Small-scale liposome extruder

Abstract

1. An apparatus for extruding liposomes, comprising the following components: means for applying a hydraulic pressure P to the liquid medium; A frame, A vertical lifting unit; a supply line in fluid communication with a temperature control chamber located within a housing, the housing having a protrusion extending parallel to a central axis (A), the housing being attached to a frame; A pressure chamber comprising an outer cartridge, a housing projection, a supply orifice, an outlet orifice, and an inner collar for mounting at least a filter element, a frame including: a cartridge connected to an outlet line, movable in the direction of a central axis (A), mounted in a socket detachably coupled to the protrusion over an overlapping range, the socket vertically guided by a vertical lifting unit; and a pressure chamber designed to withstand a hydraulic pressure P; at least one porous filter element defining an outlet of the pressure chamber, the filter element having apertures with a defined diameter D; a lifting mechanism designed to raise and lower the socket; The filter element is housed in a (filter) cartridge that is removably mounted in the socket; The lifting mechanism includes at least one rack and pinion gear, the pinion pivotally mounted within the frame, and the rack vertically guided by a guideway.

Description

[Technical Field]

[0001] The present invention relates to an apparatus for extruding liposomes and a method for producing liposomes using the apparatus. [Background technology]

[0002] Liposomes are essentially spherical structures with diameters between 25 nm and 1 μm. They contain one or more concentric lipid bilayers that enclose an aqueous interior, the so-called lipid vesicle. Liposomes are produced by dispersing lipids in an aqueous solution. Suitable lipids are, in particular, phosphatidylcholine (lecithin), phosphatidylethanolamine, or phosphatidylserine (cephalin). Liposomes are used as carriers for pharmaceutical, cosmetic, or nutraceutical active substances that are selectively concentrated in specific organs and cell groups.

[0003] A summary of methods for preparing liposomes is provided by Guo et al. Guo, P., Huang, J., Zhao, Y., Martin, CR, Zare, RN, Moses, MA: Nanomaterial Preparation by Extrusion through Nanoporous Membranes.Small 2018,14,1703493. DOI:10.1002 / smll.201703493 is described in.

[0004] One important feature of liposomes is their size distribution.In particular, liposomes for pharmaceutical, cosmetic or nutraceutical applications must have a narrow size distribution.This means that the actual size of each liposome does not significantly deviate from a specific average.Therefore, determining the appropriate size is an important step during liposome preparation.

[0005] A common approach to liposome sizing is extrusion. A feed dispersion containing liposome precursors dispersed in a liquid dispersion medium is first prepared. Fluid pressure is then applied to the feed dispersion. The pressurized feed dispersion is then extruded through a porous filter element with a defined pore size. During extrusion, the size of the precursor liposomes decreases. Besides pore size, energy input is a key parameter. Liposomes are fluid systems. They can pass through, for example, a 100 nm membrane and subsequently form particles with a diameter of 250 nm. For this reason, two or more passes through an extruder are typically required for sizing. This liposome extrusion process is generally understood as a purely physical operation without chemical interactions. Therefore, the chemical composition of the target liposomes is already provided by the liposome precursor.

[0006] In commercial liposome extrusion processes, high-density polycarbonate plates are used as filter elements. The porosity of these articles is typically between 100 nm and 5 μm.

[0007] The size of precursor liposomes typically ranges from 50 nm to 10 μm. High pressure is required to extrude the precursor liposomes through the dense filter elements. Medium-pressure processes can be performed at temperatures up to 20 × 10 5 Pa~40×10 5 Operating at fluid pressures in the range of 20-40 bar, high-pressure processes can be performed at temperatures up to 100 x 10 5 Pa~200×10 5 Achieve a nominal fluid pressure reaching 100-200 bar (100-200 bar).

[0008] Such a filter holder for liposome extrusion is described in WO 2021 / 207841 and 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 including 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.

[0009] The filter holder also 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 multiple passages before being discharged through the outlet. A comparable liposome extruder is known from Figure 4 of WO 2001 / 05373 and the associated description.

[0010] An apparatus for carrying out such a liposome extrusion process is called a liposome extruder. The essential components of a liposome extruder are a vessel into which a liquid dispersion of precursor is supplied, a means for applying fluid pressure to the precursor contained within the vessel, and a porous filter element through which the precursor is extruded from the vessel.

[0011] To withstand high pressures, the mechanical design of a liposome extruder must be sufficiently robust. For this reason, the extruder design must be capable of withstanding internal pressures even higher than the extrusion pressure. According to the general rule for pressure vessels, extruders are preferably designed to withstand increased internal pressures of 1.3 to 1.7 times higher than the nominal operating pressure. Therefore, liposome extruders must be designed to be very heavy to sustain such high pressures.

[0012] Examples of liposome extruders are known from WO 2021 / 207841 (entire document) or FIG. 4 of WO 2001 / 05373. Both articles include a pressure chamber consisting of two hemispheres, i.e., a fixed socket and a ring segment detachably coupled to the socket. The pressure chamber has a one-way inlet defined by a backpressure valve and an outlet defined by a filter element. The precursor feed is introduced into the pressure chamber through the inlet. In the pressure chamber, the feed is subjected to fluid pressure. The latter forces the precursor mixture out of the pressure chamber and through the filter element to facilitate extrusion.

[0013] In simplified operation, a liposome sizing process utilizing such an extrusion device is carried out until the filter element becomes impermeable due to clogging, the device is then depressurized, the ring segments and sockets are released from one another, the cap is removed, the impermeable filter element is replaced with a new filter, the cap and socket are reattached to one another, the device is repressurized, and liposome extrusion continues.

[0014] Liposomal formulations for pharmaceutical, cosmetic, or nutraceutical applications are subject to meticulous product development. During this process, numerous extrusion trials or evaluation tests are required to optimize formulation and process parameters. Therefore, the individual extrusion time for a specific formulation under a specific set of process parameters is much shorter than in industrial-scale production. Because the extruder must be cleaned and the filter element replaced after each test, the frequency of depressurization, filter element replacement, and repressurization is significantly higher than in industrial-scale extrusion. In pharmaceutical applications, when handling highly potent drugs (such as the anticancer drug doxorubicin), extrusion under secondary containment is also necessary to avoid contamination of production personnel. Replacing the filter element of a conventional extruder under secondary containment is a time-consuming and difficult procedure that carries the risk of spillage.

[0015] Utilizing a production extruder for testing is inefficient because the weight of the high-pressure chamber requires cumbersome handling, and the time required to remove the heavy cap of the pressure chamber is too long compared to the extrusion time. Summary of the Invention [Problem to be solved by the invention]

[0016] With this in mind, there is a need to provide an apparatus for extruding liposomes on a small scale during product development. In particular, the time required to depressurize the chamber, remove and replace the filter element, and repressurize is minimized. However, the production capacity of the intended apparatus is intended to be lower than the production capacity of extruders used for commercial production of liposomes. [Means for solving the problem]

[0017] The object is a device for extruding liposomes, comprising the following components: A means for applying a hydraulic pressure P to the liquid medium, the hydraulic pressure P being 20×10 5 Pa~200×10 5 Pa is means and A frame, a. Vertical lifting unit (8); b. a supply line in fluid communication with a temperature control chamber located within a housing, the housing having a protrusion extending parallel to the central axis (A), the housing being attached to a frame; and c. a pressure chamber comprising an outer cartridge, a housing projection, a delivery orifice, and an inner collar for mounting at least a filter element; a pressure chamber, the cartridge being connected to the outlet line, movable in the direction of a central axis (A), and attached to a socket detachably coupled to the protrusion over an overlapping range, the socket being vertically guided by a vertical lifting unit, the pressure chamber being designed to withstand a liquid pressure P; a frame comprising: At least one porous filter element defining the pressure chamber and / or the outlet of the cartridge, the porous filter element having apertures with a diameter D, the pore size D being less than or equal to 80×10 -9 m~50×10 -6 m or 100 x 10 -9 m~5×10 -6 m, and at least one porous filter element; a lifting mechanism as part of a lifting unit designed to raise and lower the socket; Equipped with The filter element is housed in a (filter) cartridge that is removably attached to the socket, The lifting mechanism comprises at least one rack and pinion gear, the pinion being pivotally mounted on a lifting unit mounted on the frame, and the rack being vertically guided; This is solved by the device.

[0018] The pressure chamber and supply lines are preferably b The bearing is designed to withstand an internal hydraulic pressure Pb calculated by =S*P, where S is a reasonable safety factor as defined in commonly known handbooks and regulations, where S is preferably selected from the range of 1.1 to 2.5, most preferably 1.3 to 1.7.

[0019] According to a preferred embodiment, the frame has a vertical lifting unit on its underside and a supply line on its upper side that is in fluid communication with a housing having a temperature-controlled chamber located on top of the housing, the housing having a protrusion on its underside extending parallel to the central axis A, and the housing is attached to the frame.

[0020] The supply line is preferably in fluid communication with a housing that includes an (internal) thermostatic chamber located in the top or upper section of the housing.

[0021] Preferably, an exit line directs the extruded liposomes (product) downstream from the pressure chamber to additional processing units, such as, but not limited to, a collection vessel, a control unit, a purification station, a confectionery station, and the like.

[0022] According to a preferred embodiment, the cartridge is connected to an outlet line and is mounted in a socket that is linearly, preferably vertically, movable in the direction of a central axis (A).

[0023] The pressure chamber in the closed position preferably comprises an outer cartridge, an inner protrusion of the housing, a supply orifice leading to the protrusion with an outlet orifice on a first side of the filter element, an inner collar for mounting at least one filter element, and an outlet orifice on an opposite side of the at least one filter element. Thus, the outlet orifice of the protrusion and the (final) outlet orifice of the pressure chamber are on opposite sides of the pressure chamber and / or the filter element. In an improved embodiment, at least one gasket element is disposed on the inner collar and / or the filter element, and the gasket element may be a sealing ring. The gasket element and the filter element are preferably removable from the cartridge. The outlet orifice is located at the free end of the protrusion when the pressure chamber is in the open (lowered) position, and the outlet orifice of the protrusion is located inside and / or part of the pressure chamber when the pressure chamber is in the closed (upper) position.

[0024] The first preferred key element of the device of the present invention is the filter cartridge, which houses the filter element. While the filter cartridge is designed as a long-lasting, reusable component, the actual filter element is intended for single-use. Thus, to replace the filter element, the entire filter cartridge is removed from the pressure chamber, and the filter element is then extracted from the filter cartridge. The filter cartridge is then cleaned, and a new filter element is reinstalled. Because the filter cartridge is relatively small compared to the entire pressure chamber, it is lightweight and easy to handle. Removal of the worn filter element, cleaning of the cartridge, and insertion of a new filter element can be performed independently of the device's installation location on an ergonomically optimized work bench.

[0025] A second important feature of the small-scale liposome extruder of the present invention is that the filter cartridge is removably attached to the socket, while the socket can be raised and lowered by a lifting mechanism. In the raised position, the socket is fixed to a stationary ring element. Essentially, the projection and socket define a pressure chamber, and the surrounding stabilizing ring element ensures compatibility with the intended high-pressure application.

[0026] The lifting mechanism allows the pressure chamber to be released quickly and with less effort by lowering the socket. Once the socket is lowered, the cartridge can be removed from the socket for replacing the filter element, as described above. Thanks to this design, the weight of the socket is fully supported by the lifting mechanism. The cartridge can be light in size compared to the weight of the socket, allowing it to be handled manually.

[0027] The fundamental principle of the device of the present invention is therefore the separation of pressure load support from filter element support. The pressure load is supported by the ring element and the socket, both of which are attached to a fixed frame. There is no need to manually move either part. The only part that needs to be handled manually is the filter cartridge, which essentially contains the filter element and at least one gasket. Because of its single function, the filter cartridge can be designed to be lightweight without significant limitations on pressure safety.

[0028] According to a preferred embodiment, the channels, protrusions and cartridges of the ring elements have a round circular cross section, preferably a round circular cross section transverse to the (vertical) axis (A).

[0029] The device of the present invention is 20 × 10 5 Pa~200×10 5 It can be operated in a wide pressure range of 20×10 Pa. 5 Pa~40×10 5 Medium-pressure processes operating at fluid pressures in the range of 100 × 10 5 Pa~200×10 5 High-pressure processes achieving nominal fluid pressures reaching 100-200 bar (60 x 10 5 Pa~70×10 5 Intermediate pressures of 100 Pa can also be used.

[0030] According to a preferred embodiment, the device further includes a lever for pivoting the pinion relative to the frame between a first (end) angular position and a second angular position, where in the first angular position the cartridge on the socket approaches the protrusion, and in the second angular position the cartridge on the socket is lowered. The lever allows for quick opening and closing of the extruder, primarily the socket and pressure chamber, for using the filter element or replacing a worn filter element. Preferably, in the first angular position, the filter cartridge is inserted into the ring element (closed position).

[0031] The first angular (end) position corresponds to a closed pressure chamber and a closed socket, and the second angular (end) position corresponds to an open pressure chamber. However, depending on the gear mechanism used as the lifting mechanism or to operate the lifting mechanism, the first and second angular positions are not limited and can be reversed or have any useful angular position. The first and second angular positions preferably include angles of 10° to 130° (+ / - 60°), most preferably 20° to 120° (+ / - 50°) or less, with the central position preferably being horizontal.

[0032] One preferred option for locking the pressure chamber is to design the device so that in the first angular position, the vertical lifting unit can be fixed to the frame so that the force flow between the socket and the ring element is at least partially transmitted through the vertical lifting unit and the frame. Alternative locking mechanisms can also be designed.

[0033] According to another preferred embodiment, the ring element is concentrically attached to the protrusion having an inner channel parallel to the axis (A) and form-locking to serve as a guide channel for the cartridge, the ring element protruding from the protrusion in the direction of the axis A.

[0034] According to another preferred embodiment, the ring element is concentrically attached to a protrusion on either the bottom of the housing or a part or region of the frame. The ring section is located on the bottom side and extends toward the vertical lifting unit in the assembled state. It can be a monolithic segment of the housing and / or the bottom segment of the housing, or a segment of the housing made as a segment permanently welded to the housing and / or its bottom segment. Alternatively, the ring section can be a detachable element, for example, screwed to the housing and / or its bottom segment. The attachment of the protrusion can be similar to that of the ring element described above, but according to a preferred embodiment, the protrusion is an integral part of the housing and / or the bottom segment of the housing and / or is welded thereto.

[0035] When the ring element is attached to the frame (1), preferably to the bottom side of its head plate, the ring element and the housing are advantageously fixed to the frame and / or the head plate on opposite sides, and the protrusion may extend through a notch in the frame and protrude concentrically and radially outward into the inner channel of the ring element.

[0036] According to a preferred embodiment, the filter element is a flat plate, preferably circular, made of a porous material selected from the group consisting of polycarbonate, sintered metal, and metal foil.

[0037] The shape of the filter element is preferably flat and circular (disk-shaped). A typical disk diameter of the filter element may be 20 mm to 50 mm, for example 25 mm. The pore diameter D of the filter element is 80×10 -9 m~50×10 -6 m or 100 x 10 -9 m~5×10 -6For example, a pore size of 0.1 μm can be used. The pore size is provided by the supplier of the filter element and can be verified by optical means, by transmission electron microscopy (TEM), or by scanning electron microscopy (SEM).

[0038] The device according to the invention works with commercially available filter elements. For example, Whatman Nuclepore polycarbonate hydrophilic membranes can be used as filter elements. The latter are available from Cytiva Europe GmbH, Freiburg, Germany.

[0039] According to a further preferred design concept, the rack may be integrated into the lifting unit, which is mechanically guided by the vertical lifting unit, which helps to reduce the weight of the entire device.

[0040] According to another preferred embodiment, the (thermostat) chamber has a supply line, at least one (first) segment of the supply line intersecting the thermostat chamber. Preferably, the thermostat chamber is connected to at least one supply line and one outlet line for the thermostat fluid and / or to a pumping station and / or a heat exchange station for the thermostat fluid. In an alternative embodiment, an electric heating device is arranged inside the thermostat chamber in thermal communication with the supply line and / or at least a segment thereof.

[0041] According to an improved version of this preferred embodiment, at least three segments of the supply line intersect the temperature control chamber; The first segment leads to a ring tube; a second segment of the supply line defined by a ring pipe; The third segment leads from the outlet of the ring tube to the supply orifice of the pressure chamber.

[0042] The term "intersects" means that a segment of supply line is somehow inside the temperature control chamber and leads from one supply location to the pressure chamber. However, the term "intersects" should not be understood to limit the path, direction, or orientation. The supply line or segment thereof may be positioned or attached to the interior wall of the housing, to a separate carrier element, and / or to be self-supporting by bridging at least a partial interior volume of the temperature control chamber.

[0043] According to another preferred embodiment, a vent line is connected to the supply line and / or a segment of the supply line upstream of the pressure chamber, preferably directly adjacent to the supply orifice of the pressure chamber, which allows for the release of internal gas in the supply line when filling the device from the supply line prior to manufacture, and the safe release of all captioned gas through the vent line and the vent outlet.

[0044] The device is designed for small scale liposome extrusion for product development, i.e., sizing of liposome precursors into target liposomes with dimensions between 50 nm and 300 nm, preferably between 80 nm and 150 nm.

[0045] Therefore, another object of the present invention is a process for preparing target liposomes from liposome precursors by using the device of the present invention, said process comprising: a) providing a device for extruding liposomes, the device comprising at least one filter element; b) providing a feed dispersion comprising liposome precursors dispersed in a liquid dispersion medium; c) 20 x 10 5 Pa~200×10 5 applying a hydraulic pressure P amounting to Pa to the feed dispersion to obtain a pressurized feed dispersion; d) forcing the pressurized feed dispersion through a filter element to obtain an extruded dispersion comprising the targeted liposomes dispersed in the dispersion medium; e) optionally recovering the targeted liposomes from the extruded dispersion; Includes:

[0046] Preferably, the method of the present invention is carried out until a predetermined degree of clogging of the filter element is reached. The device is then depressurized, and the ring element and socket holding the filter cartridge are released from each other. The filter cartridge containing the filter element with reduced permeability is replaced with a new filter cartridge containing a new filter element, and the socket is raised. This reconnects the socket with the cartridge to the protrusions and ring element, and the device is repressurized, and the process continues. This process is easily accomplished by moving a lever.

[0047] The device of the present invention is intended for small-scale production of liposomes. Optimally, the volume of the precursor-containing feed dispersion is between 0.1 L and 10 L, or between 100 mL and 2000 mL.

[0048] In particular, the device of the present invention is used for product development purposes in the field of liposomes.

[0049] Different versions of a device are also referred to as "designs." This refers exclusively to "technical designs" or "structural designs" as versions of technical embodiments with a specified number of technical features. It does not refer exclusively to appearance or artistic design.

[0050] Further advantages of the device and its intended use in the process of the present invention will become apparent from the following description of one embodiment. [Brief explanation of the drawings]

[0051] [Figure 1] FIG. 1 is a closed perspective view of the device from above. [Figure 2] FIG. 1 is a closed perspective view of the device from the bottom. [Figure 3] FIG. 1 is a front view of the closed device. [Figure 4] FIG. 1 is a side cross-sectional view of the device closed and latched. [Figure 5] FIG. 1 is an open front view of the device. [Figure 6] FIG. 1 is an open side cross-sectional view of the device. [Figure 7] FIG. 1 is an open cross-sectional perspective view of the device. DETAILED DESCRIPTION OF THE INVENTION

[0052] The same embodiment of the device 100 of the present invention is shown in all figures.

[0053] The device 100 comprises a frame 1 that can be fixed to the ground at the installation site. The essential elements of the device are a housing 32 that encloses a temperature control chamber 30 with a projection 16 and a pressure chamber 2 that is composed of a cartridge 12 and projection 16. The projection 16 is an integral part of the housing 32, and the ring element 3 is fixed to the frame 1, while the socket 4 is fixed to a lifting unit that has a lifting mechanism 5.

[0054] As shown in Figure 1, the device 100 comprises a frame 1 having a top plate 1.1, a bottom plate 1.2 and a number of side elements 1.3, a housing 32 of a temperature chamber 30 arranged on the top plate 1.1, and a lifting unit 8 having a lifting mechanism 5 arranged on the bottom plate 1.2, carrying a socket 4 and a cartridge 12. A ring element 3 is attached to the underside of the head plate 1.1 and is technically designed to support at least one filter element 14.

[0055] The supply line 17 leads to the thermostatic chamber 30 in the housing 32. The housing 32 comprises a middle segment 34, a top segment 36, and a bottom segment 38. The supply line 24 for the thermostatic fluid is connected to the middle segment 34 and the thermostatic chamber 30. Sensors 40, 42 are located at relevant locations to measure the fluid and monitor the status of the device 100. Data and / or power lines are designated by the reference numeral 44. The pressure sensor 40 is located in correspondence with the ventilation line 22, and the temperature sensor 42 is located in the thermostatic fluid supply line 24 and in the ring section 3. The edge element of the outlet line 19 is integrated with combined sensors 40, 42 for measuring the pressure and temperature in the thermostatic fluid outlet line 19 (FIG. 2), which is connected to an external thermostatic unit. The contour of the thermostatic fluid is not shown.

[0056] The supply line 17 is in fluid communication with a vent line 22 leading to a vent outlet 24 for releasing trapped gas volumes from the supply line 17 or its internal segments 17.1, 18, 17.2.

[0057] The lifting mechanism 5 includes a lifting unit 8, which is realized by a rack-and-pinion gear with two symmetrically arranged racks 6 and two pinions 7. The lifting mechanism 5 moves the socket 4 and cartridge 12 vertically toward the protrusion 16, thereby closing or forming the pressure chamber 2. The racks 6 are vertically guided by the lifting unit 8 within the frame 1, and the pinions 7 are pivotally mounted within the frame 1. Each pinion 7 is provided with a lever 9, which rotates the pinion 7 by pivoting it. When each rack 6 engages with its corresponding pinion 7, rotating the lever 9 causes linear movement of the rack 6 along the vertical guideway. The levers 9, pinions 7, and rack 6 are sized so that the levers 9 can be manually rotated between a first position and a second position, the angle between the two positions being approximately 90°.

[0058] In a first position shown in Figures 1, 2, 3 and 4, the lever 9 is directed towards the ground. In this first position, the rack 6 is raised so that the socket 4 attached to the upper end of the rack 6 approaches the ring element 3. Thus, in the first position, the ring element 3 and the socket 4 form a pressure chamber 2 in a closed state (see in particular the side cross-sectional view in Figure 4).

[0059] In the second position shown in Figures 5, 6 and 7, the pressure chamber 2 is in an open state. In the open state, the rack 6 is lowered so that the socket 4 is away from the ring element 3. The lever 9 is pointing upwards.

[0060] The pressure chamber 2 can be opened or closed by rotating the lever 9 between a first position and a second position, respectively. Due to gravity, opening is slightly lighter than closing. To maintain the closed state, a latch 10 (not shown) can be inserted into the lifting unit 8 to lock the rack 6 in the raised position (Fig. 4 only). In the latched position, the vertical force flow between the ring element 3 and the socket 4 is closed via the rack 6, the lifting unit 8, the latch 10 (not shown), and the frame 1. Therefore, in the closed position, the pressure chamber 2, consisting of the ring element 3 and the socket 4, can withstand the internal pressure.

[0061] The socket 4 has a receptacle 11 on its upper side, into which the cartridge 12 is removably placed (see Figure 4). The cartridge 12 is designed as a relatively lightweight hollow cylinder with an inner collar 13 that supports a filter element 14. The filter element 14 is made of a flat, porous polycarbonate plate with a porosity ranging from 100 nm to 5 μm, suitable for sizing liposomes by extrusion through the filter element 14. While the filter element 14 is intended as a disposable item, the cartridge 12 is designed to last a long time. The outer diameter and length of the cartridge 12 are designed to fit into the central ring channel 15 extending upward from the bottom surface of the ring element 3. Conversely, a cylindrical protrusion 16 extending downward from the ring element 3 has an outer diameter and length designed to fit into the cartridge 12. In the closed state, the front surface of the protrusion 16 rests on the upper side of the filter element 14 (Figure 4), clamping the filter element 14 onto the cartridge collar 13. Optionally, a gasket (not shown) is disposed between the projection 16 and the filter element 14 .

[0062] Liposome extrusion is performed in the closed state (FIG. 4). In the closed position, the socket is brought close to the ring element 3 and secured in this position by a latch 10 (not shown). The cartridge 12 is housed in the ring channel 15, and the projection 16 extends into the cartridge 12. Thus, in the closed position, the cartridge 12 is completely surrounded by the ring element 3 and the socket 4. The filter element 14 is clamped between the projection 16 and the collar 13.

[0063] During extrusion, pressure chamber 2 is closed as shown in Figure 4. The dispersion containing the liquid dispersion medium and enlarged particle size liposome precursor therein is pumped into pressure chamber 2 via supply line 17. Supply line 17 leads to temperature control chamber 30, which includes three sections as it passes through temperature control chamber 30 filled with temperature control fluid flowing through chamber 30, and is in communication with an external pumping and heat exchange unit (not shown).

[0064] The first section 17.1, partially indicated by a dashed line, leads from the head plate 1.1 to the ring tube 18, which defines the second segment. The ring tube 18 is a capillary tube, ensuring a defined restriction on the volumetric flow rate and providing the necessary surface for heat exchange inside the thermostat chamber 30. The third section 17.2 is the connecting line between the outlet of the ring tube 18 and the supply orifice 2.1 of the pressure chamber 2. The filter cartridge 12, carrying the outlet line 19 beginning at the outlet orifice 12.1, is inserted into the central channel 15 of the outer ring element 3, with the annular surface 16.1 (FIG. 6) of the protrusion 16 being in contact with the filter element 14 and / or at least one gasket. Radially outward, the upper part of the cartridge 12 projects a protrusion 16 concentrically in the direction of the axis A with a length 16.2.

[0065] A typical liquid pressure for the dispersion supplied to the supply line 17 and / or pressure chamber 2 is 20×10 5 Pa~200×10 5 The pressure chamber 17 is in the range of 100 Pa. Means for applying liquid pressure to the dispersion and pumping it are not shown in the drawings. On its way through the pressure chamber, the liquid dispersion may be heated by a ring tube 18 surrounded by a thermostatic fluid. According to an alternative not shown, an electric heating device is in thermal communication with the supply line 17 or a segment thereof.

[0066] The feed line 17 terminates at the front of the protrusion 16 defined by the feed orifice 2.1. The filter element 14 is therefore exposed to the precursor dispersion exiting the feed line 17 at high hydraulic pressure. This pressure is substantially borne by the ring element 3 and socket 4 surrounding the cartridge 12. The cartridge can be designed to be lightweight because it is supported on all sides by the thick-walled ring element 3 and socket 4.

[0067] Because the filter element 14 is porous, but the ring element 3 and socket 4 are dense, the precursor dispersion penetrates (extrudes) into the filter element 14 through the pores of the filter element 14. During penetration, the particle size of the liposome precursors is reduced to a target size defined by the pore size of the filter element 14.

[0068] After being extruded through filter element 14 , the target sized liposomes are still dispersed in the dispersion medium and are collected from device 100 via exit line 19 .

[0069] When the filter element 14 is worn after performing the extrusion test, the device 100 is depressurized, the latch 10 (FIG. 4) is released, and the lever 9 is rotated upward. The socket 4 is thus lowered so that the cartridge 12 is accessible to the operator (FIG. 5). The operator can then remove the outlet line 19 and filter cartridge 12 connections from the socket 4 and transport the filter element 14 to a work bench for cleaning and replacement. Meanwhile, the supply line 17 and outlet line 19 can be rinsed.

[0070] The old cartridge 12 with a new filter element 14 is then placed in the receptacle 11 of the socket 4 and the pressure chamber 2 is closed by turning the lever 9. The vertical lifting unit 8 is locked by inserting the latch 10. The device 100 is repressurized and the next extrusion run is about to begin.

[0071] The figure shows a number of edge elements connected to lines, such as lines 17, 19 or 22. These edge elements may be valves, preferably controllable valves. Alternatively, these lines are preferably connected to valve elements mounted on the outside of the device.

[0072] Those skilled in the art will appreciate that the apparatus described herein is preferably oriented with central axis A oriented vertically, primarily for ease of access and maintenance. However, the feed flow within, for example, feed line 17, its segments, pressure chamber 2, and outlet line 19, does not provide for a vertical orientation. Therefore, any description of a vertical orientation should not be understood as limiting the invention, but is intended as a descriptive description only, absent specific descriptions provided and / or technically essential details or dependencies that would be apparent to those skilled in the art. [Explanation of symbols]

[0073] 100 devices 1 frame 1.1 Head plate 1.2 Bottom Plate 1.3 Side Elements 2. Pressure Chamber 2.1 (2) Feed Orifice 2.2 (16) outlet orifices 3 Ring Elements 4 sockets 5 Mechanical units with lifting mechanism or short lifting mechanism 6 racks 7 Pinion 8 Lifting unit, vertical 9 Lever 10 Latch (not shown) 11 Receptacle 12 cartridges 12.1 (12) Exit Orifice 13 Colors 14 Filter Elements 15 (of 3) channels 16 protrusions 16.1 Torus 16.2 Length 17 Supply line (raw materials) 17.1, 17.2 Supply Line Segments 18 Ring tube (also called capillary ring tube) 19 Exit Line (Product) 20 Ventilation outlet 22 Ventilation line 24 Supply line (temperature-controlled fluid) 30 chambers, temperature control 32 (of 30) housing 34 Middle Segment 36 head segments 38 bottom segment 40 Sensor, Pressure 42 Sensor, Temperature 44 Power / Data Lines

Claims

1. An apparatus (100) for extruding liposomes, comprising the following components: means for applying a hydraulic pressure P to the liquid medium, said hydraulic pressure P being 20 x 10 ５ Pa ~ 200 x 10 ５ Pa. A frame (1), a. A vertical lifting unit (8); b. a supply line (17) in fluid communication with a temperature control chamber (30) located within a housing (32), said housing (32) having a protrusion (16) extending parallel to a central axis (A), said housing (32) being attached to said frame (1); c. A pressure chamber (2) comprising an outer cartridge (12), the protrusion (16) of the housing (32), a supply orifice (2.1), and an inner collar (13) for mounting at least a filter element (14) at an outlet orifice, a pressure chamber (2) connected to an outlet line (19), movable in the direction of the central axis (A), and attached to a socket (4) detachably coupled to the protrusion (16) over an overlapping range (16.1), the socket (4) being vertically guided by the vertical lifting unit (8), the pressure chamber (2) being designed to withstand the hydraulic pressure P; a frame (1) comprising: At least one porous filter element (14) defining an outlet of the pressure chamber (2) and / or cartridge (12), the porous filter element (14) having apertures with a diameter D, the pore size D being 80×10 －９ m~50×10 －６ m or 100 x 10 －９ m to 5 x 10 －６ m) of the porous filter element (14); a lifting mechanism (5) as part of a lifting unit (8) designed to raise and lower said socket (4); Equipped with - said filter element (14) is housed in a (filter) cartridge (12) removably attached to said socket (4); the lifting mechanism (5) comprises at least one rack (6) and pinion (7) gear, the pinion (7) being pivotally mounted on the lifting unit (8) mounted on the frame (1), and the rack (6) being vertically guided; Apparatus (100).

2. 2. The device (100) of claim 1, further comprising a lever (9) for pivoting the pinion (7) relative to the frame (1) between a first angular position and a second angular position, wherein in the first angular position, the cartridge (12) on the socket (4) approaches the protrusion (16), and in the second angular position, the cartridge (12) on the socket (4) is lowered.

3. 3. The device according to claim 1 or 2, wherein a ring segment (3) is concentrically attached to the protrusion (16) having an inner channel (15) parallel to the axis (A) and form-locking to act as a guide channel for the cartridge (12), the ring segment (3) protruding from the protrusion (16).

4. The ring segment (3) is i) the bottom of said housing (32), or ii) A device according to claim 3, which is attached to a part of the frame (1) concentrically with the projection (16).

5. 4. The device according to claim 2 or 3, wherein in said first angular position a filter cartridge (12) is inserted into said ring segment (3).

6. 4. The device according to claim 2 or 3, wherein in the first angular position, the vertical lifting unit (8) is fixable to the frame (1) so that the flow of force between the socket (4) and the ring segment (3) is at least partially transmitted via the vertical lifting unit (8) and the frame (1).

7. 7. The device (100) according to claim 1, wherein the filter element (14) is a preferably circular flat plate made of a porous material selected from the group consisting of polycarbonate, sintered metal, and metal foil.

8. The device according to at least one of claims 1 to 7, wherein the rack (6) is integrated into the vertical lifting unit (8).

9. 9. The device according to claim 1, wherein the chamber (30) has a supply line (24), and wherein at least one (first) segment (17.1) of the supply line (17) crosses the temperature-controlled chamber (30).

10. At least three segments of the supply line (17) intersect the temperature control chamber (30); The first segment (17.1) leads to a ring tube (18), a second segment of the supply line (17) defined by the ring pipe (18); 10. The device according to claim 9, wherein a third segment (17.2) leads from the outlet of the ring tube (18) to the supply orifice (2.1) of the pressure chamber (2).

11. 11. The device according to claim 1, further comprising a vent line (22) connected to the supply line (17) and / or to a segment of the supply line upstream of the pressure chamber (2), preferably directly adjacent to the supply orifice (2.1) of the pressure chamber (2).

12. 1. A method for preparing targeted liposomes from liposome precursors, comprising: a) providing a device (100) for extruding liposomes, said device (100) comprising at least one filter element (14); b) providing a feed dispersion comprising liposome precursors dispersed in a liquid dispersion medium; c) 20 x 10 ５ Pa ~ 200 x 10 ５ applying a liquid pressure P to said feed dispersion amounting to Pa to obtain a pressurized feed dispersion; d) forcing the pressurized dispersion through the filter element (14) to obtain an extruded dispersion comprising targeted liposomes dispersed in a dispersion medium; e) optionally recovering the targeted liposomes from the extruded dispersion; Including, A method, characterized in that a device (100) for extruding liposomes according to at least one of claims 1 to 11 is provided.

13. 13. The method according to claim 12, characterized in that the method is carried out until a defined degree of clogging of the filter element (14) is reached, after which the device (100) is depressurized, the ring segment (3) and the socket (4) are released from each other, the ring segment (3) is raised, the filter cartridge (12) containing the filter element (14) with reduced permeability is replaced with a new filter cartridge (12) containing a new filter element (14), the ring segment (3) is lowered, the socket (4) and the ring segment (3) are reconnected to each other, the device (100) is repressurized, and the process continues.

14. 14. The method of claim 12 or 13, wherein the volume of the feed dispersion provided is from 0.1 L to 10 L or from 100 mL to 2000 mL.

15. The method of any one of claims 12 to 14, carried out for product development purposes.

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