PROCESS FOR PRODUCING A COMPOSITION COMPRISING A CROSSLINKED HYDROGEL

Abstract

A process for producing a composition comprising a crosslinked hydrogel is proposed. The process comprises providing a container body (2), wherein the container body (2) has a body inner wall (21) and a body outer wall (22), wherein the body inner (21) wall is configured to be tempered, filling of a fluid (7) comprising at least a mixture of a polymer and water into the container body (2), and agitating the fluid. For crosslinking of the fluid (7), a container insert (3) is provided, the container insert (3) having an insert outer wall (32) which is configured to be tempered and a container assembly (1) is formed by inserting the container insert (3) into the container body (2) so that the insert outer wall (32) of the container insert (3) and the body inner wall (21) of the container body (2) are separated by a gap (9) of constant width and define a volume (6) for receiving the fluid (7). Crosslinking of the fluid (7) is then performed while tempering the insert outer wall (32) and the body inner wall (21) to form a crosslinked hydrogel.

Claims

1-19. (canceled)

20. A process for producing a composition comprising a crosslinked hydrogel comprising the steps of providing a container body (2), wherein the container body (2) has a body inner wall (21) and a body outer wall (22), wherein the body inner wall (21) is configured to be tempered, filling of a fluid (7) comprising at least a mixture of a polymer and water into the container body (2), agitating the fluid (7), providing a container insert (3), the container insert (3) having an insert outer wall (32) which is configured to be tempered, forming of a container assembly (1) by inserting the container insert (3) into the container body (2) so that the insert outer wall (32) of the container insert (3) and the body inner wall (21) of the container body (2) are separated by a gap (8) of constant width and define a volume (6) for receiving the fluid, and crosslinking of the fluid (7) while tempering the insert outer wall (32) and the body inner wall (21) to form a crosslinked hydrogel.

21. The process of claim 20, wherein the container assembly (1) further comprises a scrapper (41) having a cross section equivalent to the cross section of the volume (6) defined by the insert outer wall (32) and the body inner wall (21), and wherein after inserting of the container insert (3) and before tempering the scrapper (41) is moved along the insert outer wall (32) and the body inner wall (21) in order to wipe off any residual fluid.

22. The process of claim 21, wherein, after scrapping, the scrapper (41) is moved such that it rests on the fluid surface and thus covers the fluid.

23. The process of claim 20, wherein the container body (2) and the container insert (3) have a cylindrical shape and the scrapper (41), if present, has an annular shape.

24. The process of claim 20, wherein an agitating device is provided and is inserted into the container body (2) during the step of agitating the fluid.

25. The process of claim 24, wherein the agitating device comprises at least one kneading hook, anchor, or mixing blade.

26. The process of claim 20, wherein the body inner wall (21) and/or the insert outer wall (32) are configured to be tempered by a temperature control medium.

27. The process of claim 26, wherein a piping system for the temperature control medium is arranged within a space defined between the body outer wall (22) and the body inner wall (21) of the container body (2) and/or within the insert outer wall (32) of the container insert (3).

28. The process of claim 26, wherein the body inner wall (21) and the body outer wall (22) of the container body (2) and/or the insert outer wall (32) and a further wall (31) of the container insert (3) define a space for guiding the temperature control medium.

29. The process of claim 28, wherein baffles are arranged within the space defined by the body outer wall (22) and body inner wall (21) and/or defined by the insert outer wall (32) and the further wall (31).

30. The process of claim 20, wherein the width of the gap (8) is in the range of from 5 mm to 100 mm.

31. The process of claim 20, wherein the step of crosslinking is carried out at a temperature In the range of 4° C. to 98° C.

32. The process of claim 20, wherein the polymer is a hyaluronic acid and/or a sodium salt thereof.

33. The process of claim 20, wherein after crosslinking the container insert (3) is removed from the container body (2).

34. The process of claim 20, wherein, after crosslinking, the crosslinking is terminated and the crosslinked hydrogel is subsequently subjected to dialysis or diafiltration or the crosslinked hydrogel is subjected to dialysis or diafiltration for termination of crosslinking.

35. The process of claim 20, wherein the crosslinked hydrogel is blended with a further polymer and/or at least one further component.

36. The process of claim 34, wherein, after dialysis or diafiltration, the crosslinked hydrogel or a blend comprising the crosslinked hydrogel is filled into a syringe and the syringe is sterilized.

37. The process of claim 35, wherein, after dialysis or diafiltration, the crosslinked hydrogel or a blend comprising the crosslinked hydrogel is filled into a syringe and the syringe is sterilized.

38. A composition comprising a crosslinked hydrogel obtained by a process of claim 20.

39. A method for treating a subject, comprising the use of the composition of claim 38 in a cosmetic application or as a dermatological filler.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0091] The Drawings Show

[0092] FIG. 1 a cross-sectional view of a container body,

[0093] FIG. 2 a cross-sectional view of the container body and an agitator,

[0094] FIG. 3 a cross-sectional view of a container assembly comprising the container body and a container insert,

[0095] FIG. 4 a diagram showing the temperature inside different container assemblies, and

[0096] FIG. 5 product comprising over-crosslinked particles when prepared according to the prior art.

[0097] FIG. 1 shows a cross-sectional view of a container body 2 for use in the described process for producing crosslinked hydrogels. The container body 2 as shown in FIG. 1 has a circular cylindrical shape and has a body inner wall 21 and a body outer wall 22. Within a space defined by the body inner wall 21 and the body outer wall 22, means for tempering of the body inner wall 21 are arranged which are not shown in the schematic view of FIG. 1. The means for tempering are, for example, a piping system for a temperature control fluid which is in contact with the body inner wall 21. A fluid 7 is received in the container body 2.

[0098] The fluid 7 is, for example, a precursor for the production of a hydrogel and may, for example, comprise a mixture of hyaluronic acid, water and a crosslinker.

[0099] FIG. 2 shows a cross-sectional view of a container body 2 as described with respect to FIG. 1, wherein an agitator 5 has been inserted into the container body. The agitator 5 comprises in the shown example embodiment two kneading hooks 51 which engage the container body 2 and are partially submerged in the fluid 7 received in the container body 2.

[0100] By means of the agitator 5 the fluid 7 may be homogenized.

[0101] FIG. 3 shows a container assembly 1 comprising the container body 2 as described with respect to FIG. 1 and a container insert 3. The container insert 3 comprises an insert outer wall 32 and an insert further wall 31. Within a space defined by the insert further wall 31 and the insert outer wall 32, means for tempering of the insert outer wall 32 are arranged which are not shown in the schematic view of FIG. 1. The means for tempering are, for example, a piping system for a temperature control fluid which is in contact with the insert outer wall 32.

[0102] In the situation shown in FIG. 3, the container insert 3 has been inserted into the partially filled container body 2 so that the fluid 7 is partially displaced by the container insert 3. The insert outer wall 32 and the body inner wall 21 are arranged parallel with respect to each other and the distance between the body inner wall 21 and the insert outer wall 32 defines the width of a gap 8. The gap 8 defines a volume 6 which receives the fluid 7.

[0103] The container assembly 1 further comprises a scrapper 4. The scrapper 4 has a cross section equivalent to the cross section of the volume defined by the insert outer wall 32 and the body inner wall 21. The scrapper 4 may be moved along the insert outer wall 32 and the body inner wall 21 in order to wipe off any residual fluid 7.

[0104] In the situation shown in FIG. 3, the scrapper 4 has been moved such that it rests on the fluid surface and thus covers the fluid 7.

[0105] The space defined by the gap 8 is formed such that every part of the volume of the fluid 7 is located near one of the tempered surfaces, namely the body inner wall 21 and the insert outer wall 32. Thus, the entire volume of the liquid 7 will easily arrive at a set temperature with minimal temperature gradient so that the temperature of the liquid 7 is nearly homogeneous.

[0106] The diagram of FIG. 4 shows the temperature vs. time for two different container assemblies 1. The sensor used for temperature measurement was located within the volume formed by the gap. For temperature control, a different sensor is used which is preferably arranged at or near the inner wall 22 of the container body 2. A first curve 82 shows the temperature of a first container assembly 1 having a volume of 20 I. A second curve 83 shows the temperature of a second container assembly 1 having a volume of 3 I. The volume refers in each case to the volume of the container body 2 with the container insert 3 removed. A third curve 81 shows the temperature set point which in this example was first set to 40° C. and then reduced to 5° C. after completion of the crosslinking.

[0107] FIG. 5 shows a picture of the production of a hydrogel with a process not according to the invention. In particular a conventional mixing vessel having only a container body 2 is used. No container insert 3 is provided. Without the use of the container insert 3, tempering of the fluid may only be effected by tempering the inner wall of the mixing vessel. Accordingly, there is a large temperature gradient within the received fluid.

[0108] Due to the temperature gradient, the crosslinking reaction is non-homogeneous. Due to evaporation (i.e. dehydration) on the gel surface the crosslinking reaction becomes more intense and solid particles form. In the picture of FIG. 5, a kneading hook 51 is just removed from the mixing vessel. Crosslinked hydrogel 71 having particles 72 are visible. These particles do not dissolve in the subsequent process and lead to rejects in the final product. The production of such particles 72 may be avoided by means of the proposed process making use of the container insert 3 during the step of crosslinking.

LIST OF REFERENCE NUMERALS

[0109] 1 container assembly [0110] 2 container body [0111] 3 container insert [0112] 4 scrapper [0113] 5 agitator [0114] 6 volume for receiving fluid [0115] 7 fluid [0116] 8 gap [0117] 21 container body inner wall [0118] 22 container body outer wall [0119] 23 container body temperature control medium inlet [0120] 24 container body temperature control medium outlet [0121] 31 container insert further wall [0122] 32 container insert outer wall [0123] 51 kneading hooks [0124] 71 crosslinked product [0125] 72 over-crosslinked particles [0126] 81 temperature set point [0127] 82 temperature 201 container [0128] 83 temperature 31 container