter screwed to the filtration device, or a sieving channel. The size of the in-line filter can range from 0.5 mm to 2540 mm. The sieving channel can be a tubular structure, or a cross-hatch mixing device, or a screen with a woven mesh, or a plate with perforations, or a bonded (non-woven) mesh with holes that is easy to clean.

[0169] In some configurations, the second collection device is a collection chamber disposed inside the first collection device. In such embodiments, the viscous material is stored in the chamber (i.e., the second collection device mounted inside the first collection device) after passing through a filter / sieve mounted inside the first collection device.

[0170] In some embodiments, the device may further comprise an extruder that extrudes the viscous / dermal filler material under pressure through a filter / sieve. The extruder pressure may be controlled by electronic or mechanical means. Alternatively, the pressure may be applied using a plunger, extruder, manual compression, syringe pump, platen compression, rollers for flexible tubing, or compressor, or some similar mechanism. It is important to control the pressure to prevent unintended particle mercerization or unnecessary damage to particle morphology. The extruder pressure may be controlled by electronic or mechanical means.

[0171] In alternative embodiments, the device design can be modified so that the first collection device is connected to a series of pre-filter collection devices, thereby pre-filtering the viscous or dermal filler material at least before passing through the filter / sieve. The second collection device can simply be a collection chamber for collecting and storing the filtered material, especially if multiple batches of material are being filtered / pre-filtered. The collected material can be transferred to a dispensing / administration / injection device or syringe for ultimate administration of the filtered material to the patient.

[0172] The first collection device can be a series of containers with different dimensions, a storage unit or chamber, a Luer lock connector device, an industrial mixer, an industrial dispenser, an intermediate transfer container, an injection syringe, a large injection syringe, a discharge system, or a compressible tubing. The second collection device can be a transfer container, a storage bottle, an injection syringe, a filler cartridge, a series of containers with different dimensions, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, a large injection syringe, a Luer lock connector device, a discharge system, or a compressible tubing. The at least one pre-filtration device can be a series of injection devices, syringes, a discharge system, an injection device with a Luer lock connector, compressible or non-compressible tubing, a cylinder, or a large-scale syringe. The dispensing / administration / injection device can be a series of injection devices, injection syringes, Luer lock syringes, large-scale syringes, and can also have needle sizes ranging from 18 to 34G.

[0173] Similar to other device configurations, in some embodiments, the filter / sieve used in the final passing / filtration step has an opening size smaller than the particle size of the viscous material. The smaller size aids in mercerization of the particles to achieve a substantially uniform or controlled particle distribution. The filter / sieve opening size can range from 1 to 1000 μm. The filter / sieve opening size can range from 1 to 1000 μm.

[0174] In some embodiments, a luer lock connector can be attached to the inside of the first retrieval device. The luer lock connector can accommodate a filter / sieve, i.e., the filter / sieve can be placed inside the luer lock connector instead of placing it at the bottom of the first retrieval device.

[0175] Promising solutions and configurations The present invention is now described with respect to potential exemplary configurations that may be employed to perform a pressure sieving process to remove aggregates of individual particles from a given viscous material. There are several potential applications for the claimed technology, such as filtering aggregates from drug formulations, dermal filler applications, soft tissue implants, lubricants, and vehicles for delivering small peptides or cells.

[0176] Figure 8 shows an in-line pressure filtration process that may be employed when implementing a pressure filtration / sieving process on a large scale. The in-line pressure filtration system includes a discharge system that is used to force the viscous material through a mesh screen. When implementing an in-line process, the mesh screen can be installed between the discharge system (injection device) and a collection vessel, such as a loading vessel. A schematic diagram of the in-line mesh screen shown in the figure is provided by Charles Ross & Son Company (left portion of the figure). The filtered viscous material is collected in the collection vessel before being transferred into a smaller transfer syringe.

[0177] As shown, the screen can be a mesh sieve (pre-installed in the discharge system or installable prior to the filtration process). The syringe can be placed between the syringe adapter (followed by the extension of the fill tube) and the discharge system. As previously pointed out, this configuration is more appropriate for highly viscous materials or when several batches of material are being processed simultaneously.

[0178] Typically, the discharge system includes a large vessel, a platen or extruder, a valve, and an extrusion port, and when the valve is opened, the platen forces the material out through the extrusion port.

[0179] FIG. 9 shows an in-syringe process configuration for treating viscous materials and removing aggregates. In an in-syringe process, an injection device with a pre-attached filter / sieve is used. When used in a pressure filtration process, a smaller version of the filter is placed inward toward the bottom of the injection device so that the viscous material passes through the filter / sieve and then flows out of the injection device. The filtered material can be collected in a loading vessel / transfer syringe or a separate collection container. In this configuration, the filtration force is provided by an extruder. The force of the extruder pushes the material through the filter / sieve so that the material passes through the filter and flows out of the injection device after being filtered. In some embodiments, the filtered material can be administered to a patient by collecting it in a small transfer syringe. In such instances, the material is administered directly to the patient using the transfer syringe, so there is no collection device for collecting the filtered viscous material. In an alternative embodiment, the filtered material can be stored in a separate collection container. This configuration, the in-syringe process, is more suitable for small scale applications.

[0180] In some embodiments, the injection device is a syringe with a needle size of 18G to 34G. The filter / sieve located at the base of the syringe can be selected from nylon mesh screens, stainless steel mesh screens, polytetrafluoroethylene (Teflon) mesh screens, or nitrocellulose mesh screens. The loading container / transfer syringe can be an injection syringe, a drainage system, a Luer lock connector device, or a compressible tubing. Types of viscous substances that can be filtered using this process include dermal fillers; sealants; adhesives; complex mixtures of mammalian cells; scaffolding materials; bone pastes; bone cements; cartilage biomaterials; injectables, including those for venous stasis; protein hydrogels; carbohydrate hydrogels containing cellulose, pectin, and lignin; cellular material mixtures; thickeners; gelling agents; and stabilizers.The method described involves the use of other substances such as gums and hydrocolloids, cassia gum powder, guar gum powder, rapidly hydrating guar gum powder, locust bean gum powder, tamarind kernel powder, sesbania gum powder, fenugreek gum powder, psyllium husk powder, kappa carrageenan gum powder, locust bean gum powder, date palm mucilage, guar meal, "erba barreira" mucilage, guar gum, kondagogu gum, konjac glucomannan, taro, gellan gum, curdlan gum, starch, wheat starch, corn starch, barley starch, modified starch, arrowroot starch, corn starch, tapioca powder, potato starch, stabilizers, acacia (gum arabic), agar-agar, ammonium alginate, calcium alginate, carob bean gum (locust bean gum), carrot extract (carrageenan), ghatti gum, guar gum It can also be used to remove aggregates from gum, pectin, potassium alginate, sodium alginate, sterculia gum (karaya gum), tragacanth (tragacanth gum), thickeners, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, carrageenan, locust bean gum, guar gum, karaya gum, gellan gum, mannitol, konjac, pectin, cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, isomalt, maltitol, xylitol, oxidized starch, phosphated monostarch, phosphated distarch, gelling agents, alginic acid, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, gellan gum, konjac, pectin, cellulose, methylcellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

[0181] Figure 10 shows an in-line syringe process configuration in which a smaller version of the filter / sieve is placed within a custom Luer lock connector device between the needle and syringe. The Luer lock connector syringe provides the ability to achieve leak-free transfer of material between the syringe and needle and, most importantly, provides protection against accidental needle removal or accidental spillage of the material contents. In this configuration, the filtration power can be provided by the extruder, and similar to the in-line syringe process, the material is filtered just before reaching the needle. In this configuration, the filter is not placed within the syringe. The intermediate Luer lock connection allows for easy and quick attachment of the filter / sieve.

[0182] The processed / filtered material poses significant challenges during filling due to its high viscosity. To avoid damaging the end cap seal of the injection device / syringe and to prevent excessive silicone peeling during multiple passes through the plunger, the material can be back-loaded using a large-bore transfer needle, particularly an 8-10G needle. A stopper is then placed using a commercially available vent tube stoppering method.

[0183] The core concept of the present invention is the use of pressure-driven filtration to break up agglomerates and filter out large individual particles. This concept is applicable at multiple levels or scales. In its simplest form, the process involves forcing bulk material through small openings, such as a mesh screen or perforated sheet, and then collecting the filtered material in a smaller syringe or collection vessel. This filtration process concept is shown in block diagram form in Figure 11.

[0184] The techniques of the present invention can be applied multiple times and / or at multiple scales. Figure 12 provides a block diagram showing how the process can be applied at large, medium, or small scales.

[0185] Figure 12(I) shows an exemplary large-scale operation. In large-scale operations, the input material (or material to be processed) is supplied in bulk. Large batches of material can be processed in an industrial high-viscosity mixer / dispenser, where the filter / sieve can be an in-line filter, gated impeller, static mixer, high-shear mixer, viscous mixer, or filter screwed to or mounted inside the mixer / dispenser unit. The processed or filtered material can be collected in a large-format container or multiple smaller containers. Alternatively, the material can be stored in storage bottles, large transfer syringes, or fill cartridges.

[0186] Figure 12(II) shows an exemplary medium-scale operation. In medium-scale operations, the input material (or material to be processed) can still be in bulk quantities. The material can be processed in intermediate transfer containers, such as filling lines, large syringes, filling cartridges, etc. Large batches of material can be processed in intermediate containers, in which case the filter can be a mesh screen, a filter tip placed inside the intermediate container, or a luer-lock attachment fixed onto the container. The processed or filtered material can be collected in a large-format container or multiple smaller containers. Alternatively, the material can be loaded into final transfer syringes for injection / direct administration to the patient.

[0187] Figure 12(III) shows an exemplary small-scale operation. In small-scale operation, the material to be filtered / treated is loaded into a final transfer syringe, e.g., a 1 cc syringe, for direct injection into the patient. A filter / sieve, e.g., a mesh filter, may be placed inside (or screwed onto) the final syringe for injection into the patient, e.g., a mesh screen luer lock attachment between the syringe and needle for injection into the patient. In such an example, the treated / filtered material is administered directly into the patient's body and does not include a storage or collection container.

[0188] Each method has different applications or advantages. For substances that tend to recombine and reform aggregates, small-scale processing immediately prior to injection into a patient is perfectly adequate. In contrast, large- or medium-scale operations are more suitable for less sticky substances. Such operations have a higher throughput and lower material costs compared to small-scale methods.

[0189] As will be appreciated by those skilled in the art, one or more exemplary embodiments have been described by way of example, and it will be understood by those skilled in the art that certain changes and modifications may be made without departing from the scope of the present invention as defined in the claims.

Claims

1. 1. A method for removing agglomerates of individual particles from a viscous substance for administration to a patient, comprising: loading the viscous material into an extrusion system equipped with at least one filter / sieve; passing the viscous material through the at least one filter / sieve to cause removal of agglomerates of the individual particles from the viscous material; wherein the filtered viscous material is suitable for administration to the patient.

2. 10. The method of claim 1, wherein the characteristics or morphology of at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the viscous material are not altered.

3. 10. The method of claim 1, wherein the passing step further comprises forcing the viscous material through at least one filter / sieve under / by applying pressure.

4. 4. The method of claim 3, wherein the viscous material is forced through at least one filter / sieve by applying pressure using a device that can utilize a plunger, an extruder, manual compression, a syringe pump, a platen compression, a roller for flexible tubing, a compressor, or similar mechanisms.

5. 10. The method of claim 1, wherein the agglomerates are removed from the viscous material by breaking / disintegrating the agglomerates.

6. 10. The method of claim 1, wherein the agglomerates are removed from the viscous material by filtering / sieving out the agglomerates that are unable to pass through at least one filter / sieve.

7. 10. The method of claim 1, wherein the viscous material is pre-filtered through a plurality of pre-filtration devices, the pre-filtration step occurring before the passing step.

8. 8. The method of claim 7, wherein the viscous material is pre-filtered through a first pre-filtration device followed by a second pre-filtration device.

9. 8. The method of claim 7, wherein the plurality of pre-filtration devices is a series of injection devices, injection syringes, a discharge system, an injection device with a luer lock connector, a compressible tube, a non-compressible tube, a cylinder, or a large scale syringe.

10. 9. The method of claim 8, wherein the first and second pre-filtration devices are a series of injection devices, injection syringes, or large scale syringes, and the first pre-filtration device has a larger opening size than the second pre-filtration device.

11. 9. The method of claim 8, wherein the opening size of the first pre-filtration device is in the range of 18G to 34G.

12. 9. The method of claim 8, wherein the opening size of the second pre-filtration device is in the range of 18G to 34G.

13. 10. The method of claim 1, wherein the viscous material is passed through at least one filter / sieve having a pore size / opening size smaller than the individual particle sizes of the viscous material.

14. 14. The method of claim 13, wherein the pore size of at least one filter / sieve is in the range of 1 to 1000 μm and the individual particle sizes are in the range of 20 to 1000 μm.

15. 14. The method of claim 13, wherein the pore size of at least one filter / sieve is in the range of 25-500 μm and the individual particle sizes are in the range of 40-500 μm.

16. 14. The method of claim 13, wherein the pore size of at least one filter / sieve is in the range of 50-200 μm and the individual particle sizes are in the range of 75-200 μm.

17. 10. The method of claim 1, wherein the filtered viscous material is collected in a loading vessel / transfer syringe.

18. 18. The method of claim 17, wherein the filtered viscous material does not clog the loading vessel / transfer syringe when expelled out of the loading vessel / transfer syringe.

19. 20. The method of claim 18, wherein the filtered viscous material has a substantially uniform or controlled extrusion profile when expelled out of the loading vessel / transfer syringe.

20. 20. The method of claim 19, wherein the filtered viscous material is expelled out of the loading vessel / transfer syringe without pressure buildup after an initial characteristic burst / breaking force.

21. 10. The method of claim 1, wherein the individual particles of the viscous material have an intact morphology.

22. 10. The method of claim 1, wherein the filtered viscous material, when administered, elicits a desired immune response in a patient.

23. 10. The method of claim 1, wherein the extrusion system is selected from the group consisting of an injection syringe, an ejection system, a luer lock connector device, or a compressible tube.

24. 24. The method of claim 23, wherein the extrusion system is a syringe, and the syringe has a needle size ranging from 18G to 34G.

25. 10. The method of claim 1, wherein the loading vessel / transfer syringe is selected from the group consisting of an injection syringe, a discharge system, a luer lock connector device, or a compressible tube.

26. 26. The method of claim 25, wherein the loading container / transfer syringe is a syringe, said syringe having a needle size of 18G to 34G.

27. 27. The method of any of claims 17 to 26, wherein the volume of the extrusion system exceeds the volume of the loading vessel / transfer syringe or the extrusion system has a smaller cross-sectional area compared to the loading vessel / transfer syringe.

28. 28. The method of any of claims 1 to 27, wherein at least one filter / sieve is selected from the group consisting of nylon mesh, stainless steel mesh, polytetrafluoroethylene mesh, or nitrocellulose mesh.

29. 28. The method of any one of claims 1 to 27, wherein at least one filter / sieve is located inside, outside, or adjacent to the extrusion system, or screw-mounted onto the extrusion system.

30. 10. The method of claim 1, wherein at least one filter / sieve is replaced with an in-line filter, a gated impeller, a static mixer, a high shear mixer, a viscous mixer, or a sieving channel.

31. 31. The method of any preceding claim, wherein the passing step sizes individual particles of the viscous substance to create a substantially uniform or controlled particulate matrix for administration.

32. 10. The method of claim 1, wherein the extrusion system is a luer lock connector device and at least one filter / sieve is attached / placed inside the luer lock connector portion of the device.

33. 33. The method of claim 32, wherein the viscous substance is forced under / by pressure through at least one filter / sieve attached / placed inside the luer lock connector portion.

34. 34. The method of claim 33, wherein the pressure is applied using a device that utilizes a plunger, an extruder, manual compression, a syringe pump, a platen compression, a roller for flexible tubing, a compressor, or similar mechanisms.

35. 34. The method of claim 33, wherein the pressure is applied using a plunger or an extruder.

36. 10. The method of claim 1, wherein the passing step is repeated with multiple filters / sieves.

37. 37. The method of claim 36, wherein the plurality of filters / sieves are the same size or have different sizes.

38. 37. The method of claim 36, wherein the pore size of at least one filter / sieve is in the range of 1 to 1000 μm.

39. 39. A method according to any of claims 36 to 38, wherein the step of passing the material through a plurality of filters / sieves reduces the viscosity of the viscous material or adjusts its particle size distribution to a desired level, preferably in the range of 50 to 750 μm.

40. 32. The method of claim 31, wherein the extrusion force required to expel the viscous material out of the extrusion system is reduced.

41. 10. The method of claim 1, wherein the viscous substance is selected from the group consisting of dermal fillers; sealants; adhesives; complex mixtures of mammalian cells; scaffolding materials; bone pastes; bone cements; cartilage biomaterials; injectables including for venous stasis applications; protein hydrogels; carbohydrate hydrogels including cellulose, pectin, and lignin; cellular material mixtures; thickeners; gelling agents; and stabilizers.

42. 1. A method for removing agglomerates of individual particles from a viscous dermal filler material for administration to a patient, comprising: Filling the dermal filler material into an extrusion system that includes at least one filter / sieve; passing the dermal filler material through the at least one filter / sieve to cause removal of agglomerates of the individual particles from the dermal filler material; Including, The method, wherein the filtered dermal filler material is suitable for administration to the patient.

43. 43. The method of claim 42, wherein the characteristics or morphology of at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the dermal filler material are not altered.

44. 43. The method of claim 42, wherein the passing step further comprises forcing the dermal filler substance through at least one filter / sieve under / by applying pressure.

45. 45. The method of claim 44, wherein the dermal filler material is extruded through the at least one filter / sieve by applying pressure using a device that can utilize a plunger, an extruder, manual compression, a syringe pump, a platen compression, a roller for flexible tubing, a compressor, or similar mechanism.

46. 43. The method of claim 42, wherein the agglomerates are removed from the dermal filler material by breaking / disintegrating the agglomerates.

47. 43. The method of claim 42, wherein the agglomerates are removed from the dermal filler material by filtering / sieving out any agglomerates that are unable to pass through at least one filter / sieve.

48. 43. The method of claim 42, wherein the dermal filler material is pre-filtered through a plurality of pre-filtration devices, the pre-filtering step occurring before the passing step.

49. 49. The method of claim 48, wherein the viscous material is pre-filtered through a first pre-filtration device followed by a second pre-filtration device.

50. 49. The method of claim 48, wherein the plurality of pre-filtration devices is selected from the group of a series of injection devices, injection syringes, evacuation systems, injection devices with luer lock connectors, compressible tubing, non-compressible tubing, cylinders, or large scale syringes.

51. 50. The method of claim 49, wherein the plurality of pre-filtration devices is a series of injection devices, injection syringes, or large scale syringes, and wherein a first pre-filtration device has a larger opening size than a second pre-filtration device.

52. 52. The method of claim 51, wherein the opening size of the first pre-filtration device is in the range of 18G to 34G.

53. 52. The method of claim 51, wherein the opening size of the second pre-filtration device is in the range of 18-34G.

54. 43. The method of claim 42, wherein the dermal filler material is passed through at least one filter / sieve having a pore size / opening size smaller than the individual particle sizes of the viscous material.

55. 43. The method of claim 42, wherein the pore size of at least one filter / sieve is in the range of 1 to 1000 μm and the individual particle sizes are in the range of 20 to 1000 μm.

56. 43. The method of claim 42, wherein the pore size of at least one filter / sieve is in the range of 25-500 μm and the individual particle sizes are in the range of 40-500 μm.

57. 43. The method of claim 42, wherein the pore size of at least one filter / sieve is in the range of 50-200 μm and the individual particle sizes are in the range of 75-200 μm.

58. 43. The method of claim 42, wherein the filtered dermal filler material is collected in a loading container / transfer syringe.

59. 59. The method of claim 58, wherein the filtered dermal filler material does not clog the loading container / transfer syringe when expelled out of the loading container / transfer syringe.

60. 60. The method of claim 59, wherein the filtered dermal filler material has a substantially uniform or controlled extrusion profile when expelled out of the loading container / transfer syringe.

61. 61. The method of claim 60, wherein the filtered dermal filler material expels out of the loading container / transfer syringe after an initial characteristic burst / breaking force without pressure buildup.

62. 43. The method of claim 42, wherein the individual particles of the dermal filler material have an intact morphology.

63. 43. The method of claim 42, wherein the filtered dermal filler material, upon administration, elicits a predicted immune response in the patient.

64. 43. The method of claim 42, wherein the extrusion system is selected from the group consisting of an injection syringe, an ejection system, a luer lock connector device, or a compressible tube.

65. 65. The method of claim 64, wherein the extrusion system is a syringe, the syringe having a needle size ranging from 18G to 34G.

66. 43. The method of claim 42, wherein the loading vessel / transfer syringe is selected from the group consisting of an injection syringe, a discharge system, a luer lock connector device, or a compressible tube.

67. 67. The method of claim 66, wherein the loading container / transfer syringe is a syringe, said syringe having a needle size of 18G to 34G.

68. 68. The method of any one of claims 58 to 67, wherein the volume of the extrusion system exceeds the volume of the loading vessel / transfer syringe or the extrusion system has a smaller cross-sectional area compared to the loading vessel / transfer syringe.

69. 69. The method of any of claims 42-68, wherein at least one filter / sieve is selected from the group consisting of nylon mesh, stainless steel mesh, polytetrafluoroethylene mesh, or nitrocellulose mesh.

70. 70. The method of any one of claims 42 to 69, wherein at least one filter / sieve is located inside, outside, or adjacent to the extrusion system, or screw-mounted onto the extrusion system.

71. 43. The method of claim 42, wherein at least one filter / sieve is replaced with an in-line filter, gated impeller, static mixer, high shear mixer, viscous mixer, or sieving channel.

72. 72. The method of any of claims 42 to 71, wherein the passing step sizes individual particles of the dermal filler material to create a substantially uniform or controlled particulate matrix for administration.

73. 43. The method of claim 42, wherein the extrusion system is a luer lock connector device and at least one filter / sieve is attached / positioned inside the luer lock connector portion of the device.

74. 74. The method of claim 73, wherein the dermal filler material is extruded under / by application of pressure through at least one filter / sieve attached / placed inside the luer lock connector portion.

75. 75. The method of claim 74, wherein the pressure is applied using a device that utilizes a plunger, an extruder, manual compression, a syringe pump, a platen compression, a roller for flexible tubing, a compressor, or similar mechanism.

76. 75. The method of claim 74, wherein the pressure is applied using a plunger or an extruder.

77. 43. The method of claim 42, wherein the passing step is repeated with multiple filters / sieves.

78. 78. The method of claim 77, wherein the multiple filters / sieves are the same size or have different sizes.

79. 80. The method of claim 79, wherein the pore size of at least one filter / sieve is in the range of 1 to 1000 μm.

80. 80. The method according to any of claims 77 to 79, wherein passing the material through a plurality of filters / sieves reduces the viscosity of the dermal filler material or adjusts its particle size distribution to a desired level, preferably within the range of 50 to 750 μm.

81. 81. The method of claim 80, wherein the extrusion force required to expel the dermal filler material out of the extrusion system is reduced.

82. 36. The method of claim 35, wherein the dermal filler material is selected from the group consisting of sealants; adhesives; composite mixtures of mammalian cells; scaffolding materials; bone pastes; bone cements; cartilage biomaterials; injectables including for venous stasis applications; protein hydrogels; carbohydrate hydrogels including cellulose, pectin, and lignin; cellular material mixtures; thickeners; gelling agents; and stabilizers.

83. 1. A method for removing agglomerates of individual particles from a viscous substance for administration to a patient, comprising: loading the viscous material into a first collection vessel comprising at least one filter / sieve; passing the viscous material through the at least one filter / sieve to cause removal of agglomerates of the individual particles from the viscous material; collecting the viscous material in a second collection container; Including, The method, wherein the filtered viscous material collected in the second collection container is suitable for administration to the patient.

84. 84. The method of claim 83, wherein the first collection vessel comprises an extrusion system, said extrusion system comprising at least one filter / sieve.

85. 84. The method of claim 83, wherein the characteristics or morphology of at least 98%, at least 95%, at least 92%, at least 89%, at least 86%, at least 83%, or at least 80% of the individual particles of the viscous material are not altered.

86. 84. The method of claim 83, wherein the passing step further comprises forcing the viscous material through at least one filter / sieve under / by applying pressure.

87. 71. The method of claim 70, wherein the viscous substance is forced through at least one filter / sieve by applying pressure using a device that can utilize a plunger, an extruder, manual compression, a syringe pump, a platen compression, a roller for flexible tubing, a compressor, or similar mechanism.

88. 84. The method of claim 83, wherein the aggregates are removed from the viscous material by disrupting / disintegrating the aggregates.

89. 84. The method of claim 83, wherein the agglomerates are removed from the viscous material by filtering / sieving out any agglomerates that are unable to pass through at least one filter / sieve.

90. 84. The method of claim 83, wherein the viscous material is pre-filtered through a plurality of pre-filtration devices, the pre-filtration step occurring before the passing step.

91. 91. The method of claim 90, wherein the viscous material is pre-filtered through a first pre-filtration device followed by a second pre-filtration device.

92. 84. The method of claim 83, wherein the plurality of pre-filtration devices is selected from the group of a series of injection devices, injection syringes, evacuation systems, injection devices with luer lock connectors, compressible tubing, non-compressible tubing, cylinders, or large scale syringes.

93. 92. The method of claim 91, wherein the plurality of pre-filtration devices is a series of injection devices, injection syringes, or large scale syringes, and a first pre-filtration device has an opening size greater than a second pre-filtration device.

94. 92. The method of claim 91, wherein the opening size of the first pre-filtration device is selected from 18-34G.

95. 92. The method of claim 91, wherein the opening size of the second pre-filtration device is selected from 18-34G.

96. 84. The method of claim 83, wherein the viscous substance is passed through at least one filter / sieve having a pore size / opening size smaller than the individual particle sizes of the viscous substance.

97. 84. The method of claim 83, wherein the pore size of at least one filter / sieve is in the range of 1 to 1000 μm and the individual particle sizes are in the range of 20 to 1000 μm.

98. 84. The method of claim 83, wherein the pore size of at least one filter / sieve is in the range of 25-500 μm and the individual particle sizes are in the range of 40-500 μm.

99. 84. The method of claim 83, wherein the pore size of at least one filter / sieve is in the range of 50-200 μm and the individual particle sizes are in the range of 75-200 μm.

100. 84. The method of claim 83, wherein the filtered viscous material collected in the second collection container is dispensed / extracted using a dispensing device.

101. 101. The method of claim 100, wherein the filtered viscous substance does not clog the dispensing device when dispensed / extruded out of the dispensing device.

102. 101. The method of claim 100, wherein the filtered viscous material has a substantially uniform or controlled extrusion profile when dispensed / extruded out of the dispensing device.

103. 103. The method of claim 102, wherein the filtered viscous material dispenses / ejects out of the dispensing device after an initial characteristic burst / breaking force without building up pressure.

104. 104. The method of claim 103, wherein the individual particles of the viscous substance have an intact morphology.

105. 84. The method of claim 83, wherein the filtered viscous material, when administered, elicits the expected immune response in the patient.

106. 101. The method of claim 100, wherein the dispensing device is selected from the group consisting of a series of injection devices, an injection syringe, an ejection system, an injection device with a Luer lock connector, a compressible tube, a non-compressible tube, a cylinder, or a large scale syringe.

107. 84. The method of claim 83, wherein the dispensing device is a syringe, the syringe having a needle size of 18G to 34G.

108. 84. The method of claim 83, wherein the at least one filter / sieve is selected from the group consisting of nylon mesh, stainless steel mesh, polytetrafluoroethylene mesh, or nitrocellulose mesh.

109. 84. The method of claim 83, wherein at least one filter / sieve is located inside, outside, or adjacent to the first collection vessel or screw-mounted onto the extrusion system.

110. 84. The method of claim 83, wherein at least one filter / sieve is replaced with an in-line filter, gated impeller, static mixer, high shear mixer, viscous mixer, or sieving channel.

111. 84. The method of claim 83, wherein the passing step sizes individual particles of the viscous substance to create a substantially uniform or controlled particulate matrix for administration.

112. 84. The method of claim 83, wherein at least one filter / sieve is disposed inside a luer lock connector attached to the inside of the first collection container / the luer lock connector portion of the first collection container.

113. 113. The method of claim 112, wherein the viscous substance is forced under / by application of pressure through at least one filter / sieve located inside the luer lock connector portion.

114. 114. The method of claim 113, wherein the pressure is applied using a device that can utilize a plunger, extruder, manual compression, syringe pump, platen compression, rollers for flexible tubing, compressor, or similar mechanism.

115. 114. The method of claim 113, wherein the pressure is applied using a plunger or an extruder.

116. 84. The method of claim 83, wherein the passing step is repeated with multiple filters / sieves.

117. 117. The method of claim 116, wherein the multiple filters / sieves are the same size or have different sizes.

118. 117. The method of claim 116, wherein the size of at least one filter / sieve is in the range of 1 to 1000 μm.

119. 117. The method of claim 116, wherein the step of passing the material through a plurality of filters / sieves reduces the viscosity of the viscous material or adjusts its particle size distribution to a desired level, preferably within the range of 50 to 750 μm.

120. 120. The method of claim 119, wherein the extrusion force required to expel the viscous material out of the extrusion system is reduced.

121. 84. The method of claim 83, wherein the viscous substance is selected from the group consisting of dermal fillers, sealants; adhesives; complex mixtures of mammalian cells; scaffolding materials; bone pastes; bone cements; cartilage biomaterials; injectables including for venous stasis applications; protein hydrogels; carbohydrate hydrogels including cellulose, pectin, and lignin; cellular material mixtures; thickeners; gelling agents; and stabilizers.

122. 84. The method of claim 83, wherein the first collection vessel is a series of vessels of different sizes, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, an injection syringe, a large injection syringe, a luer lock connector device, a discharge system, or a compressible tube.

123. 84. The method of claim 83, wherein the second collection vessel is selected from at least one of a transfer container, a storage bottle, an injection syringe, a filler cartridge, a series of containers having different sizes, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, a large injection syringe, a luer lock connector device, a discharge system, or a compressible tube.

124. 124. The method of claim 123, wherein a second collection container is used to dispense / expel the filtered viscous material for administration to a patient.

125. 84. The method of claim 83, wherein the first collection vessel has a greater volume than the second collection vessel.

126. 126. Use of the method according to any of claims 1 to 41 or 83 to 125 for reducing the viscosity of a viscous substance or adjusting its particle size distribution to a desired level, preferably within the range of 50 to 750 μm.

127. Use of the method according to claims 42 to 82 for reducing the viscosity of a dermal filler material or adjusting its particle size distribution to a desired level, preferably within the range of 50 to 750 μm.

128. 126. Use of the method of any of claims 1 to 41 or 83 to 125 to break up agglomerates / aggregates within a viscous substance.

129. 83. Use of the method of claims 42 to 82 for breaking down clumps / aggregates within dermal filler materials.

130. 126. Use of the method of any of claims 1 to 41 or 83 to 125 to prevent needle blockage in an injection or dispensing device during delivery of a viscous substance.

131. Use of the method according to claims 42 to 82 to prevent needle blockage in an injection or dispensing device during delivery of a dermal filler substance.

132. 126. Use of the method of any of claims 1 to 41 or 83 to 125 to size individual particles of a viscous substance so that the substance has an approximately / substantially uniform individual particle size.

133. 83. Use of the method according to claims 42 to 82 for sizing individual particles of a dermal filler material such that the dermal filler material has an approximately / substantially uniform individual particle size.

134. 126. Use of the method according to any of claims 1 to 41 or 83 to 125 for reducing the individual particle size of a viscous substance without affecting / impacting its rheological properties.

135. 126. Use of the method of any of claims 1 to 41 or 83 to 125 for reducing the individual particle size of a viscous substance without affecting / impacting / changing the characteristics or morphology of the individual particles of said viscous substance.

136. Use of the method according to claims 42 to 82 for reducing the individual particle size of a viscous substance without affecting / influencing its rheological properties.

137. 83. Use of the method according to any of claims 42 to 82 for reducing the individual particle size of a viscous substance without affecting / impacting / changing the characteristics or morphology of the individual particles of said viscous substance.

138. 126. Use of the method of any of claims 1 to 41 or 83 to 125 for filtering a viscous substance so that the viscous substance has a uniform or controlled particulate matrix for administration.

139. 83. Use of the method according to claims 42 to 82 for filtering a dermal filler so that the dermal filler has a uniform or controlled particulate matrix for administration.

140. 126. The use of the method of any of claims 1-41 or 83-125, wherein the viscous substance is selected from the group of dermal fillers; sealants; adhesives; complex mixtures of mammalian cells; scaffolding materials; bone pastes; bone cements; cartilage biomaterials; injectables including for venous stasis applications; protein hydrogels; carbohydrate hydrogels comprising cellulose, pectin, and lignin; cellular material mixtures; thickeners; gelling agents; and stabilizers.

141. 126. Use of the method of any of claims 1 to 41 or 83 to 125 to reduce the individual particle size of a viscous material, thereby reducing the extrusion force required to eject the viscous material out of an extrusion system.

142. 83. Use of the method of any of claims 42 to 82 to reduce the individual particle size of a dermal filler material, thereby reducing the extrusion force required to expel the dermal filler material out of an extrusion system.

143. 1. A device for removing agglomerates of individual particles from a viscous substance, comprising: an extrusion system; at least one filter / sieve located inside, outside, or adjacent to the extrusion system, or screw-mounted onto the extrusion system; wherein passing the viscous substance through the at least one filter / sieve causes removal of agglomerates of individual particles from the viscous substance.

144. 144. The device of claim 143, further comprising an extruder for extruding the viscous substance through at least one filter / sieve under / by application of pressure.

145. 145. The device of claim 144, wherein the extruder pressure is controlled by electronic means.

146. 143. The device of claim 142, wherein at least one filter / sieve is selected from the group consisting of nylon, stainless steel, polytetrafluoroethylene, or nitrocellulose.

147. 143. The device of claim 142, wherein at least one filter / sieve is a nylon mesh or a stainless steel mesh.

148. 143. The device of claim 142, wherein at least one filter / sieve is replaced with an in-line filter, gated impeller, static mixer, high shear mixer, viscous mixer, or sieving channel.

149. 149. A device as claimed in claim 148, wherein the dimensions of the in-line filter or sieving channel are in the range of 0.5mm to 2540mm.

150. 143. The device of claim 142, wherein the extrusion system is connected to a plurality of pre-filtration devices for pre-filtering the viscous material before passing the material through at least one filter / sieve.

151. 151. The device of claim 150, wherein the extrusion system is in communication with at least one pre-filtration device and a loading vessel / transfer syringe, and the at least one pre-filtration device is in communication with the loading vessel / transfer syringe.

152. 143. The device of claim 142, wherein the extrusion system is coupled to a loading vessel / transfer syringe for collecting the filtered viscous material.

153. 143. The device of claim 142, wherein at least one filter / sieve has an opening size smaller than the individual particle sizes of the viscous substance.

154. 143. The device of claim 142, wherein at least one filter / sieve has an opening size in the range of 1 to 1000 μm and individual particle sizes in the range of 20 to 1000 μm.

155. 143. The device of claim 142, wherein at least one filter / sieve has an opening size in the range of 25-500 μm and individual particle sizes in the range of 40-500 μm.

156. 143. The device of claim 142, wherein at least one filter / sieve has an opening size in the range of 50-200 μm and individual particle sizes in the range of 75-200 μm.

157. 143. The device of claim 142, wherein the extrusion molding system is selected from the group of an injection syringe, an ejection system, a luer lock connector device, or a compressible tube.

158. 143. The device of claim 142, wherein the extrusion system is a syringe.

159. The device of claim 158, wherein the syringe has a needle size of 18G to 34G.

160. 143. The device of claim 142, wherein the loading vessel / transfer syringe is selected from the group of an injection syringe, an evacuation system, a luer lock connector device, or a compressible tube.

161. 143. The device of claim 142, wherein the loading container / transfer syringe is a syringe.

162. The device of claim 161, wherein the syringe has a needle size of 18G to 34G.

163. 143. The device of claim 142, wherein the extrusion system has a volume greater than the volume of the loading vessel / transfer syringe or the extrusion system has a smaller cross-sectional area compared to the loading vessel / transfer syringe.

164. 143. The device of claim 142, wherein the extrusion molding system is a Luer lock connector injection device.

165. 165. The device of claim 164, wherein at least one filter / sieve is disposed inside the luer lock connector.

166. 1. A device for removing agglomerates of individual particles from a viscous substance, comprising: a first collection container; at least one filter / sieve attached to, or screwed to, the interior, exterior, or adjacent to the first collection vessel; a second collection vessel coupled to the first collection vessel for collecting the filtered viscous material; wherein passing the viscous material through the at least one filter / sieve causes removal of agglomerates of individual particles from the viscous material.

167. 167. The device of claim 166, wherein the first collection vessel comprises an extrusion system as defined in any one of claims 143 to 165.

168. 167. The device of claim 166, wherein the first collection container is selected from the group consisting of a series of containers of different sizes, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, an injection syringe, a large injection syringe, a luer lock connector device, an evacuation system, or a compressible tube.

169. 167. The device of claim 166, wherein the second collection vessel is selected from the group of a transfer container, a storage bottle, an injection syringe, a filler cartridge, a series of containers of different sizes, a storage unit or chamber, an industrial mixer, an industrial dispenser, an intermediate transfer container, a large injection syringe, a luer lock connector device, an evacuation system, or a compressible tube.

170. 167. The device of claim 166, wherein an additional filter / sieve is attached inside the second collection container.

171. 167. The device of claim 166, wherein the second collection container is a collection chamber disposed inside the first collection container.

172. 167. The device of claim 166, wherein the device further comprises an extruder for extruding the viscous substance through at least one filter / sieve under / by applying pressure.

173. 10. The device of claim 1, wherein the extruder pressure is controlled by electronic means.

174. 167. The device of claim 166, wherein at least one filter / sieve has an opening size in the range of 1 to 1000 μm and individual particle sizes in the range of 20 to 1000 μm.

175. 167. The device of claim 166, wherein at least one filter / sieve has an opening size in the range of 25-500 μm and individual particle sizes in the range of 40-500 μm.

176. 167. The device of claim 166, wherein at least one filter / sieve has an opening size in the range of 50-200 μm and individual particle sizes in the range of 75-200 μm.

177. 168. The device of claim 167, wherein at least one filter / sieve is selected from nylon mesh, stainless steel mesh, polytetrafluoroethylene mesh, or nitrocellulose mesh.

178. 167. The device of claim 166, wherein at least one filter / sieve is replaced with an in-line filter, gated impeller, static mixer, high shear mixer, viscous mixer, or sieving channel.

179. 167. The device of claim 166, wherein the first collection vessel is connected to a plurality of pre-filtration devices for pre-filtering the viscous material before passing the material through at least one filter / sieve.

180. 167. The device of claim 166, wherein a first collection container connects to a plurality of pre-filtration devices, and the pre-filtration device connects to a second collection container.

181. 167. The device of claim 166, wherein a first collection container connects to a first pre-filtration device and a second pre-filtration device, and each of the pre-filtration devices connects to a second collection container.

182. 167. The device of claim 166, wherein at least one filter / sieve has an opening size smaller than the individual particle sizes of the viscous substance.

183. 167. The device of claim 166, wherein a luer lock connector is attached to the inside of the first collection container.

184. 184. The device of claim 183, wherein at least one filter / sieve is disposed within a luer lock connector attached to the inside of the first collection container.

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