Filter holder for liposome extrusion

Abstract

The filter holder for a liposome extruder includes a housing having an inlet and an outlet configured to receive material to be extruded, and a filter support member disposed within the housing between the inlet and the outlet. The filter support member 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 passages extending through the filter support member from the filter support surface to the downstream side. The filter holder further includes an outlet cavity in fluid communication with the outlet, and the filter holder is configured so that the material to be extruded flows through the membrane filter assembly and into the outlet cavity via the plurality of passages before being discharged through the outlet.

Description

[Technical Field]

[0001] The present invention relates to a filter holder for extrusion, in particular for the extrusion of liposomes.

[0002] Background technology Liposome extruders can be used to produce small, uniformly sized lipid vesicles (or liposomes). For example, liposomes are most commonly made in a two-step process. First, a crude lipid or liposome suspension containing large, heterogeneous liposome aggregates is formed. Subsequently, a liposome extruder can be used to reduce the size of the lipid aqueous suspension by forcing it 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 as carriers of therapeutic agents, diagnostic agents, cosmetics, or nutraceuticals, among others, in pharmaceutical, diagnostic, cosmetic, and nutraceutical products. However, existing liposome extruders have several drawbacks. First, the pores of the membrane filter tend to clog, especially when large volumes are required for large-scale commercial production of liposome products or when working with concentrated lipid suspensions, which are necessary to maximize the amount of agent (e.g., therapeutic or diagnostic agent) that can be incorporated into the liposome carrier. Replacing each clogged membrane filter opens the extruder to the environment, potentially risking product contamination and exposing personnel and manufacturing equipment to potentially hazardous drugs (e.g., cytotoxic drugs that are commonly compounded into liposome carriers using the extrusion process). Thus, dealing with dirty or clogged membrane filters can require additional time and expense in the extrusion process and can compromise product quality.

[0003] The shortcomings of currently available liposome extruders are particularly severe when extruding certain types of lipids. Lipid bilayers are in a "rigid" gel phase below Tc, the gel-liquid crystal phase transition temperature, and in a "fluid" liquid crystalline state above Tc. Lipids with Tc values ​​above room temperature are particularly difficult to extrude through membrane filters, and the suspension may need to be heated above Tc. The Tc value for a particular lipid depends on several factors, including the length and degree of saturation of the lipid's hydrocarbon chain. Lipids with longer, more saturated hydrocarbon chains (so-called gel-like lipids) tend to have higher Tc values ​​above room temperature (and therefore tend to be more difficult to extrude through membrane filters) than lipids with shorter, less saturated hydrocarbon chains. Liposomes composed of gel-like lipids are the preferred drug carrier system for the intravenous administration of a wide variety of therapeutic agents. Commonly used gel-phase lipids in liposome formulations, such as hydrogenated soy phosphatidylcholine (HSPC) and distearoylphosphatidylcholine (DSPC), have Tc values ​​above 50°C and must be heated to 60–65°C (at least 10°C above Tc) for extrusion. As mentioned above, clogged or contaminated membranes must be replaced, increasing production costs and processing time. Prolonged exposure to high temperatures increases the likelihood of degradation of temperature-sensitive materials (lipids and liposome-associated materials), so increased processing time can also affect product quality.

[0004] The filter support structure in existing extruders exacerbates the problem of membrane filter clogging. An example of an existing filter holder 10 for a liposome extruder is shown in FIG. 1. The filter holder 10 includes an upper housing plate (or inlet plate), a lower housing plate (or outlet plate), and a flat filter support disk 14 having a plurality of passages 18 extending therethrough. The filter support disk 14 is disposed within a recess 22 in a lower housing plate 26. The recess 22 includes radially extending channels 30 extending from and communicating with a central outlet opening 34.

[0005] Existing filter holders, such as the filter holder 10 shown in FIG. 1, limit the effective surface area of ​​the membrane filter that can be utilized. For example, referring to FIG. 2, extruded material flows only through holes in the membrane filter adjacent to passages 18A in the filter support disk 14, which are aligned with channels 30. Little to no flow occurs through holes in the membrane filter adjacent to passages 18B, which are not aligned with channels 30. Material does not flow through the remaining surface area where the support plate rests flat on the lower housing plate. Therefore, only a small portion of the membrane filter's total surface area is actually utilized during extrusion. This accelerates fouling (the formation of material deposits on the filter and rapid pressure buildup) and membrane filter clogging, necessitating frequent filter replacement. Furthermore, the limited effective surface area results in lower throughput and higher extrusion pressures. As discussed above, both of these can increase processing time and affect product quality. Maximizing surface area utilization is important to reduce filter clogging and improve throughput and product quality.

[0006] overview According to one aspect of the present disclosure, a filter holder for a liposome extruder is provided, the filter holder comprising: a housing having an inlet configured to receive a material to be extruded; an outlet; and a filter support member disposed within the housing between the inlet and the outlet. The filter support member 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 passages extending through the filter support member from the filter support surface to the downstream side. The filter holder further includes an outlet cavity in fluid communication with the outlet, and the filter holder is configured such that the material to be extruded flows through the membrane filter assembly and into the outlet cavity via the plurality of passages before being discharged through the outlet.

[0007] In another aspect, the present disclosure provides a filter holder for a liposome extruder. The filter holder includes a housing defining a central longitudinal axis, the housing including an inlet extending from an inlet cavity and an outlet extending from an outlet cavity, and a filter support member disposed within the housing between the inlet and outlet cavities. The filter support member has a filter support surface configured to support a membrane filter assembly, the filter support member including an upstream side adjacent to the inlet cavity, a downstream side opposite the upstream side adjacent to the outlet cavity, and a plurality of passages extending therethrough from the upstream side to the downstream side. The filter holder is configured such that material to be extruded flows through the membrane filter assembly via the plurality of passages into the outlet cavity before being discharged through the outlet.

[0008] In another aspect, the present disclosure provides an extrusion system including a supply reservoir containing extruded material, a pressure source configured to pressurize the extruded material drawn from the reservoir, and a filter holder. The filter holder includes a housing having an inlet configured to receive the pressurized extruded material and an outlet configured to release the extrudate, a membrane filter assembly disposed between the inlet and the outlet, and a filter support member disposed within the housing. The filter support member includes an upstream side having a filter support surface configured to support the membrane filter assembly, a downstream side opposite the upstream side including a first recess, and a plurality of passages extending through the filter support member from the filter support surface to the first recess. The filter holder further includes an outlet cavity at least partially defined by the first recess. The outlet cavity is in fluid communication with the outlet. The extrusion system further includes a collection reservoir configured to receive extrudate from the outlet of the filter holder.

[0009] In some embodiments, multiple filter holders can be combined in parallel to increase throughput. If product heating is required, one or more heat exchangers may be included to help maintain and control the product temperature. Multiple extrusion passes can be performed by circulating the product from a feed vessel to a collection vessel and back again.

[0010] Other features and aspects of the present disclosure will become apparent by consideration of the following detailed description and accompanying drawings. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is an exploded view of a prior art filter holder. [Figure 2] FIG. 2 is a plan view showing the passages and channels of the filter holder of FIG. 1. [Figure 3] FIG. 1 is a perspective view of a filter holder according to one embodiment of the present disclosure. [Figure 4]FIG. 4 is an exploded view of the filter holder of FIG. 3. [Figure 5] FIG. 4 is a cross-sectional view of the filter holder of FIG. 3. [Figure 5A] FIG. 4 is a schematic diagram of the filter holder of FIG. 3 connected to a temperature adjustment assembly. [Figure 6] 4 is a perspective view showing the upper surface of a filter support member of the filter holder of FIG. 3. FIG. [Figure 7] 6 is a perspective view showing the bottom surface of the filter support member of FIG. 5. FIG. [Figure 8] FIG. 6 is a cross-sectional view of the filter support member of FIG. 5. [Figure 8A] FIG. 10 is a cross-sectional view of a filter support member according to another embodiment. [Figure 9] FIG. 10 is a perspective view of a filter support member according to another embodiment. [Figure 10] FIG. 10 shows a bottom view of a filter support member according to another embodiment. [Figure 11] FIG. 10 is a perspective view showing the bottom surface of a filter support member according to another embodiment. [Figure 12] FIG. 12 is a cross-sectional view of the filter support member of FIG. [Figure 13] FIG. 1 is a schematic diagram illustrating an extrusion system according to one embodiment of the present disclosure. [Figure 14] 1 is a graph comparing the extrusion pressure of a liposome extruder equipped with a prior art filter holder of FIG. 1 ("LIPEX1") and a liposome extruder equipped with a filter holder embodying an embodiment of the present disclosure, such as the filter holder of FIG. 3 ("LIPEX2"), at a flow rate of 10 mL / min using a 47 mm filter. [Figure 15] 1 is a graph comparing the extrusion pressure of LIPEX1 and LIPEX2 at a flow rate of 20 mL / min using a 47 mm filter. [Figure 16] 1 is a graph comparing the extrusion pressure of LIPEX1 and LIPEX2 at a flow rate of 110 mL / min using a 47 mm filter. [Figure 17] 1 is a graph comparing the extrusion pressure of LIPEX1 and LIPEX2 at a flow rate of 220 mL / min using a 47 mm filter. [Figure 18] This is a graph comparing the extrusion pressure of LIPEX1 and LIPEX2 at a flow rate of 5 mL / min using a 25 mm filter. [Figure 19] 1 is a graph comparing the extrusion pressure of LIPEX1 and LIPEX2 at a flow rate of 25 mL / min using a 25 mm filter.

[0012] Before describing any embodiments of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0013] Detailed Description FIG. 3 illustrates a filter holder 100 according to one exemplary embodiment of the present disclosure. The filter holder 100 may be configured for use with a liposome extruder, such as a LIPEX™ extruder, or other small-bore extruders that may be used in industries such as the pharmaceutical, nutraceutical, biotechnology, and cosmetics industries. The filter holder 100 includes a housing 104, which in the illustrated 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 and lower housing portions 108 and 112. The housing 104 is generally cylindrical and, in the illustrated embodiment, extends along a central longitudinal axis L ( FIG. 4 ). In alternative embodiments, the housing 104 may have other shapes and may include any number of housing portions.

[0014] Referring to FIG. 4 , the housing portions 108, 112, and 116 are coupled to one another by a plurality of fastener assemblies 120 (e.g., four fastener assemblies 120 in the illustrated embodiment). Each fastener assembly 120 includes a peg 124, a washer 128, and a nut 132. The pegs 124 extend from the lower housing portion 112 through the middle housing portion 116 and the upper housing portion 108. Each peg 124 has a first threaded end 124A and a second threaded end 124B opposite the first threaded end 124A. The nut 132 is threaded onto the first threaded end 124A of the peg 124, and the washer 128 is disposed between the nut 132 and the upper housing portion 108. The second threaded end 124B of the peg 124 is threaded into the lower housing portion 112. Thus, nuts 132 can be tightened to clamp housing portions 108, 112, 116 together, or loosened and / or removed from pegs 124 to allow for disassembly of housing 104 (e.g., for maintenance, filter replacement, etc.). In alternative embodiments, housing portions 108, 112, 116 may be secured together using other types and / or arrangements of fastener assemblies, threaded connections, tri-clamp connections, or any other suitable devices.

[0015] 3 and 4, filter holder 100 includes an inlet 136 for receiving extruded material (e.g., an aqueous suspension containing large, non-uniformly sized liposomes) and an outlet 140 for discharging extrudate (e.g., liposomes that are smaller and more uniformly sized than the liposomes prior to extrusion). In the illustrated embodiment, inlet 136 is located in upper housing portion 108, and outlet 140 is located in lower housing portion 112. Inlet 136 may include tubing or a sanitary tri-clamp connection, a threaded hole or peg, or any other suitable interface for receiving extruded material from a source such as a pump or pressure vessel. Inlet 136 may have a nominal outer diameter of about 0.25 inches to about 1.0 inches in some embodiments, or inlet 136 may have other nominal outer diameters, such as about 0.25 inches to about 2.5 inches, about 0.25 inches to about 5.0 inches, etc. Similarly, outlet 140 may include tubing or a sanitary tri-clamp connection, a threaded hole or a stake, or any other suitable interface for connection to a downstream reservoir or the like configured to receive the extrudate exiting filter holder 100. Outlet 140, in some embodiments, may have a nominal outer diameter of about 0.25 inches to about 1.0 inches, or outlet 140 may have other nominal outer diameters outside this range. In some embodiments, inlet 136 and outlet 140 may have the same diameter or different diameters.

[0016] 4 and 5, the intermediate housing portion 116 may surround and at least partially support the filter support member 144. In the illustrated embodiment, the filter support member 144 is concentrically supported within the intermediate housing portion 116. That is, the intermediate housing portion 116 surrounds the outer periphery of the filter support member 144. In some embodiments, the filter support member 144 may be integrally formed with the intermediate housing portion 116. In other embodiments, the filter support member 144 may be formed separately and secured to the intermediate housing portion 116 by welding, brazing, a threaded connection, or any other suitable means.

[0017] The illustrated filter support member 144 has an upstream side 146 facing the inlet 136 and a downstream side 147 opposite the upstream side 146 facing the outlet 140. The upstream side 146 has a first or upper recess 148 formed therein that is configured (i.e., sized and shaped) to receive a membrane filter assembly 152 ( FIG. 4 ). The membrane filter assembly 152 has a circular perimeter in the illustrated embodiment. However, in other embodiments, the shape of the membrane filter assembly 152 (and the corresponding shape of the upper recess 148) may be different. For example, in some embodiments, the membrane filter assembly 152 and upper recess 148 may be oval, square, hexagonal, etc.

[0018] Membrane filter assembly 152 may include one or more membrane filters having a diameter between 5 mm and 600 mm, preferably between 13 mm and 293 mm. For example, in certain embodiments, membrane filter assembly 152 may have a diameter of 13 mm, 25 mm, 47 mm, 90 mm, 142 mm, or 293 mm. Each of the one or more membrane filters in membrane filter assembly 152 may have a pore size of, for example, about 10 nanometers to about 1 micrometer. In some embodiments, each membrane filter may have a pore size between about 50 nanometers and about 200 nanometers. In some embodiments, each membrane filter may have a pore size of about 100 nanometers. Membrane filters according to such embodiments are particularly suitable for extrusion of liposomes. The membrane filters may be made of polycarbonate. In other embodiments, membrane filter assembly 152 may include one or more membrane filters made of other materials (e.g., polyethylene terephthalate, aluminum oxide, or any other suitable membrane material) and having other dimensions and / or pore sizes.

[0019] In some embodiments, the membrane filter assembly 152 may include a drain disk (e.g., a polyester drain disk) to provide support for the membrane filter within the membrane filter assembly 152, improve flow, and prevent shrinkage and tearing. In such embodiments, the membrane filter is disposed on top of the drain disk. Drain disks can also be inserted between multiple membrane filters. In some embodiments, the membrane filter and drain disk may be disposed on a filter support mesh or screen. Thus, the membrane filter assembly 152 includes at least one membrane filter and, optionally, one or more drain disks and / or filter support screens. This assembly is disposed within a first or upper recess 148 formed in the upstream side 146.

[0020] 5, the illustrated filter support member 144 further 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 member 144 and the upper housing portion 108, and a lower seal 160 surrounds the lower recess 154 at the interface between the filter support member 144 and the lower housing portion 112. In the illustrated embodiment, the upper seal 156 and the lower seal 160 are O-rings (e.g., formed from rubber or any other suitable elastomeric or non-elastomeric sealing material), although other types of seals may be used. The seals 156, 160 may be compressed between the filter support member 144 and the upper and lower housing portions 108, 112, respectively, when the housing 104 is assembled.

[0021] 6-8 , the illustrated filter support member 144 has a filter support surface 164 within the upper recess 148 and an outlet surface 168 within the 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, such that the outlet surface 168 may be substantially flush with the remainder of the filter support member 144 and / or mid-housing portion 116.

[0022] The filter support surface 164 has a diameter or maximum width D1 (FIG. 8) sized to accommodate the membrane filter assembly 152. For example, in some embodiments, the diameter D1 may be from about 5 mm to about 600 mm, preferably from about 13 mm to about 293 mm, to accommodate a membrane filter assembly 152 having a corresponding diameter. For example, in certain embodiments, the diameter D1 may be 13 mm, 25 mm, 47 mm, 90 mm, 142 mm, or 293 mm. In the illustrated embodiment, the filter support surface 164 is planar. However, in other embodiments, the filter support surface 164 may be non-planar (e.g., concave or convex).

[0023] Exit surface 168 defines a maximum width D2, which in some embodiments may be from about 0.5 inches (or 12.7 mm) to about 15 inches (or 381 mm). In the illustrated embodiment, exit surface 168 is a curved concave surface. Exit surface 168 may also be, for example, hemispherical, dished, ellipsoidal, or frustoconical. In other embodiments, exit surface 168 may be flat.

[0024] A plurality of passages 172 extend through and between surfaces 164, 168. In some embodiments, filter support member 144 includes between 4 and 3,000 passages 172. In the embodiment shown in FIG. 8, passages 172 extend parallel to longitudinal axis L. In another embodiment, shown in FIG. 8A, one or more of passages 172 may extend at a non-zero angle relative to longitudinal axis L. For example, one or more of passages 172 may extend at an angle of about 5 degrees to about 60 degrees relative to longitudinal axis L in some embodiments, or at an angle of about 10 degrees in some embodiments. In the embodiment shown in FIG. 8A, outlet surface 168 has a maximum width D2 that is less than diameter D1 of filter support surface 164. In other embodiments, outlet surface 168 has a maximum width D2 that is greater than or equal to diameter D1 of filter support surface 164.

[0025] 8 and 8A, each passageway 172 is cylindrical with a constant diameter Dp of about 0.0625 inches (or 1.59 mm) to about 0.25 inches (or 6.35 mm). In another embodiment, the diameter Dp of each passageway 172 may be about 0.125 inches (or 3.175 mm). Each passageway 172 may have the same diameter Dp, or different passageways 172 of the plurality of passageways 172 may have different diameters Dp. In yet another embodiment, one or more of the passageways 172 may have a variable diameter Dp (e.g., so that the passageway 172 may have a conical shape).

[0026] Filter support member 144, in some embodiments, has a minimum thickness T of about 0.125 inches (or 3.175 mm) to about 5 inches (or 127 mm). Thickness T is sized to provide filter support member 144 with sufficient strength to withstand the pressures applied to filter support member 144 during extrusion. The curved design of outlet face 168 advantageously provides high strength to filter support member 144 while minimizing thickness T. This can reduce weight and footprint, thereby increasing ease of handling in large, commercial-scale extrusion equipment, especially for applications requiring high extrusion pressures in the range of several thousand psi.

[0027] 5 , the inlet 136 is in fluid communication with an inlet cavity 176 adjacent the upstream side 146 of the filter support member 144, and the outlet 140 is in fluid communication with an outlet or drain cavity 180 adjacent the downstream side 147 of the filter support member 144. In the illustrated embodiment, the inlet cavity 176 is defined, at least in part, by the filter support surface 164, the upper seal 156, and a recess 184 formed in the lower surface of the upper housing portion 108. In the illustrated embodiment, the recess 184 has a generally frustoconical shape that tapers outward from the inlet 136. The frustoconical shape of the recess 184 may aid in distributing extruded material over the surface of the membrane filter assembly 152. The outlet cavity 180 is defined, at least in part, by the outlet surface 168 of the filter support member 144, the lower seal 160, and a recess 188 formed in the upper surface of the lower housing portion 112. Like recess 184, recess 188 has a generally frusto-conical shape that tapers outward from outlet 140. The frusto-conical shape of recess 188 can facilitate the flow of extrudate from outlet cavity 180 to outlet 140. In alternative embodiments, recess 184 and / or recess 188 can be cylindrical or have other shapes.

[0028] 5A, the filter holder 100 may further include a temperature adjustment assembly 192. In the illustrated embodiment, the intermediate housing portion 116 includes a fluid inlet port 196 and a fluid outlet port 200. The fluid inlet and outlet ports 200 are in fluid communication with a generally annular volume 204 that surrounds the filter support member 144. In the illustrated embodiment, the filter support member 144 has a circumferential groove 208, with the annular volume 204 being at least partially defined within the circumferential groove 208.

[0029] The temperature regulation assembly 192 may include a heating / cooling system, such as a heating / cooling bath or a fully integrated heating / cooling process temperature control system (e.g., a Mokon™ system), connected to the fluid inlet port 196 and / or fluid outlet port 200 to circulate a heat transfer fluid through the annular volume 204, thereby efficiently heating or cooling the filter support member 144. For example, in some embodiments, the temperature regulation assembly 192 includes a fluid circulator, such as a pump 209, and a heat transfer system 210 including a heat exchanger or heating / cooling group 211 and a temperature controller 212. The heat transfer fluid may include air, water, glycol, refrigerant, etc. In some embodiments, the filter support member 144 may include indentations or other flow-affecting features in the circumferential grooves 208, which create turbulence within the flow of the heat transfer fluid, thereby enhancing heat transfer by convection.

[0030] In some embodiments, the heat transfer system 210 may be omitted and the filter support member 144 may be heated or cooled by a heat transfer fluid via natural convection. In some embodiments, heating / cooling may also be achieved by a heating coil or band or heat blanket wrapped around the periphery of the filter holder, or by immersing the filter holder in a heating / cooling liquid / bath.

[0031] Temperature adjustment assembly 192 may be configured differently in other embodiments. For example, in some embodiments, temperature adjustment assembly 192 may include a coil wrapped around and in thermally conductive contact with filter support member 144. A heat transfer fluid may be conveyed through the coil to heat or cool filter support member 144. In yet other embodiments, filter holder 100 may not include a temperature adjustment assembly 192.

[0032] Referring to FIG. 5, during operation, the material to be extruded enters filter holder 100 through inlet 136 at an elevated extrusion pressure (e.g., in some embodiments, from about 50 psi to about 2500 psi, or in some embodiments, greater than 2500 psi). From inlet 136, the extruded material flows into inlet cavity 176, where it is dispersed across membrane filter assembly 152 (FIG. 5). The material is forced under pressure through the pores in the membrane filter, and the extrudate flows through passageway 172 and into outlet cavity 180. From outlet cavity 180, the extrudate exits filter holder 100 through outlet 140. A temperature regulation assembly 192 (FIG. 5A) can regulate the temperature of filter support member 144 by controlling the temperature and / or flow rate of a temperature-control fluid.

[0033] The filter holder 100 described and illustrated herein advantageously provides high membrane filter utilization, which reduces clogging and fouling of the membrane filter and further reduces extrusion pressures. In particular, the inlet and outlet cavities 176, 180 provide improved filter utilization and reduced extrusion pressures. Rather than communicating with separate channels 30 as in existing filter support assemblies, the passages 172 of the filter holder 100 open directly into the cavities 176, 180. Thus, none of the passages 172 are blocked. Additionally, the passages 172 may be more numerous and / or larger in diameter than the passages 18 ( FIGS. 1-2 ) in existing filter support assemblies. This configuration of the passages 172 reduces flow resistance and further increases the area on the membrane filter of the membrane filter assembly 152 through which material can flow.

[0034] The filter support member 144 can be thicker than the filter support disk 14 in existing filter support assemblies to provide the necessary strength to withstand the high pressures experienced during extrusion. However, the concave outlet face 168 of the filter support member 144 minimizes the thickness and mass of the filter support member 144 while also providing volume for the outlet cavity 180. In some embodiments, the filter holder 100 can be rated for pressures up to 2500 psi. In some embodiments, the filter holder 100 can be rated for pressures greater than 2500 psi.

[0035] Computational fluid dynamics simulation testing of filter holder 100 showed significantly improved filter utilization and reduced extrusion pressure compared to filter holder 10 at constant flow rate. Test results are shown in Table 1: [Table 1] Thus, filter holder 100 had a 500% increase in effective filter area and a 71% decrease in extrusion pressure compared to filter holder 10.

[0036] By increasing the effective filter area, the membrane filters of the membrane filter assembly 152 can be used for longer periods without clogging or fouling. This can reduce processing time and costs and improve extrudate quality. Furthermore, due to the lower extrusion pressures and the higher maximum operating pressure provided by the filter holder 100, more membrane filters can be stacked on top of each other. This can increase the extruder size reduction potential, allowing certain products that would otherwise require multiple passes through the extruder to be extruded in a single pass.

[0037] 9 illustrates another embodiment of a filter support member 344. The filter support member 344 is configured as a filter support disk that can replace a flat filter support disk in an existing filter holder, such as the filter support disk 14 of the filter holder 10 described above with respect to FIG.

[0038] The illustrated filter support member 344 has an upstream side 346, a downstream side 347 opposite the upstream side 346, and a plurality of passages 372 extending between the upstream side 346 and the downstream side 347. The upstream side 346 includes a planar filter support surface 364 configured to support a membrane filter. The downstream side 347 has an outlet face 368 opposite the filter support surface 364, a central relief 369, a plurality of radial channels 371 extending radially outward from the central relief 369, and an annular channel 373 radially disposed between the central relief 369 and the outer periphery of the filter support member 344.

[0039] The central relief 369, the radial channels 371, and the annular channel 373 are interconnected and collectively define a lower recess 354 formed on the downstream side 347 of the filter support member 344. In alternative embodiments, the lower recess 354 may be defined by other combinations and / or arrangements of channels formed on the downstream side 347 of the filter support member 344. The lower recess 354 at least partially defines an outlet cavity, which allows flow through a greater number of passages 372 than existing filter support disks 14, thereby increasing the effective area of ​​the membrane filter, reducing clogging and fouling, and reducing extrusion pressures. In some embodiments, the central relief 369, the radial channels 371, and the annular channel 373 may be at least partially aligned with the channel 30 ( FIG. 1 ) in the housing plate 26. In such embodiments, the outlet cavity may be collectively defined by the lower recess 354 and the channel 30.

[0040] Figure 10 illustrates another embodiment of a filter support member 444. Similar to filter support member 344 described above with reference to Figure 9, filter support member 444 is configured as a filter support disk that can replace a planar filter support disk in an existing filter holder, such as filter support disk 14 of filter holder 10 (Figure 1).

[0041] The illustrated filter support member 444 has an upstream side (not shown), a downstream side 447 opposite the upstream side, and a plurality of passages 472 extending between the upstream side and the downstream side 447. The upstream side includes a flat filter support surface configured to support a membrane filter. The downstream side 447 includes an outlet face 468 opposite the filter support surface. A plurality of spacers 475 are disposed relative to the downstream side 447. In the illustrated embodiment, three spacers 475 are provided, although other numbers of spacers 475 may be used.

[0042] Spacer 475 may have a thickness in some embodiments of about 0.01 inches to about 0.5 inches, in some embodiments of about 0.02 inches to about 0.3 inches, in some embodiments of about 0.05 to about 0.15 inches, or in some embodiments, about 0.1 inches. Spacer 475 is preferably sized so that filter support member 444 can still be accommodated within recess 22 (FIG. 1) of existing filter support 10. In the illustrated embodiment, spacer 475 has passages 477, which may be aligned with and / or in fluid communication with overlapping passages 472 in filter support member 444. However, passages 477 may be omitted in other embodiments.

[0043] When filter support member 444 is placed in recess 22 (FIG. 1) of housing plate 26, spacer 475 maintains a gap between downstream side 447 of filter support member 444 and the opposing surface of recess 22. This gap provides an outlet cavity adjacent downstream side 447 of filter support member 444, which increases the effective area of ​​the membrane filter, reduces clogging and fouling, and reduces extrusion pressures.

[0044] Because the filter support members 344, 444 described above with reference to Figures 9 and 10 maintain the disk configuration of the existing filter support disk 14 (Figure 1), the filter support member 444 can advantageously be retrofitted into existing filter holders, such as filter holder 10, to provide improved performance.

[0045] Testing of filter support members 344 and 444 demonstrated improved pressure reduction due to filter utilization compared to the existing filter support disk 14. Water was pumped at a constant flow rate of 3 liters per minute through a series of three membrane filters, each with a pore size of 100 nanometers. The tested filter support disk 14 and filter support members 344 and 444 each had a nominal diameter of 293 mm. The test results are shown in Table 2: [Table 2]

[0046] Thus, filter support member 344 of FIG. 9 advantageously provided a 23% reduction in extrusion pressure compared to filter support disk 14 of FIG. 1, and filter support member 444 advantageously provided a 56% reduction in extrusion pressure compared to filter support disk 14 of FIG. 1.

[0047] 11 and 12 illustrate another embodiment of a filter support member 544. Filter support member 544 is similar to filter support member 144, and features of filter support member 544 that correspond to features of filter support member 144 described above are labeled with the same reference numerals.

[0048] 12, the illustrated filter support member 544 includes an upstream side 146 having an upper recess 148 and a filter support surface 164 within the upper recess 148. The downstream side 147 of the filter support member 544 includes a first lower recess 154a and a second lower recess 154b. The first lower recess 154a is centered along 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 has a first outlet face 168a, and the second lower recess 154b has a second outlet face 168b.

[0049] In the illustrated embodiment, the filter support surface 164 has a diameter or maximum width D1 sized to accommodate the membrane filter assembly 152. In the illustrated embodiment, the diameter D1 is 293 mm, although in other embodiments, the diameter D1 may vary. The first outlet surface 168a defines a maximum width D2, and the second outlet surface 168b defines a width D3. The outer diameter of the second outlet surface 168b defines a diameter D4. In the illustrated embodiment, D2 is approximately 5.1 inches (or 129.4 mm), D3 is approximately 2.25 inches (or 57.2 mm), and D4 is approximately 10.84 inches (or 275.4 mm). Thus, in the illustrated embodiment, the ratio of D2:D4 is approximately 1:2. In other embodiments, the ratio of D2:D4 may be between 1:1 and 1:5.

[0050] A plurality of passages 172 extend through and between the filter support surface 164 and the first and second outlet surfaces 168a, 168b. In the embodiment shown in FIG. 12 , the passages 172 extend parallel to the longitudinal axis L, although one or more passages 172 may extend at a non-zero angle relative to the longitudinal axis L. In the illustrated embodiment, the passages 172 do not extend through the annular support wall 169.

[0051] 11 , annular support wall 169 has a plurality of flat support surfaces 171 separated by a plurality of radial channels 173. When filter support member 544 is assembled into a filter holder, such as filter holder 100, support surfaces 171 engage the upper surface of lower housing portion 112. In some embodiments, support wall 169 may be located at the midpoint of the radius of filter support member 544. The additional support provided by support wall 169 allows filter support member 544 to be used without deformation under high extrusion pressures. Radial channels 173 provide a fluid flow path from second lower recess 154b to first lower recess 154a.

[0052] 13 illustrates an extrusion system S according to one embodiment of the present disclosure. The illustrated extrusion system S includes a plurality of filter holders 500, such as filter holders 100 described above with respect to FIGS. 3-8 and / or filter holders incorporating one of the filter support members 344, 444, 544 described above with respect to FIGS. 9-12, fluidly disposed between a supply reservoir 504 containing the material to be extruded and a collection reservoir 508 configured to receive extrudate from the filter holders 500. The illustrated system S also includes a pressure source 512, such as a pump, operable to draw the material to be extruded from the supply reservoir 504 and pressurize the extruded material for dispensing to the filter holders 500.

[0053] The supply reservoir 504, collection reservoir 508, pressure source 512, and filter holder 500 are interconnected by a fluid transfer assembly 514, which includes fluid transfer components such as piping, valves, pressure release, sensing, and / or metering components. Additionally, the extrusion system S may include one or more heat exchangers 515 for adjusting the temperature of the material before and / or after extrusion. In the illustrated embodiment, the filter holders 500 are connected in parallel between the supply reservoir 504 and the collection reservoir 508. Thus, each filter holder 500 can be operated individually or simultaneously during the extrusion operation. This provides the system S with a greater throughput capacity compared to a system with a single filter holder 500. In another embodiment, one or more filter holders 500 may be connected in series. In such an embodiment, a greater size reduction in the extrudate can be achieved in a single pass.

[0054] 13, the illustrated system S further includes a purge gas supply 516 and a pressure relief capture vessel 520. The purge gas supply 516 may include a pressurized gas, such as air, nitrogen, carbon dioxide, argon, or any other gas suitable for removing material from the fluid transfer assembly 514 (e.g., for cleaning purposes, maintenance, etc.). The pressure relief capture vessel 520 may be configured to receive exhaust gas or liquid released from one or more pressure relief valves of the fluid transfer assembly 514.

[0055] The following examples demonstrate the improved performance of a liposome extruder equipped with a prior art filter holder of Figure 1 ("LIPEX1") and a liposome extruder equipped with a filter holder embodying aspects of the present disclosure ("LIPEX2"), such as the filter holder of Figure 3. These examples were performed using the same control variables on both LIPEX2 and LIPEX1 of comparable size.

[0056] These examples demonstrate that LIPEX2 can extrude a given liposome formulation at significantly lower pressures, higher flow rates, and greater total throughput than LIPEX1. The following procedure was repeated for each extruder size (25 mm and 47 mm). The only controlled parameters that were changed between sizes were the reported multilamellar vesicle (MLV) volume and the reported flow rate. For each size, the lowest reported flow rate represents a flow rate that would typically be used by those skilled in the art. The relatively high reported flow rates represent flow rates that are generally too high for most applications using LIPEX1, which in the prior art would result in too high an extrusion pressure and consequent batch error.

[0057] The lipid formulation described in the following examples contains egg phosphatidylcholine (EPC) and cholesterol in a 55:45 mole % ratio, dissolved in absolute ethanol, and hydrated with aqueous ammonium sulfate buffer to a final concentration of 40 mg / mL. The formulation selected is chosen by way of example only and should not be considered limiting.

[0058] A lipid solution (400 mg / mL EPC and cholesterol in absolute ethanol) was prepared, stirred, and heated at 50°C. A separate aqueous buffer solution (250 mM ammonium sulfate) was prepared, filtered through a 0.2 / 0.45 μm Sartobran Size 4 filter, and added to the lipid solution to give a final lipid MLV concentration of 40 mg / mL. The MLV solution was mixed and heated at 50°C for 5 minutes.

[0059] The following items were placed on the extruder filter support, from bottom to top: one stainless steel support disk (LIPEX1 only), one stainless steel support screen, one polyester drain disk, and one 0.1 μm track-etched polycarbonate membrane. The extruder was connected to a piston pump via stainless steel tubing and fittings. A pressure gauge was installed in-line to monitor pressure measurements.

[0060] An initial aliquot of the MLV solution was taken and measured for particle size. The MLV stock solution was then pumped from the extruder to a receiving container at the reported flow rate for one extrusion pass. Additional extrusion passes were performed at the reported flow rate until up to five total extrusion passes were completed or until the extrusion pressure exceeded the maximum allowable operating pressure of the extruder. If the pressure exceeded the maximum allowable operating pressure of the extruder, the batch was considered an error. Aliquots were taken after each pass and measured for particle size. Pressure measurements were observed and recorded at the reported time increments.

[0061] Figure 14 shows a comparison of extrusion pressure between the 47 mm LIPEX1 and LIPEX2 extruders at a flow rate of 10 mL / min. The extrusion pressure of LIPEX2 was on average 119 PSI lower than LIPEX1, which is a 39% reduction in extrusion pressure.

[0062] Figure 15 shows a comparison of extrusion pressure between the 47 mm LIPEX1 and LIPEX2 extruders at a flow rate of 20 mL / min. The extrusion pressure of LIPEX2 was on average 148 PSI lower than LIPEX1, which is a 44% reduction in extrusion pressure.

[0063] Figure 16 shows a comparison of extrusion pressure between the 47 mm LIPEX1 and LIPEX2 extruders at a flow rate of 110 mL / min. The extrusion pressure of LIPEX2 was on average 298 PSI lower than LIPEX1, which is a 37% reduction in extrusion pressure.

[0064] Figure 17 shows a comparison of extrusion pressure between the 47 mm LIPEX1 and LIPEX2 extruders at a flow rate of 220 mL / min. LIPEX1 was only able to extrude for 2 minutes before the pressure exceeded the maximum operating pressure, resulting in a batch error. However, LIPEX2 was able to extrude in all five passes. The extrusion pressure for LIPEX2 averaged 627 PSI, which is the best extrusion pressure and is well below the maximum operating pressure.

[0065] Figure 18 shows a comparison of extrusion pressure between the 25 mm LIPEX1 and LIPEX2 extruders at a flow rate of 5 mL / min. The extrusion pressure of LIPEX2 was on average 15 PSI lower than LIPEX1, which is an 11% reduction in extrusion pressure.

[0066] Figure 19 shows a comparison of extrusion pressures between the 25 mm LIPEX1 and LIPEX2 extruders at a flow rate of 25 mL / min. LIPEX1 failed to extrude in more than two passes without the pressure exceeding the extruder's maximum operating pressure, resulting in a batch failure. However, LIPEX2 was able to extrude in all five passes. The extrusion pressure for LIPEX2 averaged 250 PSI, which is the best extrusion pressure and is well below the maximum operating pressure.

[0067] In summary, all of the above examples showed a clear decrease in extrusion pressure, which became even more pronounced as flow rate and throughput increased. For both the 25 mm and 47 mm extruder sizes at high flow rates, LIPEX2 was able to successfully extrude material through all five passes, while LIPEX1 consistently failed after one to two passes.

[0068] In another example, flow simulations were performed to directly compare the fluid dynamics between LIPEX1 and LIPEX2. SOLIDWORKS™ 3D, a mechanical computer-aided design (CAD) and computational fluid dynamics (CFD) simulation software, was used to simulate the fluid dynamics inside the extruder. These examples simulated water being pumped at a controlled flow rate through an equivalent experimental setup to that shown in the previous example: the extruder contained one stainless steel support disk (LIPEX1 only), one stainless steel support screen, one polyester drain disk, and one inserted 0.1 μm track-etched polycarbonate membrane. The resulting pressure drop across the filter membrane was observed and reported.

[0069] Simulations for each extruder were set up using the same method. Water was selected as the simulation liquid. The reported volumetric flow rate at the extruder inlet and static pressure at the extruder outlet were applied as boundary conditions. A 0.1 μm filter membrane, like the one used in the previous examples, was simulated using the SOLIDWORKS™ porous membrane feature, along with the pressure vs. flow rate data from the previous examples. The same filter membrane properties were used for LIPEX1 and LIPEX2, allowing direct comparisons. Simulations were performed for each extruder size (25 mm, 47 mm, 90 mm, 142 mm, and 293 mm).

[0070] The filter membrane properties were extrapolated for the 90 mm, 142 mm, and 293 mm extruders. Because the same filter membrane properties were used for LIPEX1 and LIPEX2, the generated pressures could be evaluated and reliably compared between LIPEX1 and LIPEX2.

[0071] Table 3 below contains summary data for each flow simulation: [Table 3]

[0072] All simulations showed that LIPEX 2 could be extruded at a significantly lower extrusion pressure at a given flow rate compared to LIPEX 1. Conversely, this means that LIPEX 2 could be extruded at a much higher flow rate than LIPEX 1 while maintaining the same extrusion pressure. Furthermore, the simulation results support the experimental results in the examples shown in Figures 14 to 19.

[0073] Although the invention has been described in detail with reference to certain preferred embodiments, variations and modifications exist within the scope and spirit of one or more independent aspects of the invention described.

[0074] Various features of the invention are set forth in the following claims.

[0075] Clause 1. A filter holder for a liposome extruder, the filter holder comprising: a housing including an inlet configured to receive the material to be extruded, and an outlet; a filter support member disposed within the housing between the inlet and the outlet, the filter support member comprising: an upstream side having a filter support surface configured to support the membrane filter assembly; the downstream side opposite the upstream side, and a filter support member including a plurality of passages extending through the filter support member downstream from the filter support surface; an outlet cavity in fluid communication with the outlet; In a filter holder having The filter holder is configured to allow extruded material to flow through the membrane filter assembly and into the outlet cavity via a plurality of passageways before being discharged through the outlet.

[0076] Clause 2. The filter holder of clause 1, wherein the housing includes an upper housing portion, a lower housing portion, and an intermediate housing portion between the upper and lower housing portions, the intermediate housing portion surrounding an outer periphery of the filter support member.

[0077] Clause 3. The filter holder of clause 2, wherein the downstream side includes a first recess and the lower housing portion includes a second recess, the first recess and the second recess at least partially defining the outlet cavity.

[0078] Clause 4. The filter holder of clause 3, wherein the upper housing portion includes a recess, the recess and the filter support surface at least partially defining an inlet cavity, and the plurality of passageways are in fluid communication with the inlet cavity.

[0079] Clause 5. The filter holder of clause 2, wherein the upper housing portion includes a recess, the recess and the filter support surface at least partially defining an inlet cavity, and the plurality of passageways are in fluid communication with the inlet cavity.

[0080] Clause 6. The filter holder of clause 1, wherein at least one of the plurality of passages extends parallel to a central longitudinal axis of the housing.

[0081] Clause 7. The filter holder of any one of clauses 2 to 5, wherein at least one of the plurality of passages extends parallel to a central longitudinal axis of the housing.

[0082] Clause 8. The filter holder of clause 1, wherein at least one of the plurality of passages extends at a non-zero angle relative to a central longitudinal axis of the housing.

[0083] Clause 9. The filter holder of any one of clauses 2 to 6, wherein at least one of the plurality of passages extends at a non-zero angle relative to a central longitudinal axis of the housing.

[0084] Clause 10. The filter holder of clause 1, wherein the filter support member has a circumferential groove.

[0085] Clause 11. The filter holder of any one of clauses 2 to 6 or 8, wherein the filter support member has a circumferential groove.

[0086] Clause 12. The filter holder of clause 11, further comprising a temperature regulation assembly configured to circulate a heat transfer fluid through the circumferential groove.

[0087] Clause 13. The filter holder of clause 10, further comprising a temperature regulation assembly configured to circulate a heat transfer fluid through the circumferential groove.

[0088] Clause 14. The filter holder of clause 1, wherein the membrane filter assembly includes a polycarbonate membrane having a pore size between 10 nanometers and 1 micrometer.

[0089] Clause 15. The filter holder of any one of clauses 2 to 6, 8, 10, or 13, wherein the membrane filter assembly includes a polycarbonate membrane having a pore size of 10 nanometers to 1 micrometer.

[0090] Clause 16. The filter holder of clause 1, wherein the downstream side includes a recess having a curved surface, the recess at least partially defining the outlet cavity.

[0091] Clause 17. The filter holder of any one of clauses 2 to 6, 8, 10, 13, or 14, wherein the downstream side includes a recess having a curved surface, the recess at least partially defining the outlet cavity.

[0092] Clause 18. The filter holder of clause 17, wherein the curved surface is hemispherical.

[0093] Clause 19. The filter holder of clause 16, wherein the curved surface is hemispherical.

[0094] Clause 20. The filter holder of clause 1, wherein the filter support member has a plurality of interconnected channels formed on a downstream side of the filter support member.

[0095] Clause 21. The filter holder of any one of clauses 2 to 6, 8, 10, 13, and 14, wherein the filter support member has a plurality of interconnected channels formed on a downstream side of the filter support member.

[0096] Clause 22. The filter holder of clause 1, wherein the filter support surface has a maximum width of 5 mm to 600 mm.

[0097] Clause 23. The filter holder of clause 1, wherein the filter support surface has a maximum width of 13 mm to 293 mm.

[0098] Clause 24. A filter holder for a liposome extruder, the filter holder comprising: a housing defining a central longitudinal axis, the housing including an inlet extending from an inlet cavity and an outlet extending from an outlet cavity; a filter support member disposed within the housing between the inlet cavity and the outlet cavity, the filter support member comprising: an upstream side adjacent the inlet cavity having a filter support surface configured to support the membrane filter assembly; a downstream side adjacent the outlet cavity opposite the upstream side; and a filter support member including a plurality of passages extending through the filter support member from an upstream side to a downstream side; In a filter holder having The filter holder is configured to allow extruded material to flow through the membrane filter assembly and into the outlet cavity via a plurality of passageways before being discharged through the outlet.

[0099] Clause 25. The filter holder of clause 24, wherein the housing includes an upper housing portion, a lower housing portion, and an intermediate housing portion between the upper and lower housing portions, and the filter support member is disposed within the intermediate housing portion.

[0100] Clause 26. The filter holder of clause 25, wherein the lower housing portion includes a lower recess at least partially defining the outlet cavity, and the upper housing portion includes an upper recess at least partially defining the inlet cavity.

[0101] Clause 27. The filter holder of clause 25, wherein the lower housing portion includes a lower recess, the downstream side of the filter support member being flat and the lower recess defining the outlet cavity.

[0102] Clause 28. The filter holder of Clause 24, wherein at least one of the plurality of passages extends at a non-zero angle relative to the central longitudinal axis.

[0103] Clause 29. The filter holder of any of clauses 25 to 27, wherein at least one of the plurality of passages extends at a non-zero angle relative to the central longitudinal axis.

[0104] Clause 30. The filter holder of clause 24, wherein the housing has a recess, the filter support member is received in the recess, and the filter holder further includes a spacer disposed between a downstream side of the filter support member and an opposing surface of the recess.

[0105] Clause 31. The filter holder of clause 25 or 28, wherein the housing has a recess, the filter support member is housed in the recess, and the filter holder further has a spacer disposed between a downstream side of the filter support member and an opposing surface of the recess.

[0106] Clause 32. The filter holder of Clause 24, wherein the downstream side of the filter support member includes a concave recess that at least partially defines the outlet cavity.

[0107] Clause 33. The filter holder of clause 25, 26, or 28, wherein the downstream side of the filter support member includes a concave recess that at least partially defines the outlet cavity.

[0108] Clause 34. An extrusion system comprising: a supply reservoir containing the material to be extruded; a pressure source configured to pressurize the extruded material drawn from the reservoir; A filter holder, the filter holder comprising: a housing having an inlet configured to receive pressurized material to be extruded and an outlet configured to discharge the extrudate; a membrane filter assembly disposed between the inlet and the outlet; a filter support member disposed within the housing, the filter support member comprising: an upstream side having a filter support surface configured to support the membrane filter assembly; a downstream side opposite the upstream side, the downstream side including the first recess; and a filter support member including a plurality of passages extending through the filter support member from the filter support surface to the first recess; and an outlet cavity at least partially defined by the first recess, the outlet cavity being in fluid communication with the outlet; a filter holder having a collection reservoir configured to receive extrudate from the outlet of the filter holder; An extrusion system comprising:

[0109] Clause 35. The extrusion system of Clause 34, wherein the filter holder is one of a plurality of identical filter holders fluidly coupled in parallel to the supply reservoir and the collection reservoir.

[0110] Clause 36. The extrusion system of Clause 34, wherein the filter holder is one of a plurality of identical filter holders fluidly connected in series to the supply reservoir and the collection reservoir.

[0111] Clause 37. The extrusion system of clause 34, including one or more heat exchangers between the supply reservoir and the collection reservoir.

[0112] Clause 38. The extrusion system of clause 36 or 37, including one or more heat exchangers between the supply reservoir and the collection reservoir.

Claims

1. 1. A filter holder for a liposome extruder, said filter holder comprising: a housing including an inlet configured to receive the material to be extruded, and an outlet; a filter support member disposed within the housing between the inlet and the outlet, the filter support member comprising: an upstream side having a filter support surface configured to support the membrane filter assembly; a downstream side opposite the upstream side, and a plurality of passages extending through the filter support member from the filter support surface to the downstream side; a filter support member including: an outlet cavity in fluid communication with the outlet; In a filter holder having the filter holder is configured to allow extruded material to flow through the membrane filter assembly and through the plurality of passageways into the outlet cavity before being discharged through the outlet; The downstream side includes a recess having a curved surface, the recess at least partially defining the outlet cavity.

2. 2. The filter holder of claim 1, wherein the housing includes an upper housing portion, a lower housing portion, and an intermediate housing portion between the upper and lower housing portions, the intermediate housing portion surrounding the outer periphery of the filter support member.

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

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

5. i) at least one of the plurality of passages extends parallel to a central longitudinal axis of the housing; and / or ii) at least one of the plurality of passages extends at a non-zero angle relative to the central longitudinal axis of the housing; 5. A filter holder according to any one of claims 1 to 4.

6. 6. The filter holder according to claim 1, wherein the filter support member has a circumferential groove.

7. The filter holder of claim 6 , further comprising a temperature regulation assembly configured to circulate a heat transfer fluid through the circumferential groove.

8. 8. The filter holder of claim 1, wherein the membrane filter assembly includes a polycarbonate membrane having a pore size between 10 nanometers and 1 micrometer.

9. 9. A filter holder according to claim 1, wherein the curved surface is hemispherical.

10. 10. A filter holder according to any one of claims 1 to 9, wherein the filter support member has a plurality of interconnected channels formed on the downstream side of the filter support member.

11. 11. A filter holder according to any one of claims 1 to 10, wherein the filter support surface has a maximum width of between 5 mm and 600 mm.

12. A filter holder as described in claim 11, wherein the filter support surface has a maximum width of 13 mm to 293 mm.

13. 1. A filter holder for a liposome extruder, said filter holder comprising: a housing defining a central longitudinal axis, the housing including an inlet extending from an inlet cavity and an outlet extending from an outlet cavity; a filter support member disposed within the housing between the inlet cavity and the outlet cavity, the filter support member comprising: an upstream side adjacent the inlet cavity having a filter support surface configured to support a membrane filter assembly; a downstream side opposite the upstream side and adjacent the exit cavity; and a filter support member including a plurality of passages extending through the filter support member from the upstream side to the downstream side; In a filter holder having the filter holder is configured to allow extruded material to flow through the membrane filter assembly and through the plurality of passageways into the outlet cavity before being discharged through the outlet; The downstream side includes a recess having a curved surface, the recess at least partially defining the outlet cavity.

14. 14. The filter holder of claim 13, wherein the housing includes an upper housing portion, a lower housing portion, and an intermediate housing portion between the upper and lower housing portions, and the filter support member is disposed within the intermediate housing portion.

15. 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 the upper housing portion includes an upper recess that at least partially defines the inlet cavity.

16. 15. The filter holder of claim 14, wherein the lower housing portion includes a lower recess, the downstream side of the filter support member being flat, and the lower recess defining the outlet cavity.

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

18. A filter holder as described in any one of claims 13 to 17, wherein the housing has a recess, the filter support member is accommodated in the recess, and the filter holder further has a spacer arranged between the downstream side of the filter support member and the opposing surface of the recess.

19. 19. A filter holder according to any one of claims 13 to 18, wherein the downstream side of the filter support member includes a concave recess that at least partially defines the outlet cavity.

20. 1. An extrusion system comprising: a supply reservoir containing the material to be extruded; a pressure source configured to pressurize the extruded material drawn from the supply reservoir; A filter holder, the filter holder comprising: a housing having an inlet configured to receive the material to be extruded under pressure and an outlet configured to discharge the extrudate; a membrane filter assembly disposed between the inlet and the outlet; a filter support member disposed within the housing, the filter support member comprising: an upstream side having a filter support surface configured to support the membrane filter assembly; a downstream side opposite the upstream side, the downstream side including a first recess; and a filter support member including a plurality of passages extending through the filter support member from the filter support surface to a first recess; and an outlet cavity at least partially defined by the first recess, the outlet cavity being in fluid communication with the outlet; a filter holder having Equipped with the first recess has a curved surface, the first recess at least partially defining the outlet cavity; The filter support member has a minimum thickness at a center side of the first recess, An extrusion system, wherein a collection reservoir is configured to receive extrudate from the outlet of the filter holder.

21. The filter holder is connected to the supply reservoir and the collection reservoir. i) in parallel, or ii) in series 21. The extrusion system of claim 20, wherein the filter holder is one of a plurality of identical filter holders in fluid communication.

22. 22. The extrusion system of claim 20 or 21, including one or more heat exchangers between the supply reservoir and the collection reservoir.

Images