Easy-to-use liposome extruder

Abstract

The object of the invention is to provide a device (0) for extruding liposomes under high fluid pressure (P) through a filter element (5) that can be easily and quickly handled in a cleanroom environment. The basic design principle of the device (0) is a pressure chamber (3) that approximates a lentil-shaped ellipsoid (E). The pressure chamber (3) consists of two hemispheres, namely a fixed socket (3a) and a removable cap (3b). The pressure vessel (3) can be opened by lifting the cap (3b). The device (0) is equipped with an integrated guideway (2) designed to guide the cap (3b) vertically. The concept of this guideway (2) is to maintain the alignment of the cap (3b) to the socket (3a) when the cap (3b) is released. Since the guideway (2) allows only vertical translation of the cap (3b), tilting and offsetting of the cap (3b) are eliminated. This effect is further supported by the flattened shape of the cap (3b). This constellation helps to remove and replace the cap (3b) quickly without complex alignment.

Description

[Technical Field]

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

[0002] Liposomes are essentially spherical structures with a diameter ranging from 25 nm to 1 μm. They contain one or more concentric lipid bilayers, so-called lipid vesicles, surrounding a water-soluble interior. Liposomes are produced by dispersing lipids in an aqueous solution. Suitable lipids include phosphatidylcholine (lecithin), phosphatidylethanolamine, or phosphatidylserine (cephalin). Liposomes are used as carriers for pharmaceutical, cosmetic, or dietary supplement active substances selectively concentrated in specific organs and cell populations.

[0003] An overview of the process for preparing liposomes is provided by Guo et al. Guo, P., Huang, J., Zhao, Y., Martin, CR, Zare, RN, Moses, MA: Preparation of nanomaterials by extrusion through nanoporous membranes. Small 2018, 14, 1703493 DOI:10.1002 / smll.201703493

[0004] One important characteristic of liposomes is their size distribution. In particular, liposomes intended for use in pharmaceutical, cosmetic, or nutritional supplement applications need to have a size distribution within a high-density range. This means that the actual size of individual liposomes does not deviate significantly from a specific mean. Therefore, defining appropriate sizes is a crucial step in liposome preparation.

[0005] A common approach to sizing liposomes is extrusion. This involves first preparing a feed dispersion containing liposome precursors dispersed in a liquid dispersion medium. This feed dispersion is then subjected to fluid pressure. The pressurized feed dispersion is then extruded through a porous filter element having a defined pore size. During extrusion, the size of the precursor liposomes is reduced. In addition to pore size, energy input is a crucial parameter during extrusion. Liposomes are fluid systems. They can, for example, pass through a 100 nm membrane and then form particles with an average size of 250 nm. Therefore, for effective diameter reduction, liposomes generally need to pass through the extruder more than once. Such liposome extrusion processes are generally understood as purely physical operations without chemical interactions. Thus, the chemical composition of the target liposomes is already given by the liposome precursors.

[0006] In commercially available liposome extrusion processes, high-density polycarbonate plates are used as filter elements. The porosity of these materials typically ranges from 100 nm to 5 μm.

[0007] The size of precursor liposomes is typically in the range of 50 nm to 10 μm. High pressure is required to achieve extrusion of precursor liposomes through a high-density filter element. The medium-pressure process is 20*10 5 Pa to 40*10 5 It operates at fluid pressures in the range of Pa (20 to 40 bar), while high-pressure processes use 100*10 5 Pa to 200*10 5 Achieves nominal fluid pressures of Pa (100 to 200 bar).

[0008] The apparatus used for extruding liposomes in this manner is called a liposome extruder. The essential components of a liposome extruder are a container through which a liquid dispersion of the precursor is supplied, and means for applying fluid pressure to the precursor and porous filter elements contained in the container, thereby extruding the precursor from the container.

[0009] To withstand high pressure, the mechanical design of a liposome extruder must be sufficiently robust. For safety reasons, the extruder design must be able to accommodate internal pressures even higher than the extrusion pressure. According to general regulations regarding pressure vessels, extruders must be designed to withstand internal pressures 1.3 to 1.7 times higher than the nominal operating pressure. Therefore, liposome extruders need to be designed to be very heavy in order to maintain such high pressures.

[0010] Examples of liposome extruders are known from International Publication No. 2021 / 207841 or Figure 4, and the relevant description in International Publication No. 01 / 05373. Both articles described in the respective publications feature a pressure chamber consisting of two hemispheres, i.e., a fixed socket and a cap detachably coupled to the socket. The pressure chamber has a one-way inlet defined by a back pressure valve and an outlet defined by a filter element. A precursor feed is introduced into the pressure chamber through the inlet. In the pressure chamber, the feed is subjected to fluid pressure. The latter expels the precursor mixture from the pressure chamber through the filter element to facilitate extrusion.

[0011] In daily operations, the liposome sizing process using such an extruder is carried out until the filter element loses its permeability due to clogging. Then, the apparatus is depressurized, the cap and socket are separated, the cap is removed, the reduced permeability of the filter element is replaced with a new filter, the cap and socket are reconnected, the apparatus is repressurized, and liposome extrusion continues.

[0012] When liposomes are manufactured for pharmaceutical, cosmetic or nutraceutical use, strict requirements regarding hygiene conditions need to be met. Therefore, the liposome extruder is installed in a clean room where only staff wearing protective clothing can enter. In pharmaceutical applications when handling potent drugs (such as the anticancer drug doxorubicin etc.), extrusion is also required to be carried out under secondary containment in order to avoid contamination of the manufacturing personnel. Due to the hygiene requirements, the handling of heavy extruder parts is highly desired. For example, the cap of a typical high-pressure chamber reaches a weight of up to 50 kg. Therefore, a crane for operation is required. Operating the crane while wearing high-level protective clothing and / or under secondary containment and replacing the filter element is very strenuous for the staff. In particular, the exact alignment of the cap to the socket to enable a secure seal is highly desired. Therefore, replacing the filter element of a conventional liposome extruder under enhanced hygiene requirements takes a long time of 20 to 30 minutes even when two operators are involved. An unplanned long setup time can cause a Good Manufacturing Practice (GMP) deviation.

Summary of the Invention

Problems to be Solved by the Invention

[0013] In light of this, an object of the present invention is to provide an apparatus for extruding liposomes under high fluid pressure through a filter element that can be easily and quickly handled in a clean room environment. In particular, it is intended that the worn filter element can be replaced in a short time.

Means for Solving the Problems

[0014] This object is an apparatus for extruding liposomes, comprising the following components: · Means for applying a fluid pressure P to a liquid medium, wherein the fluid pressure P reaches from 20*10 5 Pa to 200*10 5 Pa, and · A frame with a vertical guideway, · A pressure chamber having sockets and caps releasably coupled to each other, wherein the socket is fixed to the frame, the cap is vertically guided by the vertical guideway, and the pressure chamber is configured to withstand an internal fluid pressure P b calculated by P = S*P, where S is a reasonable safety factor, S is preferably selected from the range of 1.3 to 1.7, and the cap has an inner surface approximated by the equation: b x x 2 / a 2 +y 2 / b 2 +z 2 / c 2 =1 and includes an inner surface approximated by an ellipsoid defined by where x, y, and z are Cartesian coordinates, x and y are horizontally oriented, z is vertically oriented, a, b, and c are defined as the lengths of the semi-axes of the ellipsoid, the pressure chamber is designed such that the lengths of the semi-axes a, b, c of the ellipsoid satisfy both c < a and c < b, and the cap (x) is designed such that the lengths of the semi-axes a and b of the ellipsoid (E) satisfy the condition a = b < 500 mm or a = b < 300 mm, a pressure chamber, · A filter holder removably attached to the socket, · At least one porous filter element defining an outlet of the pressure chamber, the filter element including apertures having a diameter D, the pore diameter D ranging from 50*10 -9 m to 50*10 -6 m or from 80*10 -9 m to 5*10 -6 m, whereby the filter element is accommodated in the filter holder, at least one porous filter element, is solved by an apparatus comprising.

[0015] The inner surface of the cap, which approximates the ellipsoid defined by the equations described above, is to mean a sub-region of the entire inner surface of the cap. According to one useful version of the apparatus, the (partial) inner surface according to the given equations covers at least 60% of the entire inner surface of the cap, preferably at least 70%, and most usefully at least 80%.

[0016] This apparatus is the first subject of the present invention.

[0017] The basic design principle of this device is a pressure chamber having a cap that approximates an ellipse shape with an inner surface, so that the vertical diameter of the ellipsoid is smaller than its horizontal diameter. Therefore, the ellipsoid is flattened, similar to a lentil. The cap is part of the pressure chamber, which consists of two hemispheres: a fixed socket and the cap (removable). The pressure vessel can be opened by lifting the cap. The extruder is equipped with an integrated guideway designed to guide the cap vertically. The concept of this guideway is to maintain the horizontal alignment of the cap and the socket when the cap is released. In addition, the axial position of the cap relative to the socket is maintained. Both help to realign both hemispheres when the cap is mounted to the socket, i.e., the guideway only allows vertical translation of the cap, so tilting of the cap and offset is eliminated. This effect is further supported by the flattened shape of the cap, i.e., the tilt moment out of the horizontal plane is higher due to the expansion of the horizontal diameter, so the cap is more stable in the horizontal plane than an ideal sphere with the same diameter in all directions. This constellation helps to remove and replace the cap quickly without complicated alignment.

[0018] A further beneficial feature of this device is the filter holder that houses the porous filter element. The filter element is intended for use only for a limited operating time. Its lifespan is governed by its permeability, the latter of which decreases due to clogging over time. The filter holder is intended for permanent use. Because it is detachably mounted in the socket, it can be quickly picked up when the pressure vessel is opened by lifting the cap. Since the filter holder does not withstand pressure, it can be designed to be lightweight. Due to its light weight, one operator can easily remove the filter holder by hand. The actual replacement of the filter element can be achieved at a location away from the fixed socket. In particular, it is possible to transport the filter holder to a remote location under better ergonomic conditions. The worn filter element is replaced there with a new one, and the filter holder is returned to the socket.

[0019] In short, compared to conventional equipment, the design of the liposome extruder of the present invention allows for faster replacement of filter elements, even in a cleanroom environment, while reducing the workload on staff.

[0020] According to the present invention's concept of a flattened elliptical cap for a pressure chamber, the vertical semi-axis c of the ellipsoid is shorter than the horizontal semi-axis a and b. However, the horizontal semi-axis a and b do not necessarily have to be identical. Therefore, in the horizontal plane, the pressure chamber may have an elliptical circumference. However, to optimize the clamping capacity, it is desirable to have an ideal circumference in the horizontal plane. Therefore, according to a preferred embodiment, the cap of the pressure chamber is designed such that the lengths of the semi-axis a and b of the ellipsoid satisfy the condition a=b. They have identical horizontal semi-axis a and b, and the circumference in the horizontal plane is circular. According to a preferred embodiment, the dimensions of a and b are less than 500 mm or even less than 300 mm, and the lower limit of a and b may be 100 mm. The vertical dimension c (length of the z semi-axis) may be between 10 mm and 20 mm.

[0021] For good handling, the weight of the cap should be kept to a minimum. Therefore, the amount of material needs to be reduced. A small amount of material results in high mechanical stress under internal pressure. To ensure safety, the shape of the pressure chamber must be designed to optimize the stress. The latter can be achieved by using a convex ellipsoid. Convex means that an imaginary line segment between two points on the ellipsoidal surface of the pressure chamber extends into the interior of the pressure chamber. A convex curved pressure chamber can be constructed to be lighter than a concave curved pressure chamber for the same pressure resistance.

[0022] According to a preferred embodiment of the apparatus, the filter holder includes a substantially flat support screen and one or more filter elements, thereby the flat support screen extending substantially horizontally. Such a flat support screen can be fitted very comfortably into a socket. It preferably extends within the horizontal mating surface between the socket and the cap. The support screen may comprise either a single filter element or an array of several parallelized filter elements.

[0023] The support screen itself may be porous and configured to allow the liquid medium to flow through the filter holder.

[0024] Optionally, the filter holder further comprises at least one flat porous drainage element positioned between the support screen and the filter element. The pore size of the drainage element is larger than the pore size of the filter element but smaller than the pore size of the flat support screen. Such a drainage element prevents the filter element from being pushed out into the pores of the support screen.

[0025] Preferably, the filter holder includes at least two handles for gripping to remove the filter holder from the socket. In particular, if the filter holder is configured as a flat support screen, such a lightweight filter holder can be operated manually if it has such handles.

[0026] However, if the extrusion pressure requires a heavier structure, the filter holder shall be made of a material having a higher magnetic permeability than the socket material. This allows the filter holder to be picked up with a lift magnet attached to a crane. If the magnetic permeability of the socket is the same as that of the filter holder, the magnetic lifter will stick to both parts. Therefore, it would be impossible to release the filter holder. Preferably, the filter holder is made of stainless steel and the socket is made of diamagnetic stainless steel. Examples of suitable steel grades are 1.4016, 1.3813, 1.3952, 1.3964, and 1.3974.

[0027] The filter element may consist of a plate made of a porous material selected from the group consisting of polycarbonate, sintered metal, and metal foil, according to an approved design. The plate is preferably circular.

[0028] The filter element is preferably flat and circular (disk-shaped). The typical disk diameter of the filter element is 20 mm to 50 mm, for example, 25 mm. The hole diameter D of the filter element is 50 * 10 -9 m to 50*10 -6 Up to m, or 80*10 -9 m to 5*10 -6 The pore size shall be up to m. For example, a pore diameter of 0.1 μm can be used. The pore size is provided by the filter element supplier and can be verified by optical means, by transmission electron microscopy (TEM), or by scanning electron microscopy (SEM).

[0029] The apparatus of the present invention operates with commercially available filter elements. For example, a Whatman Nuclepore polycarbonate hydrophilic membrane can be used as the filter element. The latter is available from Cytiva Europe GmbH in Freiburg, Germany.

[0030] The guideway is designed to maintain the correct alignment of the cap relative to the socket. However, it cannot provide the force to lift the cap. The latter is applied manually by the operator or by an external crane if the cap is heavy. To speed up the handling of heavy caps, the device is preferably characterized by a lifting mechanism designed to lift the cap. The lifting mechanism eliminates the need for an external crane. This is desirable when the cap is too heavy to be handled manually.

[0031] Preferably, the lifting mechanism is functionally separated from the guideway. This construction approach allows for more precise guidance compared to an integrated design. The separated design means that the function of the vertical guide is achieved by different components than the lifting function.

[0032] According to a further improved embodiment, the frame of the apparatus comprises one, preferably exactly one, vertically erected beam extending outward from the pressure chamber, the beam forming a guide rail, and the cap comprising a lid, the lid being vertically movable on the rail such that the guideway is composed of the guide rail and the lid. Such a single-beam structure allows for easier access to the pressure chamber, which is open for removing filter holders over a wide sector, compared to a multi-beam design.

[0033] Preferably, the socket and cap are releasably connected to each other by a threaded connection, the threaded connection including a plurality of vertically extending bolts positioned on a horizontally arranged bolt circle, thereby directing the effective axis of the vertical guideway to point around the bolt circle. Such a design has been identified as stable and easily accessible.

[0034] When using a bolt connection, at least one bolt can be pivotably mounted to the socket, with the axis of rotation between the bolt and the socket extending horizontally. The cap is equipped with a hook-shaped receptacle for a nut screwed onto the bolt. In particular, high-pressure chambers require heavy screws that need to be operated similarly. When the bolt is pivoted horizontally, the operator does not need to introduce the heavy bolt into the screw hole (which is very time-consuming). In this embodiment, the bolt is simply pivoted so that the nut is received by the corresponding hook of the cap. The number of rotations required to secure this bolt connection is fewer than when screwing the bolt perpendicularly into the screw hole. This results in faster handling. Beyond that, the bolt will not be lost. Preferably, all bolts are pivoted horizontally in this manner.

[0035] Due to its robust structure, the device of the present invention is 20*10 5 Pa to 200*10 5 It can operate over a wide pressure range of Pa. This is 20*10 5 Pa to 40*10 5 Intermediate pressure processes operating at fluid pressures in the range of Pa (20 to 40 bar), and 100*10 5 Pa to 200*10 5 High-pressure processes that achieve nominal fluid pressures reaching Pa (100 to 200 bar) are also covered. For example, 60*10 5 Pa to 70*10 5 Intermediate pressures in Pa are also possible.

[0036] Another subject of the present invention is a process for preparing target liposomes from liposome precursors using the apparatus of the present invention. This method involves the following steps: a) The step of providing the apparatus of the present invention, b) Providing a feed dispersion containing liposome precursors dispersed in a liquid dispersion medium, c) Add 20*10 to the feed dispersion. 5 Pa to 200*10 5A step of applying a liquid pressure P that reaches Pa to obtain a pressurized feed dispersion, d) The step of extruding the pressurized feed dispersion through the filter element of the apparatus to obtain an extruded dispersion containing target liposomes dispersed in a dispersion medium, e) Optionally, a step of recovering target liposomes from the extruded dispersion, Includes.

[0037] The manufacturing method of the present invention is carried out in the same manner as conventional liposome extrusion processes. Conventional equipment only needs to be replaced with the liposome extruder of the present invention. Therefore, the implementation of the new process can be achieved quickly. Since the extrusion pressure and filter elements are the same as conventional ones, the same product quality can be expected. Therefore, during normal operation, the liposome extrusion process of the present invention achieves the same results as conventional processes.

[0038] The advantage over conventional preparation methods is achieved when the process is carried out until a predetermined degree of clogging is reached in the filter element. This is a normal phenomenon due to clogging of the filter element. Thanks to the design of the apparatus of the present invention employed, worn filter elements can be replaced quickly and easily in the following steps: after the apparatus reaches a predetermined degree of clogging, the pressure is reduced, the cap and socket are separated from each other, the cap is lifted, the filter holder containing the filter element with reduced permeability is replaced with a new filter holder containing a new filter element, the cap is lowered, the socket and cap are reconnected, the apparatus is repressurized, and the process continues.

[0039] A particular advantage is that the horizontal and axial position of the cap relative to the socket is maintained by the guideway, eliminating the need to align the cap to the socket in a complex manner before recombining. Furthermore, the filter element is removed together with the filter holder. The filter holder can be transported to a location with optimized ergonomic conditions for removing the filter element from the filter holder and installing a new one. This is particularly beneficial when the filter holder contains many single filter elements that need to be replaced. Moreover, it is possible to prepare a new filter holder with a new filter element while the device is in operation. When the running process is stopped, only the filter holder carrying the worn filter element is replaced with a new one. This is even faster than replacing the filter element of the filter holder during shutdown. However, this requires at least two filter holders, with the first filter holder in operation and the second filter holder being prepared to replace the first filter holder. Thus, "new filter holder" in the sense of the present invention may be either the same article as the filter holder that previously carried the worn filter element, or a second article that is not currently in operation.

[0040] Thanks to the excellent handling of this device, filter element replacement can be achieved in a short time. In particular, the steps of depressurizing the device, separating the cap and socket from each other, raising the cap, replacing the filter holder containing the filter element with a new filter holder containing the new filter element, lowering the cap, reconnecting the cap and socket, and repressurizing the device can all be performed within 5 minutes.

[0041] If the filter holder is made of a material with a higher magnetic permeability than the socket material, the filter holder may be removed from the socket by a magnetic manipulator. The latter may be a magnetic lifter attached to a crane. This allows for easy removal of heavier versions of the filter holder that cannot be carried by hand. It is worth noting that the filter holder is lighter than the cap of the pressure chamber in any case, since the filter holder is located inside the chamber and therefore does not need to carry the full internal pressure like the cap and socket. The pressure is concentrated only in the area of ​​the filter element. Therefore, the filter element can be sized to be lighter.

[0042] The present invention will be described in more detail by drawings illustrating exemplary embodiments. In particular, the following will be shown. [Brief explanation of the drawing]

[0043] [Figure 1] This is a perspective view of the device with its cap lifted. [Figure 2] This is a side view of the device with the cap lifted. [Figure 3] This is a cross-sectional view from Figure 2 showing the device with its cap lifted. [Figure 4] This is an overhead view of the device from above. [Figure 5] This is a perspective view of the cap connected to the socket of the device. [Figure 6] This is a cross-sectional view of the cap connected to the socket of the device. [Figure 7] This is an overhead view of the filter holder from above. [Figure 8] This is a cross-sectional view of the filter holder. [Figure 9] This is a perspective view of ellipsoid E. [Modes for carrying out the invention]

[0044] Regarding general orientation, some diagrams show the directions of Cartesian coordinates x, y, and z. Typically, x and y are oriented horizontally, and the z axis is parallel to the direction of gravity, and therefore perpendicular.

[0045] Figure 1 shows a perspective view of an embodiment of the apparatus 0 of the present invention, a so-called liposome extruder. Apparatus 0 comprises a fixed frame 1 on which a vertical guideway 2 is provided. The guideway 2 consists of a guide rail 2a and a movable rider 2b fixed to the beam of the frame 1. The rider 2b is movable only in the vertical direction, i.e., in the z-axis direction. The guide rail 2a constitutes the non-movable portion of the vertical guideway 2. The rider 2b and rail 2a may be designed as dovetails (not shown).

[0046] The central part of the device is a pressure chamber 3, which consists of a socket 3a and a cap 3b. The socket 3a is fixed to the frame 1, and the cap 3b is fixed to the rider 2b of the vertical guideway 2, and is therefore movable only in the vertical (z) direction. Movement in the z direction is translational only. Any further movement of the cap 3b (translation in the x or y direction or pivoting around the x, y, or z axis) is restricted by the vertical guideway 2.

[0047] Socket 3a is provided with a receptacle for a filter holder 4. The filter holder 4 is configured as a substantially flat screen containing a plurality of inserted filter elements 5. The latter is best shown in Figure 7. Each filter element 5 is configured as a flat plate made of porous polycarbonate.

[0048] A further part of the device 0 is a means (not shown) for applying fluid pressure and a lifting mechanism 6 for lifting the cap 3b. The lifting mechanism 6 is functionally separated from the vertical guideway 2. This means that while the lifting mechanism 6 applies a force for lifting and holding the cap 3b, the guideway only defines the direction of movement. The lifting mechanism 6 may be a worm gear with a motor or a hydraulic piston.

[0049] During operation (Figs. 5, 6, 7), the filter holder 4 in which the filter element 5 is housed is arranged within the socket 3a. The cap 3b is arranged on the socket 3a, and both parts 3a, 3b are fixed to each other by the bolt connection 7. The inlet to the pressure chamber 3 is established by a means (not shown) for applying pressure, and the outlet from the pressure chamber is defined by the filter element 5.

[0050] As shown in Fig. 6, the pressure chamber 3 constituted by the socket 3a and the attached cap 3b defines an inner cavity 8 having an elliptical shape. In particular, the inner surface 9 of the cap 3b approximates an ellipsoid E defined by the following equation. x 2 / a 2 +y 2 / b 2 +z 2 / c 2 =1

[0051] In this equation, x, y and z are Cartesian coordinates, and a, b and c are defined as the lengths of the semi-axes of the ellipsoid. The ellipsoid E and its dimensions are shown in Fig. 9. The inner surface 9 of the cap 3b defining the edge of the inner cavity 8 is configured such that the lengths of the semi-axes a, b, c of the ellipsoid satisfy both conditions, i.e., c < a = b. This means that the ellipsoid E is circular in a vertical view but flattened in any horizontal view.

[0052] To extrude liposomes, a feed dispersion containing liposome precursors is supplied to the cavity of a closed pressure chamber and subjected to fluid pressure P. Fluid pressure P can be applied hydraulically or pneumatically. The high-pressure apparatus is 100*10 5 Pa to 200*10 5 The range is Pa, and the medium pressure equipment is 20*10 5 Pa to 40*10 5 It is Pa.

[0053] The pressure chamber 3, in particular the socket 3a, cap 3b, and bolt connection 7, is subjected to an even higher internal pressure P. b It is sized to withstand the force generated from it. For security reasons, the pressure chamber has an internal pressure P equivalent to 1.6 times the actual operating pressure P. b It can withstand the following. 1.6 is an example of a safety factor S. The latter may be lower or higher depending on local requirements. Typical safety factors for pressure vessels range from 1.3 to 1.7. Those skilled in the art can select an appropriate safety factor.

[0054] The fluid pressure P causes the dispersion containing the liposome precursor to exit the pressure chamber 3 through the filter element 5. Since the filter element 5 has a specified porosity, the size of the liposomes is reduced to the size of the pores after passing through a certain number of times. Therefore, by selecting the filter element 5 with a given porosity, the pressure, and the number of passes, the size distribution of the liposomes exiting the filter element 5 is determined.

[0055] The extruded dispersion containing target liposomes of the desired size is removed from the apparatus 0. This may be used directly as the intended dosage form of the liposomes, or it may be subjected to further manufacturing steps. For example, residual organic solvents may be removed, or the liposomes may be filled with the active ingredient downstream of the liposome extruder. The liposomes can be separated from the dispersion as needed.

[0056] Due to clogging, the pores of filter element 5 become blocked after a certain operating time in the liposome extrusion process. As a result, the flow through the filter descends and stops at a certain point. To re-establish a high-density size distribution, the worn filter element 5 needs to be replaced with a new one.

[0057] For this purpose, by removing the cap 3b from the socket 3a and lifting the cap 3b, the fluid pressure P is released and the pressure chamber 3 is opened.

[0058] Removal is achieved by opening the bolt connection 7. The bolt connection consists of multiple bolts 7a, each bolt screwed into its respective nut 7b, which is fastened to a U-shaped hook 7c with a cap 3b. Opening the bolt connection 7 is very easy because each bolt 7a is pivotably mounted around a horizontal axis oriented tangentially to the circumference of the socket 3a. After loosening the nut 7b, the bolt 7a with the nut 7b attached can be pivoted around the horizontal axis to release the hook 7c. The bolt 7a will not be lost because it is attached to the socket. Furthermore, there is no need to lift the bolt 7a, and the pivoting is lighter. Finally, since there is no need to remove the nut 7b from the bolt, the number of rotations required to tighten or loosen the screw connection is reduced. More rotations are required to completely remove the bolt from the threads. At first glance, the bolt connection 7 of this device can be opened and closed quickly.

[0059] When the bolt connection 7 is released, the cap 3b can be lifted by the lifting mechanism 6. Once the cap 3b is lifted, the filter holder 4 can be removed from the socket 3a by gripping the handle 10. If only one filter holder 4 is available, a new filter element 5 can be inserted into the filter holder by replacing the worn filter element. A faster method is to provide two filter holders, with the new one being prepared during extrusion. This reduces the process shutdown time.

[0060] In the overhead view in the z direction shown in Figure 4, it is most clearly visible that bolt 7a is located on bolt circle 7d. The axis of the vertical guideway 2 is located inside bolt circle 7d. This allows easy access to all bolts from all sides and provides a wider sector for removing the filter holder 4 from the socket.

[0061] Figures 5 and 6 are similar to Figures 1 and 3, but with cap 3b closed.

[0062] Figure 7 shows the filter holder 4 separately in an overhead view (x / y plane). The filter element (not shown) will be placed in the central receptacle 11 which has a porous flat support screen 12. Since the filter holder 4 is located inside the pressure chamber, it does not need to withstand high pressure loads. Therefore, it is designed to be lightweight. For easy movement by hand, the filter holder 4 is equipped with two handles 10. The filter holder 4 is intended for continuous use, while the filter element is replaced when worn.

[0063] From the cross-sectional view of the filter holder 4 in Figure 8, the receptacle 11 for the filter element and the porous flat support screen 12 can be easily derived.

[0064] A flat, porous drainage element placed between the support screen 12 and the filter element 5 is not shown here. The porosity of the drainage element is selected such that the pore diameter of the drainage element is larger than that of the filter element 5 but smaller than that of the support screen 12. Such a drainage element prevents the filter element 5 from being pushed out into the pores of the support screen 12. [Explanation of Symbols]

[0065] x First horizontal axis y Second horizontal axis z vertical axis 0 Equipment / Liposome Extruder 1 frame 2 Guideway 2a Guide rail 2b Rider 3. Pressure Chamber 3a socket 3b cap 4 filter holders 5 filter elements 6. Lifting mechanism 7 Bolt connection 7a Bolt 7b Nut 7c hook 7d Bolt Circle 8 Cavity 9. Inner self 10 handles 11 Receptacles 12 Porous flat support screen E ellipsoid a. Length of the semi-axis of the ellipsoid in the x-direction b. Length of the semi-axis of the ellipsoid in the y direction. c. Length of the semi-axis of the ellipsoid in the z direction P Fluid pressure P b internal pressure S Safety Factor D Diameter of the pores in the filter element

Claims

1. A device (0) for extruding liposomes, comprising the following components: - A means for applying fluid pressure P to a liquid medium, wherein the fluid pressure P is 20 * 10 ５ Pa to 200*10 ５ The means to reach Pa, - A frame (1) equipped with a vertical guideway (2), - A pressure chamber (3) comprising a socket (3a) and a cap (3b) that are releasably coupled to each other, wherein the socket (3a) is fixed to the frame (1), the cap (3b) is guided vertically by the vertical guideway (2), and the pressure chamber (3) is P ｂ Internal fluid pressure P calculated by = S * P ｂ Designed to withstand and support, where S is a reasonable safety factor, and S is preferably selected from the range of 1.3 to 1.7, and the cap (3b) is given by equation: x ２ / a ２ +y ２ / b ２ +z ２ / c ２ =1 It includes an inner surface (9) that approximates an ellipsoid (E) defined by, x, y, and z are Cartesian coordinates, x and y are oriented horizontally, z is oriented vertically, a, b, and c are defined as the semi-axis lengths of the ellipsoid (E), the pressure chamber (3) is designed such that a, b, and c, which are the semi-axis lengths (E) of the ellipsoid, satisfy both the conditions c < a and c < b, and the cap (x) is designed such that a and b, which are the semi-axis lengths of the ellipsoid (E), satisfy the conditions a = b < 500 mm or a = b < 300 mm, and is connected to the pressure chamber (3), - A filter holder (4) is detachably attached to the socket (3a), - At least one porous filter element (5) defining the outlet of the pressure chamber (3), wherein the filter element (5) includes an opening having a diameter D, and the diameter of the opening D is 50 * 10 －９ m to 50*10 －６ m or 80*10 －９ m to 5*10 －６ A porous filter element (5) that reaches m, thereby housing the filter element (5) in the filter holder (4), A device (0) equipped with the following:

2. The apparatus (0) according to claim 1, wherein the cap (3b) is designed such that the semi-axis lengths a and b of the ellipsoid (E) satisfy the condition a = b.

3. The apparatus (0) according to claim 1 or 2, characterized in that the ellipsoid (E) is convex.

4. The apparatus according to at least one of claims 1 to 3, wherein the cap (3b) is designed such that the semi-axis length c of the ellipsoid (E) satisfies the condition 10 < c < 20 mm.

5. The apparatus (0) according to at least one of claims 1 to 4, wherein the filter holder (4) comprises a substantially flat support screen (12) and one or more filter elements (5), so that the flat support screen (12) extends substantially horizontally, and the flat support screen (12) is porous and configured so that a liquid medium can flow through the filter holder (4).

6. The apparatus (0) according to claim 5, wherein the filter holder (4) further comprises at least one flat porous drainage element located between the support screen (12) and the filter element (5), the pore size of the drainage element being larger than the pore size of the filter element (5) and the pore size of the drainage element being smaller than the pore size of the support screen (12).

7. The apparatus (0) according to at least one of claims 1 to 6, wherein the filter holder (4) includes at least two handles (10) to be gripped for removing the filter holder (4) from the socket (3a).

8. The apparatus (0) according to at least one of claims 1 to 7, wherein the filter holder (4) is made of a material having a higher magnetic permeability than the material of the socket (3a).

9. The apparatus (0) according to at least one of claims 1 to 8, characterized in that the filter element (5) is a flat plate made of a porous material selected from the group consisting of polycarbonate, sintered metal, and metal foil, and thereby the flat plate is preferably circular in shape.

10. The apparatus (0) according to at least one of claims 1 to 9, further comprising a lifting mechanism (6) designed to raise and lower the cap (3b).

11. The apparatus (0) according to claim 10, wherein the lifting mechanism (6) is functionally separated from the guideway (2).

12. The apparatus (0) according to claim 11, wherein the frame (1) comprises one, preferably exactly one, vertically erected beam extending outward from the pressure chamber (3), the beam forming a guide rail (2a), the cap (3b) comprising a rider (2b), and the rider (2b) being vertically movable on the rail (2a) such that the guideway (2) is composed of the guide rail (2a) and the rider (2b).

13. The apparatus (0) according to claim 12, characterized in that a socket (3a) and a cap (3b) are releasably connected to each other by a bolt connection (7), the bolt connection (7) includes a plurality of vertically extending bolts (7a) located on a horizontally arranged bolt circle (7d), and the effective axis of the vertical guideway (2) points around the bolt circle (7d).

14. The apparatus (0) according to claim 13, characterized in that at least one bolt (7a) is pivotably attached to the socket (3a), and the axis of rotation between the bolt (7a) and the socket (3a) extends horizontally.

15. A process for preparing target liposomes from liposome precursors, comprising the following steps: a) Providing an apparatus (0) for extruding liposomes according to at least one of claims 1 to 14, b) Providing a feed dispersion containing liposome precursors dispersed in a liquid dispersion medium, c) Add 20 * 10 ５ From 200*10 ５ A step of applying a liquid pressure P that reaches Pa to obtain a pressurized feed dispersion, d) The step of extruding the pressurized feed dispersion through the filter element (5) of the apparatus (0) to obtain an extruded dispersion containing target liposomes dispersed in a dispersion medium, e) Optionally, a step of recovering target liposomes from the extruded dispersion, A process that includes this.

16. The process according to claim 15, characterized in that the process is carried out until a predetermined degree of clogging is reached in the filter element (5), and after the predetermined degree of clogging is reached, the apparatus (0) is depressurized, the cap (3b) and socket (3a) are separated from each other, the cap (3b) is raised, the filter holder (4) containing the filter element (5) with reduced permeability is replaced with a new filter holder (4) containing a new filter element (5), the cap (3b) is lowered, the socket (3a) and cap (3b) are reconnected, the apparatus (0) is repressurized, and the process is continued.

17. The following steps, namely The apparatus (0) is depressurized, the cap (3b) and socket (3a) are separated from each other, the cap (3b) is raised, the filter holder (4) containing the filter element (5) with reduced permeability is replaced with a new filter holder (4) containing a new filter element (5), the cap (3b) is lowered, the socket (3a) and cap (3b) are reconnected, and the apparatus (0) is repressurized. The process according to claim 16, wherein the steps are performed within 5 minutes.

18. The process according to claim 17 or 18, characterized in that the filter holder (4) is made of a material having a higher magnetic permeability than the material of the socket (3a), and the filter holder (4) is removed from the socket (3a) by a magnetic manipulator.

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