Filter holder for liposome extrusion

Abstract

A filter holder for liposome extrusion includes a housing having an inlet and an outlet configured to receive material to be extruded, and a filter support element positioned within the housing between the inlet and the outlet. The filter support element includes an upstream side having a filter support surface configured to support a membrane filter assembly, a downstream side opposite the upstream side, and a plurality of channels extending through the filter support element from the filter support surface to the downstream side. The filter holder further includes an outlet chamber in fluid communication with the outlet, and the filter holder is configured such that material to be extruded flows through the membrane filter assembly and through the plurality of channels into the outlet chamber, and thereafter is expelled through the outlet.

Description

Technical Field

[0001] This invention relates to filter retainers for extrusion, and more particularly to filter retainers for liposome extrusion. Background Technology

[0002] Liposome extruders can be used to produce small and uniform lipid vesicles (or liposomes). For example, liposomes are most commonly prepared via a two-step process. First, a crude lipid or liposome suspension is formed, containing large heterogeneous groups of liposomes. Subsequently, a liposome extruder can be used to reduce the size by forcing the aqueous suspension of lipids through a membrane filter with a defined, uniform pore size, producing smaller liposomes of a defined size with a uniform size distribution. Such liposomes can be used in pharmaceutical, diagnostic, cosmetic, and nutritional products as carriers for therapeutic, diagnostic, cosmetic, or nutritional agents. However, existing liposome extruders have several drawbacks. First, the pores in the membrane filter are prone to clogging, especially when processing large quantities of liposome products requiring large-scale industrial production, and when using concentrated lipid suspensions containing reagents (e.g., therapeutic or diagnostic agents) that require the largest possible dosage in liposome carriers. Replacing each clogged membrane filter exposes the extruder to the environment and may pose a risk of product contamination, as well as exposure of personnel and production facilities to potentially hazardous reagents (e.g., cytotoxic drugs, which are often formulated in liposome carriers using extrusion methods). Therefore, membrane filters that are prone to scaling or clogging increase the time and cost of the extrusion process and may compromise product quality.

[0003] The limitations of currently available liposome extruders are particularly pronounced when extruding certain types of lipids. The lipid bilayer comprises a “rigid” gel phase below Tc (the so-called gel-to-liquid phase transition temperature) and a “fluid” liquid crystal state above Tc. Lipids with Tc values ​​greater than approximately room temperature can be particularly difficult to extrude through membrane filters and require heating the suspension above Tc. The Tc value of a particular lipid depends on many factors, including the length and saturation of the lipid hydrocarbon chain. Lipids with longer saturated hydrocarbon chains (so-called gel lipids) may have higher Tc values ​​than lipids with shorter, less saturated hydrocarbon chains, values ​​above room temperature (and therefore potentially more difficult to extrude through membrane filters). Liposomes composed of gel lipids are a preferred drug delivery system for intravenous injection of a variety of therapeutic agents. Gel-phase lipids commonly used in liposomal drug products, such as hydrogenated soybean phosphatidylcholine (HSPC) and distearate phosphatidylcholine (DSPC), have Tc values ​​above 50°C and require heating to 60-65°C (at least 10°C above Tc) for extrusion. As mentioned above, clogged or fouled membranes must be replaced, which increases production costs and processing time. The latter, in turn, affects product quality because prolonged exposure to high temperatures increases the likelihood of degradation of temperature-sensitive materials (liposomes and liposome-related reagents).

[0004] The filter support structure in existing extruders exacerbates the clogging problem of membrane filters. Figure 1 illustrates an example of an existing filter holder 10 for liposome extrusion. The filter holder 10 includes a top housing plate (or inlet plate) and a bottom housing plate (or outlet plate) and a flat filter support disc 14 having a plurality of channels 18 extending therethrough. The filter support disc 14 is located in a recess 22 in the bottom housing plate 26. The recess 22 includes a radially extending channel 30 that extends from and communicates with a central outlet 34.

[0005] Existing filter retainers, such as filter retainer 10 as shown in Figure 1, limit the effective area of ​​the applied membrane filter. For example, referring to Figure 2, the material to be extruded only flows through the orifices near channel 18A in the filter support plate 14, which is aligned with channel 30. Little or no flow flows through the orifices near channel 18B in the membrane filter, which is not aligned with channel 30. Material does not flow over the remaining surface of the support plate lying flat on the bottom housing plate. Therefore, only a small fraction of the total area of ​​the membrane filter is actually utilized during extrusion. This accelerates fouling (the formation of material deposits and rapid pressure build-up on the filter) and clogging of the membrane filter, requiring frequent filter replacements. Additionally, the limited effective area results in lower flux and higher extrusion pressure. As mentioned above, all of these increase processing time and can potentially affect product quality. To reduce filter clogging and improve flux and product quality, it is important to increase / maximize surface area utilization. Summary of the Invention

[0006] In one aspect, the present invention provides a filter holder for liposome extrusion, comprising: a housing having an inlet and an outlet configured for receiving material to be extruded, and a filter support element located within the housing between the inlet and the outlet. The filter support element includes an upstream side having a filter support surface configured for supporting a membrane filter assembly, a downstream side relative to the upstream side, and a plurality of channels extending from the filter support surface through the filter support element to the downstream side. The filter holder further includes an outlet cavity in fluid communication with the outlet, and is configured such that the material to be extruded flows through the membrane filter assembly and enters the outlet cavity through the plurality of channels, and is then discharged through the outlet.

[0007] In another aspect, the present invention provides a filter holder for liposome extrusion. The filter holder includes: a housing defining a longitudinal central axis, the housing including an inlet extending from an inlet chamber and an outlet extending from an outlet chamber; and a filter support element located within the housing between the inlet and outlet chambers. The filter support element includes: an upstream side adjacent to the inlet chamber, the upstream side having a filter support surface provided for supporting a membrane filter assembly; a downstream side adjacent to the outlet chamber and opposite to the upstream side; and a plurality of channels extending from the upstream side through the filter support element to the downstream side. The filter holder is configured such that the material to be extruded flows through the membrane filter assembly and enters the outlet chamber through the plurality of channels, and then exits through the outlet.

[0008] In another aspect, the present invention provides an extrusion system comprising a supply tank containing material to be extruded, a pressure source configured to pressurize and extract the material to be extruded from the tank, and a filter retainer. The filter retainer includes: a housing having an inlet configured to receive pressurized material to be extruded and an outlet configured to discharge extrudate; a membrane filter assembly located between the inlet and the outlet; and a filter support element located within the housing. The filter support element includes: an upstream side having a filter support surface configured to support the membrane filter assembly; a downstream side relative to the upstream side including a first groove; and a plurality of channels extending from the filter support surface through the filter support element to the first groove. The filter retainer further includes an outlet cavity defined at least partially by the first groove, the outlet cavity being in fluid communication with the outlet. The extrusion system also includes a collection tank configured to receive extrudate from the outlet of the filter retainer.

[0009] In some implementations, multiple filter holders can be combined in parallel to increase throughput. If product heating is required, one or more heat exchangers can be included to help maintain and control product temperature. Multiple extrusion passes can be implemented by circulating the product from the supply container to the collection container.

[0010] Other features and aspects of the invention will become apparent from the following detailed description and accompanying drawings. Attached Figure Description

[0011] Figure 1 is an exploded view of a prior art filter retainer.

[0012] Figure 2 is a top view of the through holes and channels of the filter retainer in Figure 1.

[0013] Figure 3 This is a perspective view of a filter holder according to an embodiment of the present invention.

[0014] Figure 4 for Figure 3 Exploded view of the filter retainer.

[0015] Figure 5 for Figure 3 A cross-sectional view of the filter holder.

[0016] Figure 5A For connection to temperature control components Figure 3 A schematic diagram of a filter holder.

[0017] Figure 6 The top perspective describes Figure 3 The filter support element of the filter retainer.

[0018] Figure 7 for Figure 5 Bottom perspective view of the filter support element.

[0019] Figure 8 for Figure 5 A cross-sectional view of the filter support element.

[0020] Figure 8A This is a cross-sectional view of a filter support element according to another embodiment.

[0021] Figure 9 A perspective view of the filter support element for another embodiment.

[0022] Figure 10 A bottom view of the filter support element for another embodiment.

[0023] Figure 11 The bottom perspective view depicts the filter support element of another embodiment.

[0024] Figure 12 for Figure 11 A cross-sectional view of the filter support element.

[0025] Figure 13 This is a schematic diagram of the extrusion system according to an embodiment of the present invention.

[0026] Figure 14 The graph compares the extrusion pressure of a liposome extruder (“LIPEX 1”) equipped with a prior art filter holder of Figure 1 with that of a filter holder embodying various aspects of the present invention, such as… Figure 3 The extrusion pressure of the liposome extruder (“LIPEX 2”) of the filter retainer, wherein a 47 mm filter is applied at a flow rate of 10 mL / min.

[0027] Figure 15 The graphs compare the extrusion pressures of LIPEX 1 and LIPEX 2 when using a 47 mm filter at a flow rate of 20 mL / min.

[0028] Figure 16 The graphs compare the extrusion pressures of LIPEX 1 and LIPEX 2 when using a 47 mm filter at a flow rate of 110 mL / min.

[0029] Figure 17 The graphs compare the extrusion pressures of LIPEX 1 and LIPEX 2 when using a 47 mm filter at a flow rate of 220 mL / min.

[0030] Figure 18 The graphs compare the extrusion pressures of LIPEX 1 and LIPEX 2 when using a 25 mm filter at a flow rate of 5 mL / min.

[0031] Figure 19 The graphs compare the extrusion pressures of LIPEX 1 and LIPEX 2 when using a 25 mm filter at a flow rate of 25 mL / min.

[0032] Before explaining any embodiment of the invention in detail, it should be understood that the application of the invention is not limited to the structural details and component arrangements shown in the following description or drawings. The invention can have other embodiments and can be practiced or implemented in various ways. Furthermore, it should be understood that the wording and terminology used herein are for descriptive purposes only and are not intended to be limiting. Detailed Implementation

[0033] Figure 3 A filter holder 100 according to an exemplary embodiment of the present invention is described. The filter holder 100 can be configured for a liposome extruder, for example... An extruder, or other small-aperture extruders applicable in industries such as pharmaceuticals, nutrition, biotechnology, and cosmetics. The filter retainer 100 includes a housing 104, which in the described embodiment includes a first or upper housing portion 108, a second or lower housing portion 112, and a third or middle housing portion 116 located between the upper housing portion 108 and the lower housing portion 112. In the described embodiment, the housing 104 is generally cylindrical and extends along a central longitudinal axis L. Figure 4 In other embodiments, housing 104 may have other shapes, and housing 104 may include any number of housing portions.

[0034] refer to Figure 4The housing portions 108, 112, and 116 are connected together by a plurality of fastening assemblies 120 (e.g., four fastening assemblies 120 in the described embodiment). Each fastening assembly 120 includes a screw 124, a washer 128, and a nut 132. The screw 124 extends from the lower housing portion 112 and passes through the middle and upper housing portions 116 and 108. Each screw 124 has a first threaded end 124A and a second threaded end 124B opposite to the first threaded end 124A. The nut 132 is threaded to the port of the first threaded end 124A of the screw 124, while the washer 128 is located between the nut 132 and the upper housing portion 108. The second threaded end 124B of the screw 124 is screwed into the lower housing portion 112. Therefore, nut 132 can be tightened to secure housing portions 108, 112, 116 together, or it can be loosened and / or removed from screw 124, thereby allowing disassembly of housing 104 (e.g., for servicing, filter replacement, etc.). In other embodiments, housing portions 108, 112, 116 can be secured together using other types and / or arrangements of fasteners, threaded connections, clamp connections, or any other suitable arrangement.

[0035] refer to Figure 3 and 4 The filter retainer 100 includes an inlet 136 for receiving the material to be extruded (e.g., an aqueous suspension containing larger liposomes of non-uniform size) and an outlet 140 for discharging the extrudate (e.g., liposomes that are smaller and more uniform in size compared to the liposomes before extrusion). In the described embodiment, the inlet 136 is provided in the upper housing portion 108, and the outlet 140 is provided in the lower housing portion 112. The inlet 136 may include a tubular or sanitary clamp connection, a threaded hole or screw, or any other suitable interface for receiving the material to be extruded from a source (such as a pump or pressure vessel). In some embodiments, the inlet 136 may have a nominal outer diameter of about 0.25-1.0 inches, or the inlet 136 may have other nominal outer diameters such as about 0.25-2.5 inches, about 0.25-5.0 inches, etc. Similarly, outlet 140 may include a pipe or sanitary clamp connection, a threaded hole or screw, or any other suitable interface for connecting to a downstream tank for receiving extruded material exiting filter retainer 100. In some embodiments, the nominal outer diameter of outlet 140 may be about 0.25-1.0 inches, or outlet 140 may have other nominal outer diameters beyond this range. In some embodiments, inlet 136 and outlet 140 may have the same or different diameters.

[0036] refer to Figure 4 and 5The central housing portion 116 surrounds and at least partially supports the filter support element 144. In the described embodiment, the filter support element 144 is concentrically supported within the central housing portion 116. That is, the central housing portion 116 surrounds the outer periphery of the filter support element 144. In some embodiments, the filter support element 144 may be integrally formed with the central housing portion 116. In other embodiments, the filter support element 144 may be formed independently and secured to the central housing portion 116 by welding, brazing, threading, or any other suitable means.

[0037] The described filter support element 144 includes an upstream side 146 facing the inlet 136 and a downstream side 147 opposite the upstream side 146 and facing the outlet 140. A first or upper recess 148 is formed on the upstream side 146 and is configured (i.e., of a certain size and shape) to accommodate the membrane filter assembly 152. Figure 4 In the described embodiment, the membrane filter assembly 152 has a circular outer periphery, but in other embodiments, the shape of the membrane filter assembly 152 (and the corresponding shape of the upper recess 148) can be varied. For example, in some embodiments, the membrane filter assembly 152 and the upper recess 148 can be elliptical, square, hexagonal, etc.

[0038] The membrane filter assembly 152 may include one or more membrane filters with a diameter of 5-600 mm, preferably 13-293 mm. For example, in some embodiments, the diameter of the membrane filter assembly 152 may be 13 mm, 25 mm, 47 mm, 90 mm, 142 mm, or 293 mm. The pore size of each of the one or more membrane filters in the membrane filter assembly 152 may be, for example, from about 10 nm to about 1 μm. In some embodiments, the pore size of each membrane filter may be about 50-200 nm. In some embodiments, the pore size of each membrane filter may be about 100 nm. The membrane filters of these embodiments may be particularly suitable for liposome extrusion. The membrane filters may be made of polycarbonate. In other embodiments, the membrane filter assembly 152 may include one or more membrane filters made of other materials (such as polyethylene terephthalate, alumina, or any other suitable membrane material) and of other sizes and / or pore sizes.

[0039] In some embodiments, the membrane filter assembly 152 may include a drainage tray (e.g., a polyester drainage tray) to provide support within the membrane filter assembly 152, improve flow, and prevent wrinkling and tearing of the membrane filter. In these embodiments, the membrane filter is positioned on top of the drainage tray. Drainage trays may also be inserted between the membrane filters. In some embodiments, the membrane filter and drainage tray may be positioned on a filter support mesh or grid. Thus, the membrane filter assembly 152 includes at least one membrane filter and optionally includes one or more drainage trays and / or filter support mesh. This assembly is positioned in a first or upper recess 148 formed in the upstream side 146.

[0040] refer to Figure 5 The described filter support element 144 also includes a lower recess 154 formed in the downstream side 147. An upper seal 156 surrounds the upper recess 148 at the interface between the filter support element 144 and the upper housing portion 108, and a lower seal 160 surrounds the lower recess 154 at the interface between the filter support element 144 and the lower housing portion 112. In the described embodiment, the upper and lower seals 156 and 160 are O-rings (e.g., made of rubber or any other suitable elastomeric or non-elastomeric sealing material), but other types of seals may also be used. When the housing 104 is assembled, the seals 156 and 160 are pressed between the filter support element 144 and the upper and lower housing portions 108 and 112, respectively.

[0041] refer to Figure 6-8 The described filter support element 144 includes a filter support surface 164 within an upper recess 148 and an outlet surface 168 within a lower recess 154. The outlet surface 168 is located opposite the filter support surface 164. In some embodiments, the lower recess 154 may be omitted, so that the outlet surface 168 may be substantially flush with the remainder of the filter support element 144 and / or the middle housing portion 116.

[0042] Determine the diameter or maximum width D1 of the filter support surface 164. Figure 8 The filter support surface 164 is used to accommodate the membrane filter assembly 152. For example, in some embodiments, the diameter D1 can be about 5-600 mm, and preferably about 13-293 mm, to accommodate the membrane filter assembly 152 having the corresponding diameter. For example, in some embodiments, the diameter D1 can be 13 mm, 25 mm, 47 mm, 90 mm, 142 mm, or 293 mm. In the described embodiments, the filter support surface 164 is planar, but in other embodiments, the filter support surface 164 can be non-planar (e.g., concave or convex).

[0043] The outlet surface 168 defines a maximum width D2, which in some embodiments can be approximately 0.5–15 inches (or 12.7–381 mm). In the described embodiments, the outlet surface 168 is a concave surface. For example, the outlet surface 168 can be a hemispherical, quasi-spherical, ellipsoidal, or truncated cone. In other embodiments, the outlet surface 168 can be flat.

[0044] Multiple channels 172 extend between and through surfaces 164 and 168. In some embodiments, the filter support element 144 contains 4-3,000 channels 172. Figure 8 In the described implementation, channel 172 extends parallel to the longitudinal axis L. Figure 8A In another embodiment described, one or more channels 172 may extend at a non-zero angle relative to the longitudinal axis L. For example, in some embodiments, one or more channels 172 may extend at an angle of about 5-60 degrees relative to the longitudinal axis L, or in some embodiments, at an angle of about 10 degrees. Figure 8A In the described embodiment, the maximum width D2 of the outlet surface 168 is less than the diameter D1 of the filter support surface 164. In other embodiments, the maximum width D2 of the outlet surface 168 may be equal to or greater than the diameter D1 of the filter support surface 164.

[0045] refer to Figure 8 and 8A Each channel 172 is cylindrical with a constant diameter Dp of approximately 0.0625-0.25 inches (or 1.59-6.35 mm). In other embodiments, the diameter Dp of each channel 172 may be approximately 0.125 inches (or 3.175 mm). Each channel 172 may have the same diameter Dp, or different channels 172 of the plurality of channels 172 may have different diameters Dp. In yet another embodiment, one or more channels 172 may have varying diameters Dp (thus, the channel 172 may be tapered).

[0046] In some implementations, the filter support element 144 has a minimum thickness T of approximately 0.125–5 inches (or 3.175–127 mm). Determining the thickness T ensures that the filter support element 144 has sufficient strength to withstand the pressures applied to it during extrusion. The curved design of the outlet surface 168 advantageously provides high strength to the filter support element 144 while minimizing the thickness T. This reduces weight and floor space, and thus increases the ease of operation of large-scale industrial extrusion equipment, particularly in applications requiring high extrusion pressures of several thousand psi.

[0047] refer to Figure 5The inlet 136 is in fluid communication with the inlet cavity 176 adjacent to the upstream side 146 of the filter support element 144, while the outlet 140 is in fluid communication with the outlet cavity or drainage cavity 180 adjacent to the downstream side 147 of the filter support element 144. In the described embodiment, the inlet cavity 176 is defined at least partially by the filter support surface 164, the upper seal 156, and a groove 184 formed on the lower side of the upper housing portion 108. The groove 184 in the described embodiment has a generally frustoconical shape, tapering outward from the inlet 136. The frustoconical shape of the groove 184 can assist in the distribution of the material to be extruded on the surface of the membrane filter assembly 152. The outlet cavity 180 is defined at least partially by the outlet surface 168 of the filter support element 144, the lower seal 160, and a groove 188 formed on the top side of the lower housing portion 112. Similar to the groove 184, the groove 188 has a generally frustoconical shape, tapering outward from the outlet 140. The truncated cone shape of groove 188 facilitates the flow of extrudate from outlet 180 to outlet 140. In other embodiments, groove 184 and / or groove 188 may be cylindrical or other shapes.

[0048] refer to Figure 5A The filter retainer 100 may also include a temperature regulating assembly 192. In the described embodiment, the central housing portion 116 includes a fluid inlet port 196 and a fluid outlet port 200. The fluid inlet port and outlet port 200 are in fluid communication with a generally annular volume 204 surrounding the filter support element 144. In the described embodiment, the filter support element 144 includes a peripheral groove 208, and the annular volume 204 is at least partially defined within the peripheral groove 208.

[0049] Temperature control assembly 192 may include a heating / cooling system, such as a heating / cooling bath connected to fluid inlet interface 196 and / or fluid outlet interface 200, or a fully integrated heating / cooling process temperature control system (e.g., The system circulates a heat exchange fluid through an annular volume 204, thereby effectively heating or cooling the filter support element 144. For example, in some embodiments, the temperature control assembly 192 includes a fluid circulator such as a pump 209 and a heat transfer system 210 including a heat exchanger or heating / cooling assembly 211 and a temperature control device 212. The heat exchange fluid may include air, water, ethylene glycol, refrigerant, etc. In some embodiments, the filter support element 144 may include recesses or other flow-influencing features in the peripheral groove 208 to generate turbulence in the flow of the heat exchange fluid, thereby enhancing convective heat transfer.

[0050] In some embodiments, the heat exchange system 210 may be omitted, and the filter support element 144 may be heated or cooled by natural convection of the heat exchange fluid. In some embodiments, heating / cooling may also be achieved by heating coils, heating belts, or heating blankets around the outer periphery of the filter holder, or by immersing the filter holder in a heating / cooling liquid / bath.

[0051] In other embodiments, the temperature regulating assembly 192 may be constructed differently. For example, in some embodiments, the temperature regulating assembly 192 may include a coil wound around and in thermal contact with the filter support element 144. Heat transfer fluid may be delivered through the coil to heat or cool the filter support element 144. In yet another embodiment, the filter retainer 100 may not include the temperature regulating assembly 192.

[0052] refer to Figure 5 In operation, the material to be extruded enters through inlet 136 of filter retainer 100 under elevated extrusion pressure (e.g., about 50-2,500 psi in some embodiments, or greater than 2,500 psi in some embodiments). The material to be extruded flows through inlet 136 and into inlet chamber 176, where it is dispersed in membrane filter assembly 152. Figure 5 The material is forced through the pores in the membrane filter under pressure, and the extruded material flows through channel 172 and into outlet 180. The extrudate flows out of outlet 180 through outlet 140 and out of filter retainer 100. Temperature control assembly 192 ( Figure 5A The temperature of the filter support element 144 can be adjusted by controlling the temperature and / or flow rate of the fluid.

[0053] The filter retainer 100 described and given herein advantageously makes high use of the membrane filter, which in turn reduces clogging and fouling of the membrane filter and also lowers extrusion pressure. Specifically, the inlet and outlet chambers 176, 180 improve filter application and reduce extrusion pressure. Unlike in existing filter support assemblies where communication with discrete channels 30 is present, the channels 172 of the filter retainer 100 open directly to the chambers 176, 180. Therefore, no clogging occurs in channel 172. In addition, channels 172 can be more numerous and / or larger in diameter than channels 18 in existing filter support assemblies (Figures 1-2). This configuration of channels 172 reduces flow resistance and further increases the area through which material can flow on the membrane filter assembly 152.

[0054] Filter support element 144 can be thicker than filter support disc 14 in existing filter support assemblies, thereby providing the strength necessary to withstand the high pressures experienced during extrusion. However, the concave outlet surface 168 of filter support element 144 minimizes the thickness and mass of filter support element 144 and also provides volume for outlet cavity 180. In some embodiments, filter retainer 100 is rated for pressures up to 2,500 psi. In some embodiments, filter retainer 100 may be rated for pressures greater than 2,500 psi.

[0055] Compared to filter retainer 10 under constant flow rate conditions, computational fluid dynamics simulation tests of filter retainer 100 demonstrate a significant improvement in filter utilization, but a significant decrease in extrusion pressure. The test results are listed in Table 1:

[0056] Table 1

[0057] Flow rate (mL / min) 100 100 Pressure (psig) 410 117 Application filter area 5％ 30％

[0058] Therefore, compared to filter retainer 10, filter retainer 100 increases the effective filter area by 500%, but reduces the extrusion pressure by 71%.

[0059] By increasing the effective filter area, the membrane filter assembly 152 can be used for a longer period without clogging or fouling. This reduces processing time and costs, and improves extrudate quality. Additionally, because the filter retainer 100 provides lower extrusion pressure and higher maximum operating pressure, more membrane filters can be stacked on top of each other. This increases the possibility of reducing extruder size and allows some products that typically require multiple passes through the extruder to be extruded in a single pass.

[0060] Figure 9 Another embodiment of the filter support element 344 is described. The filter support element 344 is configured as a filter support disk, which can replace the flat filter support disk of an existing filter holder, such as the filter support disk 14 of the filter holder 10 described above with reference to FIG1.

[0061] The described filter support element 344 includes an upstream side 346, a downstream side 347 opposite to the upstream side 346, and a plurality of channels 372 extending between the upstream side 346 and the downstream side 347. The upstream side 346 includes a filter support surface 364 configured to support a planar surface for the membrane filter. The downstream side 347 includes an outlet surface 368 opposite to the filter support surface 364, a central release tube 369, a plurality of radial channels 371 extending radially outward from the central release tube 369, and an annular channel 373 radially positioned between the central release tube 369 and the outer periphery of the filter support element 344.

[0062] The central release tube 369, radial channel 371, and annular channel 373 are interconnected and together define a lower recess 354 formed within the downstream side 347 of the filter support element 344. In other embodiments, the lower recess 354 may be defined by other combinations and / or arrangements of the channels formed within the downstream side 347 of the filter support element 344. The lower recess 354 at least partially defines the outlet cavity, which allows more channels 372 to flow through than the existing filter support disc 14, thus increasing the effective area of ​​the membrane filter, reducing clogging and fouling, and lowering the extrusion pressure. In some embodiments, the central release tube 369, radial channel 371, and annular channel 373 may be at least partially aligned with the channel 30 in the housing plate 26 (FIG. 1). In this embodiment, the outlet cavity is defined together by the lower recess 354 and the channel 30.

[0063] Figure 10 Another embodiment of the filter support element 444 is described. Similar to the reference above. Figure 9 The described filter support element 344 and filter support element 444 can be configured as a filter support disk, which can replace the flat filter support disk of an existing filter retainer, such as the filter support disk 14 of the filter retainer 10 (FIG. 1).

[0064] The described filter support element 444 includes an upstream side (not shown), a downstream side 447 opposite to the upstream side, and a plurality of channels 472 extending between the upstream and downstream sides 447. The upstream side includes a planar filter support surface configured to support the membrane filter. The downstream side 447 includes an outlet surface 468 opposite to the filter support surface. A plurality of spacers 475 are positioned opposite the downstream side 447. In the described embodiment, three spacers 475 are provided, but any number of spacers 475 can be used.

[0065] In some embodiments, spacer 475 may have a thickness of about 0.01-0.5 inches, in some embodiments about 0.02-0.3 inches, in some embodiments about 0.05-0.15 inches, or in some embodiments about 0.1 inches. Spacer 475 may preferably be sized such that filter support element 444 can still be accommodated within the recess 22 (FIG. 1) of the existing filter support 10. In the described embodiments, spacer 475 includes a channel 477 that may be aligned with and / or in fluid communication with the overlapping channel 472 in filter support element 444, but channel 477 may be omitted in other embodiments.

[0066] When the filter support element 444 is located within the recess 22 (FIG. 1) of the housing plate 26, the spacer 475 maintains a gap between the downstream side 447 of the filter support element 444 and the opposing surface of the recess 22. This gap provides an outlet for the downstream side 447 of the adjacent filter support element 444, thereby increasing the effective area of ​​the membrane filter, reducing clogging and fouling, and lowering the extrusion pressure.

[0067] Due to the above reference Figure 9 and 10 The described filter support elements 344, 444 maintain the disc construction of the existing filter support disc 14 (FIG. 1), and can be advantageously integrated into an existing filter retainer (such as filter retainer 10) to provide improved performance.

[0068] Tests on filter support elements 344 and 444 showed a pressure reduction compared to the existing filter support disc 14 due to the improved filter application. Water was pumped at a constant flow rate of 3 liters / minute through three membrane filters connected in series, each with a pore size of 100 nm. The tested filter support disc 14 and filter support elements 344 and 444 all have a nominal diameter of 293 mm. The results of this test are summarized in Table 2:

[0069] Table 2

[0070] Flow rate (L / min) 3 3 3 Pressure (psig) 430 330 190 Reduced stress - 23％ 56％

[0071] Therefore, compared to the filter support plate 14 in Figure 1, Figure 9 The filter support element 344 advantageously reduces the extrusion pressure by 23%, and compared to the filter support disc 14 of FIG1, the filter support element 444 advantageously reduces the extrusion pressure by 56%.

[0072] Figure 11 and 12 Another embodiment of the filter support element 544 is described. The filter support element 544 is similar to the filter support element 144, and the features of the filter support element 544 corresponding to the filter support element 144 described above are given by the same reference numerals.

[0073] refer to Figure 12The described filter support element 544 includes an upstream side 146 having an upper recess 148 and a filter support surface 164 within the upper recess 148. A downstream side 147 of the filter support element 544 includes a first lower recess 154a and a second lower recess 154b. The first lower recess 154a is centered on an axis L, and the second lower recess 154b surrounds the first lower recess 154a. An annular support wall 169 extends between the first lower recess 154a and the second lower recess 154b. The first lower recess 154a includes a first outlet surface 168a, and the second lower recess 154b includes a second outlet surface 168b.

[0074] In the described embodiment, the filter support surface 164 has a diameter or maximum width D1, which determines its dimensions to accommodate the membrane filter assembly 152. In the described embodiment, the diameter D1 is 293 mm, although the diameter D1 may vary in other embodiments. The first outlet surface 168a determines the maximum width D2, and the second outlet surface 168b determines the width D3. The outer diameter of the second outlet surface 168b determines the diameter D4. In the described embodiment, D2 is about 5.1 inches (or 129.4 mm), D3 is about 2.25 inches (or 57.2 mm), and D4 is about 10.84 inches (or 275.4 mm). Therefore, in the described embodiment, the D2:D4 ratio is about 1:2. In other embodiments, the D2:D4 ratio may be 1:1 to 1:5.

[0075] Multiple channels 172 extend between and pass through the filter support surface 164 and the first and second outlet surfaces 168a, 168b. Figure 8 In the embodiment described in B-8C, channel 172 extends parallel to the longitudinal axis L, but one or more channels 172 may extend at a non-zero angle relative to the longitudinal axis L. In the described embodiment, channel 172 does not extend through the annular support wall 169.

[0076] refer to Figure 11 The annular support wall 169 includes a plurality of planar support surfaces 171 alternately spaced by a plurality of radial channels 173. When the filter support element 544 is assembled with a filter retainer such as filter retainer 100, the support surfaces 171 engage the upper side of the lower housing portion 112. In some embodiments, the support wall 169 may be located at the midpoint of the radius of the filter support element 544. The additional support provided by the support wall 169 allows the filter support element 544 to be applied under high extrusion pressures without deformation. The radial channels 173 provide fluid flow channels from the second lower recess 154b to the first lower recess 154a.

[0077] Figure 13An extrusion system S according to one embodiment of the present invention is described. The described extrusion system S includes a plurality of filter holders 500 (as referenced above). Figure 3-8 The filter holder 100 described above and / or in combination with the above references Figure 9-12 The described filter retainer is one of the filter support elements 344, 444, and 544, and the filter retainer is fluidly disposed between a supply tank 504 containing the material to be extruded and a collection tank 508 disposed for receiving extrudate from the filter retainer 500. The described system S also includes a pressure source 512, such as a pump, operable to draw the material to be extruded from the supply tank 504 and pressurize the material to be extruded for distribution to the filter retainer 500.

[0078] The supply tank 504, collection tank 508, pressure source 512, and filter holder 500 can be interconnected via a fluid delivery assembly 514, which includes fluid delivery elements such as pipes, valves, pressure relief, sensing, and / or metering elements. Additionally, the extrusion system S may include one or more heat exchangers 515 for regulating the temperature of the material before and / or after extrusion. In the described embodiment, the filter holder 500 is connected in parallel between the supply tank 504 and the collection tank 508. Thus, each filter holder 500 can operate individually or simultaneously during the extrusion operation. This allows the system S to have a higher flow capacity compared to a system with a single filter holder 500. In other embodiments, one or more filter holders 500 can be connected in series. In this embodiment, a greater reduction in extrudate size can be achieved in a single pass.

[0079] Continue to refer to Figure 13 The described system S also includes a purge gas supply 516 and a pressure relief trap 520. The purge gas supply 516 may contain a pressurized gas such as air, nitrogen, carbon dioxide, argon, or any other gas suitable for removing material from the fluid delivery assembly 514 (e.g., for cleaning, maintenance, or other purposes). The pressure relief trap 520 may be configured to collect vented gas or liquid discharged from one or more pressure relief valves of the fluid delivery assembly 514.

[0080] The following embodiments describe a liposome extruder (“LIPEX1”) equipped with a prior art filter holder as shown in FIG1 and a filter holder embodying various aspects of the present invention (e.g. Figure 3 Improved performance of the liposome extruder (“LIPEX 2”) with a filter retainer. The embodiments were implemented using the same control variables on LIPEX 2 and LIPEX 1, which are of similar size.

[0081] These examples demonstrate that LIPEX 2 can extrude a given liposome formulation at significantly lower pressures, higher flow rates, and greater total throughput than LIPEX 1. The following procedure was repeated for extruders of various sizes (25 mm and 47 mm). The only control parameters varying between sizes were the recorded Multilamellar Vesicle (MLV) volume and the recorded flow rate. At each size, the lowest recorded flow rate represents the flow rate typically applied by those skilled in the art. The highest recorded flow rate represents a flow rate that is generally too high for most applications in the prior art, resulting in excessively high extrusion pressures and batch failures, as is often the case with LIPEX 1.

[0082] The lipid formulations described in the following examples comprise lecithin choline (EPC) and cholesterol in a 55:45 molar ratio, dissolved in anhydrous ethanol and hydrated with an ammonium sulfate-buffered aqueous solution to achieve a final concentration of 40 mg / mL. The selected formulations are chosen as examples only and should not be considered limiting.

[0083] Prepare a lipid solution (400 mg / mL EPC and cholesterol in anhydrous ethanol), stir, and heat at 50 °C. Prepare a separate buffer aqueous solution (250 mM ammonium sulfate), filter through a 0.2 / 0.45 μm Sartobran Size 4 filter, and add it to the lipid solution to obtain a final lipid MLV concentration of 40 mg / mL. Mix and heat the MLV solution at 50 °C for 5 minutes.

[0084] Install the following items onto the extruder's filter support in bottom-to-top order: 1 stainless steel support disc (LIPEX 1 only), 1 stainless steel support mesh, 1 polyester guide disc, and 1 polycarbonate membrane with 0.1μm etched marks. Connect the extruder to the piston pump via stainless steel pipes and fittings. Install a pressure gauge to monitor pressure measurements online.

[0085] Initial aliquots of the MLV solution were extracted and particle size was measured. The MLV stock solution was then pumped through an extruder and into a receiving container at a recorded flow rate for a single extrusion pass. Additional extrusion passes were performed at the recorded flow rate until a maximum of five total extrusion passes were completed, or until the extrusion pressure exceeded the extruder's maximum permissible operating pressure. If the pressure exceeded the extruder's maximum permissible operating pressure, the batch was considered a failure. After each pass, aliquots were extracted and particle size was measured. Pressure measurements were observed and recorded over recorded time increments.

[0086] Figure 14The extrusion pressures of the LIPEX 1 and LIPEX 2 extruders at a flow rate of 10 mL / min and a diameter of 47 mm were compared. The extrusion pressure of the LIPEX 2 was on average 119 PSI lower than that of the LIPEX 1, representing a 39% reduction in extrusion pressure.

[0087] Figure 15 The extrusion pressures of the LIPEX 1 and LIPEX 2 extruders with a flow rate of 20 mL / min and a diameter of 47 mm were compared. The extrusion pressure of the LIPEX 2 was on average 148 PSI lower than that of the LIPEX 1, representing a 44% reduction in extrusion pressure.

[0088] Figure 16 The extrusion pressures of the LIPEX 1 and LIPEX 2 extruders with a flow rate of 110 mL / min and a diameter of 47 mm were compared. The extrusion pressure of the LIPEX 2 was on average 298 PSI lower than that of the LIPEX 1, representing a 37% reduction in extrusion pressure.

[0089] Figure 17 The extrusion pressures of LIPEX 1 and LIPEX 2 extruders with a flow rate of 220 mL / min and a diameter of 47 mm were compared. LIPEX 1 resulted in batch failures because it could only extrude for 2 minutes before reaching the maximum operating pressure. However, LIPEX 2 was able to extrude in all 5 passes. The average extrusion pressure of LIPEX 2 was 627 PSI, which is the optimal extrusion pressure and well below the maximum operating pressure.

[0090] Figure 18 The extrusion pressures of LIPEX 1 and LIPEX 2 extruders at a flow rate of 5 mL / min and a diameter of 25 mm were compared. The extrusion pressure of LIPEX 2 was on average 15 PSI lower than that of LIPEX 1, representing an 11% reduction in extrusion pressure.

[0091] Figure 19 The extrusion pressures of LIPEX 1 and LIPEX 2 extruders at a flow rate of 25 mL / min and a diameter of 25 mm were compared. LIPEX 1 resulted in batch failures because it could not extrude even once at pressures not exceeding the extruder's maximum operating pressure. However, LIPEX 2 was able to extrude in all five passes. The average extrusion pressure of LIPEX 2 was 250 PSI, which is the optimal extrusion pressure and well below the maximum operating pressure.

[0092] In summary, all the above embodiments exhibited a significant reduction in extrusion pressure, which became even more pronounced with increasing flow rate and throughput. For extruder sizes of 25 mm and 47 mm, at high flow rates, LIPEX 2 was able to successfully extrude material in all 5 passes, while LIPEX 1 failed after 1-2 passes.

[0093] In another embodiment, flow simulation is performed to provide a direct comparison of the fluid dynamics between LIPEX 1 and LIPEX 2. Applications 3D, computer-aided design (CAD), and computational fluid dynamics (CFD) simulation software were used to simulate the fluid dynamics within the extruder. These embodiments simulated pumping water at a controlled flow rate through a similar experimental setup described in the above embodiments: an extruder equipped with a 1x stainless steel support plate (LIPEX 1 only), a 1x stainless steel support mesh, a 1x polyester guide plate, and a 1x polycarbonate membrane with 0.1μm etch marks. The resulting pressure drop across the filter membrane was observed and recorded.

[0094] The same method was applied to simulate each extruder. Water was chosen as the simulated fluid. The recorded volumetric flow rate at the extruder inlet and the static pressure at the extruder outlet were used as boundary conditions. The porous membrane characteristics, along with the pressure and flow rate data as described in the examples above, were used to simulate the 0.1 μm filter membranes applied in the above examples. The same filter membrane characteristics were applied to LIPEX 1 and LIPEX 2, allowing for direct comparison. Simulations were performed at each extruder size (25 mm, 47 mm, 90 mm, 142 mm, and 293 mm).

[0095] The filter membrane characteristics were extrapolated to extruders with diameters of 90 mm, 142 mm, and 293 mm. Because LIPEX 1 and LIPEX 2 use the same filter membrane characteristics, the resulting pressures can be evaluated, and confidence comparisons can be made between LIPEX 1 and LIPEX 2.

[0096] Table 3 below contains summary data for each flow simulation.

[0097] Table 3

[0098]

[0099] All simulations show that, compared to LIPEX 1, LIPEX 2 can extrude at a significantly lower extrusion pressure at a given flow rate. Conversely, this means that LIPEX 2 can extrude at higher flow rates than LIPEX 1 while maintaining a similar extrusion pressure. Furthermore, the simulation results support the discussion above. Figure 14-19 The test results in the example.

[0100] Although the invention has been described in detail with reference to some preferred embodiments, changes and modifications are still possible within the spirit and scope of one or more independent aspects of the invention described.

[0101] The various features of the present invention are described in the following claims.

[0102] The first item is a filter holder for liposome extrusion, comprising:

[0103] It has a housing with an inlet and an outlet for receiving the material to be extruded;

[0104] A filter support element is located between the inlet and outlet within the housing, the filter support element comprising:

[0105] It has an upstream side configured for supporting the filter support surface of the membrane filter assembly, and a downstream side relative to the upstream side, and

[0106] Multiple channels extending downstream from the filter support surface via filter support elements; and

[0107] The outlet cavity is connected to the outlet fluid.

[0108] The filter holder is constructed such that the material to be extruded flows through the membrane filter assembly and enters the outlet chamber through multiple channels, and is then discharged through the outlet.

[0109] The filter retainer of item 2 of item 1, wherein the housing includes an upper housing portion, a lower housing portion and a middle housing portion located between the upper housing portion and the lower housing portion, and wherein the middle housing portion surrounds the outer periphery of the filter support element.

[0110] The filter retainer of the third and second items, wherein the downstream side includes a first groove, wherein the lower housing portion includes a second groove, and wherein the first groove and the second groove at least partially define the outlet cavity.

[0111] The filter holder of item 4 of item 3, wherein the upper housing portion includes a groove, wherein the groove and the filter support surface at least partially define an inlet cavity, and wherein the plurality of channels are in fluid communication with the inlet cavity.

[0112] The filter holder of item 5, item 2, wherein the upper housing portion includes a groove, wherein the groove and the filter support surface at least partially define an inlet cavity, and wherein the plurality of channels are in fluid communication with the inlet cavity.

[0113] The filter holder of item 6, item 1, wherein at least one of the plurality of channels extends parallel to the longitudinal central axis of the housing.

[0114] The filter holder of any one of items 7-5, wherein at least one of the plurality of channels extends parallel to the longitudinal central axis of the housing.

[0115] The filter holder of item 8, item 1, wherein at least one of the plurality of channels extends at a non-zero degree angle relative to the longitudinal central axis of the housing.

[0116] The filter holder of any one of items 2-6 of item 9, wherein at least one of the plurality of channels extends at a non-zero degree angle relative to the longitudinal central axis of the housing.

[0117] The filter retainer of item 10, wherein the filter support element includes a peripheral groove.

[0118] The filter retainer of any one of items 2-6 or 8 of item 11, wherein the filter support element includes a peripheral groove.

[0119] The filter retainer of item 12 of item 11 also includes a temperature regulating component configured to circulate heat transfer fluid through the peripheral trench.

[0120] The filter retainer of item 13 of item 10 also includes a temperature regulating component configured to circulate heat transfer fluid through the peripheral trench.

[0121] The filter holder of item 14, paragraph 1, wherein the membrane filter assembly comprises a polycarbonate membrane with a pore size of 10 nm to 1 μm.

[0122] The filter retainer of any one of items 2-6, 8, 10 or 13 of item 15, wherein the membrane filter assembly comprises a polycarbonate membrane with a pore size of 10 nm to 1 μm.

[0123] The filter retainer of item 16, paragraph 1, wherein the downstream side includes a groove having a curved surface, and wherein the groove at least partially defines the outlet cavity.

[0124] The filter retainer of any one of items 2-6, 8, 10, 13 or 14 of item 17, wherein the downstream side includes a groove having a curved surface, and wherein the groove at least partially defines the outlet cavity.

[0125] The filter holder of item 18 and item 17, wherein the surface is a hemispherical surface.

[0126] The filter holder of item 19 and item 16, wherein the surface is a hemispherical surface.

[0127] The filter retainer of item 20, paragraph 1, wherein the filter support element includes a plurality of interconnected channels formed on its downstream side.

[0128] The filter retainer of any one of items 2-6, 8, 10, 13 or 14 of item 21, wherein the filter support element includes a plurality of interconnecting channels formed on its downstream side.

[0129] The filter retainer of item 22, paragraph 1, wherein the maximum width of the filter support surface is 5-600 mm.

[0130] The filter retainer of item 23, paragraph 1, wherein the maximum width of the filter support surface is 13-293 mm.

[0131] Item 24: A filter holder for liposome extrusion, comprising:

[0132] A housing with a defined longitudinal central axis, the housing comprising an inlet extending from an inlet cavity and an outlet extending from an outlet cavity; and

[0133] A filter support element is located between the inlet and outlet chambers within the housing, the filter support element comprising:

[0134] On the upstream side adjacent to the inlet cavity, the upstream side has a filter support surface for supporting the membrane filter assembly.

[0135] The downstream side adjacent to the outlet and opposite to the upstream side, and

[0136] Multiple channels extending from the upstream side through the filter support element to the downstream side,

[0137] The filter holder is constructed such that the material to be extruded flows through the membrane filter assembly and enters the outlet chamber through multiple channels, and is then discharged through the outlet.

[0138] The filter retainer of items 25 and 24, wherein the housing includes an upper housing portion, a lower housing portion and a middle housing portion located between the upper housing portion and the lower housing portion, and wherein the filter support element is located within the middle housing portion.

[0139] The filter holder of items 26 and 25, wherein the lower housing portion includes a lower recess that at least partially defines an outlet cavity, and wherein the upper housing portion includes an upper recess that at least partially defines an inlet cavity.

[0140] The filter retainer of items 27 and 25, wherein the lower housing portion includes a lower recess, and wherein the downstream side of the filter support element is flattened, such that the lower recess defines the outlet cavity.

[0141] The filter holder of items 28 and 24, wherein at least one of the plurality of channels extends at a non-zero degree angle relative to the longitudinal central axis.

[0142] The filter holder of any one of items 29 to 25-27, wherein at least one of the plurality of channels extends at a non-zero degree angle relative to the longitudinal central axis.

[0143] The filter retainer of items 30 and 24, wherein the housing includes a groove, wherein the filter support element is received within the groove, and wherein the filter retainer further includes a spacer located between the downstream side of the filter support element and the surface opposite to the groove.

[0144] The filter retainer of item 31, item 25 or 28, wherein the housing includes a groove, wherein the filter support element is received within the groove, and wherein the filter retainer further includes a spacer located between the downstream side of the filter support element and the surface opposite to the groove.

[0145] The filter retainer of items 32 and 24, wherein the downstream side of the filter support element includes a recess that at least partially defines the outlet cavity.

[0146] The filter retainer of item 33, 25, 26 or 28, wherein the downstream side of the filter support element includes a recess that at least partially defines the outlet cavity.

[0147] Item 34: An extrusion system comprising:

[0148] Supply tank containing the material to be extruded;

[0149] Set a pressure source to pressurize the material to be extruded and extract it from the storage tank;

[0150] Filter retainer, comprising:

[0151] It has a housing with an inlet for receiving pressurized material to be extruded and an outlet for discharging the extrudate.

[0152] The membrane filter assembly located between the inlet and outlet,

[0153] A filter support element located within the housing, the filter support element comprising:

[0154] It has an upstream side configured with a filter support surface for supporting the membrane filter assembly.

[0155] The downstream side, relative to the upstream side, includes a first groove, and

[0156] Multiple channels extending from the filter support surface through the filter support element to the first groove, and

[0157] An outlet cavity, at least partially defined by a first groove, which is in fluid communication with the outlet; and

[0158] A collection tank is provided for receiving the extrudate from the outlet of the filter retainer.

[0159] The extrusion system of items 35 and 34, wherein the filter retainer is one of a plurality of identical filter retainers connected in parallel to the supply tank and the collection tank.

[0160] The extrusion system of items 36 and 34, wherein the filter retainer is one of a plurality of identical filter retainers connected in series with the supply tank and the collection tank.

[0161] The extrusion system of items 37 and 34, wherein one or more heat exchangers are included between the supply tank and the collection tank.

[0162] The extrusion system of Item 38, Item 36 or 37, wherein one or more heat exchangers are included between the supply tank and the collection tank.

Claims

1. A filter holder for liposome extrusion, comprising: It has a housing with an inlet and an outlet for receiving the material to be extruded; A filter support element is located between the inlet and outlet within the housing, the filter support element comprising: It has an upstream side configured with a filter support surface for supporting the membrane filter assembly. Relative to the upstream side, the downstream side Multiple channels extending downstream from the filter support surface via filter support elements; and The outlet cavity is connected to the outlet fluid. The filter holder is configured such that the material to be extruded flows through the membrane filter assembly and enters the outlet chamber through multiple channels, and is then discharged through the outlet. The downstream side includes a first groove with a curved surface, and the first groove at least partially defines the outlet cavity.

2. The filter retainer of claim 1, wherein the housing comprises an upper housing portion, a lower housing portion, and a middle housing portion located between the upper housing portion and the lower housing portion, and wherein the middle housing portion surrounds the outer periphery of the filter support element.

3. The filter holder of claim 2, wherein the lower housing portion includes a second recess, and wherein the first recess and the second recess at least partially define the outlet cavity.

4. The filter holder of claim 2, wherein the upper housing portion includes a groove, wherein the groove and the filter support surface at least partially define an inlet cavity, and wherein the plurality of channels are in fluid communication with the inlet cavity.

5. The filter retainer according to any one of claims 1-4, wherein i) at least one of the plurality of channels extends parallel to the longitudinal central axis of the housing; and / or ii) At least one of the plurality of channels extends at a non-zero angle relative to the longitudinal central axis of the housing.

6. The filter retainer according to any one of claims 1-4, wherein the filter support element includes a peripheral groove.

7. The filter retainer of claim 6 further includes a temperature regulating component configured to circulate the heat transfer fluid through the peripheral trench.

8. The filter holder according to any one of claims 1-4, wherein the membrane filter assembly comprises a pore size of 10 nm to 1 nm. m polycarbonate film.

9. The filter holder according to any one of claims 1-4, wherein the surface of the first groove is a hemispherical surface.

10. The filter retainer according to any one of claims 1-4, wherein the filter support element includes a plurality of interconnected channels formed on its downstream side.

11. The filter retainer according to any one of claims 1-4, wherein the maximum width of the filter support surface is 5-600 mm.

12. The filter holder according to claim 11, wherein the maximum width of the filter support surface is 13-293 mm.

13. A filter holder for liposome extrusion, comprising: A housing with a defined longitudinal central axis, the housing comprising an inlet extending from an inlet cavity and an outlet extending from an outlet cavity; and A filter support element is located between the inlet and outlet chambers within the housing, the filter support element comprising: On the upstream side adjacent to the inlet cavity, the upstream side has a filter support surface for supporting the membrane filter assembly. The downstream side adjacent to the outlet and opposite to the upstream side, and Multiple channels extending from the upstream side through the filter support element to the downstream side, The filter holder is configured such that the material to be extruded flows through the membrane filter assembly and enters the outlet chamber through multiple channels, and is then discharged through the outlet. The downstream side of the filter support element includes a first groove with a curved surface, and the first groove at least partially defines the outlet cavity.

14. The filter holder of claim 13, wherein the housing comprises an upper housing portion, a lower housing portion, and a middle housing portion located between the upper housing portion and the lower housing portion, and wherein the filter support element is located within the middle housing portion.

15. The filter holder of claim 14, wherein the lower housing portion includes a lower recess that at least partially defines the outlet cavity, and wherein the upper housing portion includes an upper recess that at least partially defines the inlet cavity.

16. The filter retainer of claim 14, wherein the lower housing portion includes a lower recess, and wherein the downstream side of the filter support element is flattened, such that the lower recess defines an outlet cavity.

17. The filter holder according to any one of claims 13-16, wherein at least one of the plurality of channels extends at a non-zero degree angle relative to the longitudinal central axis.

18. The filter retainer according to any one of claims 13-16, wherein the housing includes a groove, wherein the filter support element is received within the groove, and wherein the filter retainer further includes a spacer located between the downstream side of the filter support element and the surface opposite to the groove.

19. An extrusion system comprising: Supply tanks containing materials to be extruded; Set a pressure source to pressurize the material to be extruded and extract it from the supply tank; Filter holder, comprising: It has a housing with an inlet for receiving pressurized material to be extruded and an outlet for discharging the extrudate. The membrane filter assembly located between the inlet and outlet, A filter support element located within the housing, the filter support element comprising: It has an upstream side configured with a filter support surface for supporting the membrane filter assembly. The downstream side, relative to the upstream side, includes a first groove having a curved surface. Multiple channels extending from the filter support surface through the filter support element to the first groove, An outlet cavity, at least partially defined by a first groove, which is in fluid communication with the outlet; and A collection tank is provided for receiving the extrudate from the outlet of the filter retainer.

20. The extrusion system of claim 19, wherein the filter retainer is one of a plurality of identical filter retainers fluidly connected in parallel or series to the supply tank and the collection tank.

21. The extrusion system according to claim 19 or 20, wherein one or more heat exchangers are included between the supply tank and the collection tank.

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