WO2015162273A1

WO2015162273A1 - A method to dry multiple individual frozen bodies and a system for applying this method

Info

Publication number: WO2015162273A1
Application number: PCT/EP2015/058974
Authority: WO
Inventors: Niels BRANKAERT; Tofan WILLEMSZ; Fried FAASSEN; Gerrit Jan Willem HUISKAMP; Vincent Bons; Foppe BAKKER
Original assignee: Merck Sharp & Dohme Bv
Priority date: 2014-04-25
Filing date: 2015-04-24
Publication date: 2015-10-29

Abstract

The present invention pertains to a method to dry multiple individual bodies comprising frozen liquid having a pharmaceutical compound contained therein, the method comprising providing a container having one or more walls that define a volume that contains the said multiple individual bodies, the volume of the container being closed by a top wall that prevents particulate material to pass from the environment into the container, subjecting the bodies in the container to a reduced pressure, and providing heat to the bodies to support sublimation of the frozen liquid at the reduced pressure, wherein the top wall is a vapour permeable membrane. The invention also pertains to a system for applying this method.

Description

A METHOD TO DRY MULTIPLE INDIVIDUAL FROZEN BODIES AND A SYSTEM FOR APPLYING THIS METHOD

Field of the invention The invention pertains generally to a method to dry multiple individual bodies comprising frozen liquid having a pharmaceutical compound contained therein, the method comprising providing a container having one or more walls that define a volume that contains the said multiple individual bodies, the volume of the container being closed by a top wall that prevents particulate material to pass from the environment into the container, subjecting the bodies in the container to a reduced pressure and providing heat to the bodies to support sublimation of the frozen liquid at the reduced pressure. The invention also pertains to a system suitable for applying this method.

Background art

A method as described supra is known from WO 2009/092703. In particular, the known method aims at an economic process to obtain multiple individual fast disintegrating tablets. For this, in a first step multiple individual frozen bodies are provided, which bodies contain the pharmaceutical compound, where after the bodies are transferred to a container and placed in the form of a packed bed comprising multiple layers of frozen bodies. Optionally the container is closed with a lid, that is, if the lid has holes in it to allow vapour to escape from the container. Thereafter the bodies are dried in a vacuum (also called "lyophilized"). In such a method, after a sufficient amount of the frozen liquid is sublimated, the provision of heat to the particles is stopped and the pressure may be brought back to atmospheric. A sufficient amount in this sense typically is more than 90% of the total amount of liquid originally present in the body, often more than 95%, or even more than 96%, 97% or 98% up to 100%. By packing multiple individual bodies in one single container, the drying step is operated at a significantly higher efficiency than other known methods wherein the frozen bodies are individually dried in separate containers. The lyophilization step wherein the frozen liquid is sublimated is used to increase the shelf-life of pharmaceutical products. By removing the liquid (usually water) an amorphous matrix may be created that to a great extent prevents molecules from chemical deterioration. The rate of lyophilization is dependent i.a. on the pressure during lyophilization and the amount of heat transferred to the frozen bodies. The heat is provided to a large extent by conduction through the walls of the container. However, as known from WO 2009/092703, in particular when lyophilizing multiple individual frozen bodies that are kept in one container (and thus, each body has hardly any contact with the heat conducting walls of the container), conduction alone might lead to a process which takes too long. In particular for pharmaceutical compounds, a short lyophilization time is critical since typically a substantial amount of activity of the compound is lost during the heating step in the lyophilizer. Therefore, it is proposed in WO 2009/092703 to use an additional heat source above a top layer of the packed bodies, the heat source providing radiant heat to the frozen bodies.

Object of the invention It is an object of the invention to provide an alternative method to improve the lyophilisation process as known in the art, in particular aiming at short drying times.

Summary of the invention

In order to meet the object of the invention, a method as indicated here above in the "Field of the invention" paragraph has been devised, in which method the top wall is a vapour permeable membrane. Surprisingly it has been found that applying a vapour permeable membrane as a closure to the container, the multiple individual frozen bodies can be dried in short drying times, even shorter than without applying a closure or applying a rigid lid with holes as a closure. The reason for the short drying times is not understood. A rigid cover that serves as a top wall for a freeze-drying container is generally known in the art, for example as described in EP 343 596. Typically the cover has holes to allow water vapour to pass the cover, but impermeable for coarse particulate material. A well-known downside of the use of such a cover is that the drying times are prolonged, and typically are in 72-96 hour range. The reason for this is commonly understood: by restricting the clearance of the vapour that arises from the sublimation of the frozen liquid, the sublimation process is hindered and will take longer. For many applications, such as the lyophilization of food, beverages, blood and other bulk compounds, such a long lyophilization time is not significantly detrimental for the constitution of the end product (food and beverages may lose some of their taste, and blood may lose some viability of the red blood cells, but neither of this is detrimental for the application of the products). For pharmaceutical compounds this is completely different: any loss of activity of the compound may amount to a significant economic loss, since the required activity in the end-product is specified by a license obtained from a regulatory authority. Loss of activity means fewer doses can be made with the same amount of starting material. Therefore, short drying times are very important for frozen bodies containing a pharmaceutical compound. The reason why a severe restriction in the clearance of the vapour, as is the case when applying a vapour permeable membrane, may lead to even shorter drying times when drying multiple individual frozen bodies that are packed in one container, is not clear to applicant but may be due to a possible improved heat transfer to the frozen bodies. In a situation where multiple individual frozen bodies are packed in one container (i.e. in one single volume of a receptacle), the conduction of heat to the bodies may be the bottle-neck in the drying process. If so, a restriction for the vapour to escape, which inherently leads to a more densely packed "air" around the bodies, may lead to an additional heat transfer process {viz. convection via the air). This possible increased heat transfer may contribute to a shorter drying time. Also, it may be that the very even, typically virtually homogenous distribution of the vapour permeability of a membrane, when compared to a rigid lid having holes drilled therein, may contribute to a better drying process.

The invention also pertains to a system to dry multiple individual bodies comprising frozen liquid having a pharmaceutical compound contained therein, comprising a closed room that can be subjected to a reduced pressure, a container having one or more walls that define a volume that contains the said bodies, the volume of the container being closed by a top wall that prevents particulate material to pass from the environment into the container, and a heating means to provide heat to the bodies to support sublimation of the frozen liquid at the reduced pressure, wherein the top wall is a vapour permeable membrane. Definitions

A container s a receptacle in which material can be held. It comprises one or more walls that together define a volume for holding the material. A typical rectangular container has one bottom wall and four side walls that define the volume. For a bag like container, separate bottom and side walls can often not be distinguished. A container may comprise a top wall to close the volume. The walls may join at sharp edges, such as in the case of a rectangular box-like container, or may join without sharp edges such as in the case of a bag-like container (in which type of container the bottom, side and top walls cannot be distinguished separately). Multiple other three-dimensional forms may be used to constitute a container.

A membrane is thin and pliable sheet-like structure, as opposed to a rigid plate that can maintain its shape under the force of gravity.

A Pharmaceutical compound is a compound that can be used to treat a disease or disorder, i.e. to aid in preventing, ameliorating or curing the disease or disorder. Such a substance may for example be a chemical or biological compound, such as a natural or synthetic peptide or protein, a (poly-)saccharide or any other organic or inorganic molecule, a dead or alive micro-organism, a dead or alive parasite etc.

Particulate material is material that comprises separate particles that can be seen with the un-aided human eye, i.e. particles having a diameter above 0.1 mm.

A micro-organism is an organism that has dimensions in the (sub-) micrometer range, such as a bacterium and a virus.

Reduced pressure is any pressure below 1000 mbar, in particular below 100 mbar.

Embodiments In a first embodiment the membrane does not allow passage of micro-organisms. This way, contamination of the frozen bodies with micro-organisms can be prevented. In particular for a pharmaceutical compound that needs to be administered systemically, and thus, needs to be sterile, this is an important improvement. WO 96/31748 describes such a membrane. In an embodiment the bodies are stacked in the container forming multiple layers of frozen bodies. In particular when drying multiple layers of frozen bodies the present invention is advantageous. The bodies that lie on top the bottom layer are typically not in contact with any of the walls of the container and thus, depend to a substantial extent on heat conduction via neighbouring bodies to acquire sufficient heat for the sublimation of the frozen liquid. In the beginning of the drying process this is not much of a problem. Given the high frozen liquid content, the bodies conduct heat quite well. However, during the drying process the bodies lose liquid and thereby also their heat conduction capabilities are reduced. Conduction of heat through the bed of particles is thereby hampered. It is believed that by using a cover for the container, heat transfer is improved by having a higher vapour pressure in the open space between the frozen bodies.

In still another embodiment the said one or more walls as defined here above are made of a heat conducting material (having a thermal conductivity equal to or above 0.1 W/mK), the heat being provided by heating at least one of the one or more walls. This embodiment allows a convenient basic transfer of heat to the frozen bodies present in the container.

In another embodiment in a first step multiple individual frozen bodies are produced, where after these bodies are transferred to the container. This allows for using a dedicated process for the provision of the frozen bodies, instead of a process wherein the bodies are made in the container itself.

In yet another embodiment the top wall is a separate part that is in operative connection with the one or more walls of the container. This embodiment allows more freedom of operation, when compared to a situation wherein the top wall is a unit of the container itself (such as for example when using a closed bag as the container). The top wall could for example be a lid that hinges on a side wall of the container, or a completely separate part that simply is put on top of the open volume of the container. It could also be a membrane that is taped or otherwise brought in operative connection with the container. The invention will be illustrated using the following non-limiting figures and examples. Figure 1 schematically shows the basic parts of an apparatus for obtaining frozen bodies

Figure 2 schematically shows a drying chamber for use in the present method and system

Figure 3 schematically shows various configurations of containers provided with a top wall that serves as a cover.

Example 1 describes the application of the method according to the invention and shows the obtainable effects.

Figure 1

Figure 1 schematically shows the basic parts of an apparatus for obtaining frozen bodies as is known from WO 2010/125084 (the description on pages 15-17 of this international application, as far as it relates to figures 1 and 2 of that application is incorporated herein by reference). Central parts are a cavity tray 100 and corresponding cooling element 105. Cavity tray 100 in this embodiment is a solid steel plate having a thickness of 6 mm. In the plate three rows (102, 103 and 104) of cavities are formed. Tray 100 rests under gravitational forces on cooling element 105. This element is a hollow stainless steel box, having a height of about 6 cm which box can be cooled by introducing liquid nitrogen at a temperature of about -196°C. This way the tray 100 can be cooled adequately (typically to a temperature of about -125°C) to obtain a very fast solidification process when a fluid formulation is dispensed in one (or more) of the cavities.

At the front (downstream of the tray 100) a black plastic container 15 is shown, which container has handles 16 for manually handling the container. This container 15 is placed directly against cooling element 105. The container is cooled to a temperature of about -45°C by having its support (not shown) cooled by using liquid nitrogen. At the other side of the tray 100 (upstream side) a collecting element 120 is shown, which element is divided into three compartments 121 , 122 and 123. This element travels over the surface of tray 100 (with a space of about 0.2 mm between the bottom of element 120 and the surface of tray 100) in the direction C and pushes frozen bodies out of their cavities. These bodies are then collected in each of the compartments 121 , 122 and 123 and are ultimately brought over into container 15. Attached to collecting element 120, via brackets 131 , is dispensing unit 130. This unit comprises three needles 132, 133 and 134, corresponding to cavity rows 102, 103 and 104 respectively. The needles are used to dispense the fluid formulation in each of the cavities. The fluid formulation is supplied to each of the needles via tubes 152, 153 and 154 respectively.

When operating the device, the atmosphere is cooled to a temperature of around 15°C using dry nitrogen gas. Because of this relatively high temperature of the surrounding atmosphere, a water based fluid formulation can be handled in and around the apparatus without the risk that the formulation freezes in the tubes 152, 153, 154 or the needles 132, 133 and 134. Dry nitrogen gas is used to prevent crystallization of water into ice on the various parts that are kept below 0°C. In this setup, the tray 100 will have an equilibrium temperature of about -125°C. The collecting element 120 has a temperature around -35°C, and the container 15 will have a temperature of about -45°C.

The process starts with moving the element 120 in the direction C until the needles coincide with the first (upstream) cavities. Then the movement of element 120 is temporarily stopped, and the first three cavities are filled with fluid formulation. When finished, the element 120 moves forward until the needles coincide with the next three cavities. Then, these cavities are filled with fluid formulation. This process continues till all cavities are filled with the fluid formulation. Then the element 120 is lifted somewhat (about 25 mm) and brought back to its original position at the upstream part of the tray 100. Then the element 120 travels forward again in the shown direction C. This time, the element will come across frozen bodies in each of the cavities. The bodies are pushed out of their cavities and collecting in the compartments 121 , 122 and 123 respectively. In this process, each body may remain for example between 20 and 90 seconds in its cavity (from filling until pushing out, depending i.a. on the size of the body: the larger the body, the longer the solidification process will take). At the same time, upstream of element 120, the emptied cavities are refilled as described here-above. This process continues until container 15 is adequately filled with frozen bodies.

Figure 2

In figure 2 a lyophiliser (freeze-dry apparatus) is schematically depicted. Such a lyophiliser could for example be the Christ Epsilon 2-12D as available from Salm en Kipp, Breukelen, The Netherlands. The lyophiliser 1 comprises a housing 2 and multiple shelves 3. The Epsilon 2-12D comprises 4 + 1 shelves, for matters of convenience three of these shelves (viz. shelves 3a, 3b and 3c) are shown in figure 1. Each of these shelves is provided with a heating element 5 (referred to with numerals 5a, 5b and 5c respectively) for even heating of the shelves 3. The heating is controlled by making use of processing unit 10. The housing is connected to a pump unit 1 1 for providing adequate low pressure within the housing 2. The interior of the housing can be cooled to a temperature as low as -60°C by using cooling unit 12, in particular containing a condenser (in fact, it is the condenser that is kept at about -60°C, which acts as a driving force for condensation of sublimated ice).

Placed on the shelves are container 15 and 15'. These containers are made of a heat conducting material, in this case carbon black filled polyethyleneterephtalate. The containers are in a heat conducting contact with the shelves on which they rest. In the shown arrangement, the containers are filled with frozen bodies 30 which thus form a bed 29 of packed bodies in each container. Container 15 is provided with a top cover 8 which in this embodiment is a vapour permeable membrane stretched in a frame that snugly fits the upper circumference of the side walls of the container. The fitting is tight enough to prevent any particulate material to enter the container. Container 15' is provided with a comparable top cover 8'. By heating the shelves, the particles may receive heat via the heated bottom and side walls of the containers. Ultimately, the top cover 8 will also be heated (via the connection with the side-walls and contact with the vapour) and may serve as a radiant heater for the frozen bodies. It is noted that each container 15 has a width and length of about 20 to 30 cm and a height of about 4 cm. The height of the packed bed after filling the container is typically 1 .5 to 3 cm. This leads to typical values for an aspect ratio of the bed of between 7 (=20/3) to about 20 (30/1 .5). However, monolayer arrangement of bodies can also be used.

Figure 3

Figure 3 schematically shows various configurations of containers provided with a top wall that serves as a cover. Figure 3A shows a container 15, made from a heat conductive plastic material, having a row of macroscopic vents 201 along its

circumference near the bottom. As a cover 8, a comparable container is used upside- down. This container also has a row of macroscopic vents 200. The two continuous rows of vents may be sufficient to allow vapour to escape from the inner volume of the container. Figure 3B shows an arrangement according to the invention wherein a container 15', also made from a heat conductive material, is provided with cover 8 that consists of a vapour permeable membrane 205 that is stretched in a frame 210 that cooperates with the upper circumference of the side walls of the rectangular container 15. This cooperation consists of a precise, tight fit of the frame over the side walls. In figure 3C an embodiment is shown as known from WO2009/092703, in which embodiment the cover 8" is in fact a rigid lid, provided with drilled holes (not shown), which lid hinges, using hinge 220, on the container 15".

Example 1

In this example an experiment is described wherein individual bodies comprising frozen liquid are dried to become so-called lyospheres, wherein the drying takes place by packing multiple individual bodies in one single container. The container in this experiment being a rectangular open box-like structure that is either used as such, closed with a rigid lid (Lyoguard cover) are closed with a vapour permeable membrane.

Materials

The container used in this experiment is an open container, made of carbon black filled black PETG (polyethylene terephtalateglycol), having dimensions of 307 x 245 x 24.5 (I x w x h in mm). The bodies to be dried are made as described in WO 2010/125084. The liquid which was used to make the frozen bodies comprised 86,9% of water, 4%

Montelukast sodium (Singulair, Merck USA), 1 % Gelatin BS100 (available from Gelita, Eberbach Germany), 8% mannitol (Paerlitol 160C, available from Roquette, Lestrem, France), 0.04% sucralose and 0.06% mint flavour (all mass percentages). This liquid formulation was used to produce 250μΙ spheres (about 260 mg), having oblate dimensions of 6 mm high and 8 mm wide.

For the top wall, the following cover materials were used: i) Vapour permeable membrane: Stopper bag (available as Biosafe® Aseptic

Transfer Single-Use Bag, from Sartorius, Gottingen, Germany); ii) Vapour permeable membrane: Cheese cloth (available as Sefar Nitex® 50 , from Lampe Technical Textiles BV, Sneek, The Netherlands);

iii) Rigid lid: Lyoguard cover (available from W.L. Gore & Associates, Elkton, USA). Methods

Each tray contained approximately 1320 frozen bodies (which equals approximately two layers of bodies) and was covered using the materials as described above or left uncovered. Each tray was stored in a freezer at -60°C prior to freeze-drying. A laboratory-scale freeze-dryer (Christ LPC-32; Martin Christ Gefriertrocknungsanlagen GmbH, Osterode am Harz, Germany) was used for freeze-drying. The end point of drying (leaving approximately 1 % of the water in the bodies) was determined with a temperature measurement using thermocouples that were placed between the spheres. Shelves inside the freeze dryer were pre-cooled at minus 35°C prior to loading. After loading trays the freeze drying cycle was started according to Table 1 .

Table 1: freeze-dry cycle

Results

In table 2 it is indicated how many hours in took to reach the predetermined end-point (laving 1 % of the water in the resulting lyospheres).

It is clearly shown that when using a vapour permeable membrane as cover material, the drying time can be considerably shortened, despite the fact that the vapour clearance is restricted significantly.

Table 2: required drying time

Type of cover Total drying time (hh:mm)

Stopper bag 09:52

Cheese cloth 09:37

Lyoguard 12:22

No cover 15:37

Claims

1 . A method to dry multiple individual bodies (30) comprising frozen liquid having a pharmaceutical compound contained therein, comprising:

- providing a container (15) having one or more walls that define a volume that contains the said multiple individual bodies, the volume of the container being closed by a top wall (8) that prevents particulate material to pass from the environment into the container,

- subjecting the bodies in the container to a reduced pressure, and

- providing heat to the bodies to support sublimation of the frozen liquid at the reduced pressure, characterised in that the top wall is a vapour permeable membrane.

2. A method according to claim 1 , characterised in that the membrane does not allow passage of micro-organisms.

3. A method according to any of the preceding claims, characterised in that the bodies are stacked in the container forming multiple layers (29) of frozen bodies.

4. A method according to any of the preceding claims, characterised in that the said one or more walls as defined in claim 1 are made of a heat conducting material, the heat being provided by heating at least one of the one or more walls.

5. A method according to any of the preceding claims, characterised in that in a first step multiple individual frozen bodies are produced, where after these bodies are transferred to the container.

6. A method according to any of the preceding claims, characterised in that the top wall is a separate part that is in operative connection with the one or more walls of the container as defined in claim 1 .

7. A system to dry multiple individual bodies (30) comprising frozen liquid having a pharmaceutical compound contained therein, comprising: - a closed room (2) that can be subjected to a reduced pressure,

- a container (15) having one or more walls that define a volume that contains the said bodies, the volume of the container being closed by a top wall (8) that prevents particulate material to pass from the environment into the container, the top wall being provided with multiple holes (200, 201 ) to allow vapour to pass the top wall, and

- a heating means (5) to provide heat to the bodies to support sublimation of the frozen liquid at the reduced pressure, characterised in that the top wall is a vapour permeable membrane.