US-12617903-B2 - Process for producing a composition comprising a crosslinked hydrogel

US12617903B2US 12617903 B2US12617903 B2US 12617903B2US-12617903-B2

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.

Inventors

Wolfgang Kessler
Roland Stragies
Alexander Linko

Assignees

MERZ PHARMA GMBH & CO. KGAA

Dates

Publication Date: 20260505
Application Date: 20201208
Priority Date: 20191209

Claims (20)

1 . A process for producing a composition comprising a crosslinked hydrogel, the process comprising the steps of providing a container body, wherein the container body has a body inner wall and a body outer wall, wherein the body inner wall is configured to be tempered by means of temperature control arranged within a space defined between the body outer wall and the body inner wall of the container body, filling with a fluid comprising at least a mixture of a polymer and water into the container body, agitating the fluid, providing a container insert, the container insert having an insert outer wall which is configured to be tempered by means of temperature control arranged within a space defined within the insert outer wall of the container insert, forming a container assembly by inserting the container insert into the container body so that the insert outer wall of the container insert and the body inner wall of the container body are separated by a gap of constant width that defines a volume for receiving the fluid, and crosslinking the fluid while tempering the insert outer wall by the means of the temperature control arranged within the space defined within the insert outer wall of the container insert and, while tempering the body inner wall by the means of temperature control arranged within the space defined between the body outer wall and the body inner wall of the container body to form a crosslinked hydrogel, wherein the fluid is not agitated during the crosslinking to obtain the crosslinked hydrogel free of solid particles formed during the step of crosslinking.
2 . The process of claim 1 , wherein the container assembly further comprises a scrapper having a cross section equivalent to the cross section of the volume defined by the insert outer wall and the body inner wall, and wherein after inserting of the container insert and before tempering the scrapper is moved along the insert outer wall and the body inner wall in order to wipe off any residual fluid.
3 . The process of claim 2 , wherein, after scrapping, the scrapper is moved such that it rests on the fluid surface and thus covers the fluid.
4 . The process of claim 1 , wherein the container body and the container insert have a cylindrical shape and the scrapper, if present, has an annular shape.
5 . The process of claim 1 , wherein an agitating device is provided and is inserted into the container body during the step of agitating the fluid, wherein the agitating device is removed from the container body before the container insert is inserted into the container body.
6 . The process of claim 5 , wherein the agitating device comprises at least one kneading hook, anchor, or mixing blade.
7 . The process of claim 1 , wherein the insert outer wall, and the body inner wall, are configured to be tempered by a temperature control medium.
8 . The process of claim 7 , wherein a piping system for the temperature control medium is arranged within the space defined within the insert outer wall of the container insert, and within the space defined between the body outer wall and the body inner wall of the container body.
9 . The process of claim 7 , wherein the insert outer wall and a further wall of the container insert define a space for guiding the temperature control medium, and wherein the body inner wall and the body outer wall of the container body define a space for guiding the temperature control medium.
10 . The process of claim 9 , wherein baffles are arranged within the space defined by the insert outer wall and the further wall, and wherein baffles are arranged within the space defined by the body outer wall and the body inner wall.
11 . The process of claim 1 , wherein the width of the gap is in the range of from 5 mm to 100 mm.
12 . The process of claim 1 , wherein the step of crosslinking is carried out at a temperature in the range of 4° C. to 98° C.
13 . The process of claim 1 , wherein the polymer is a hyaluronic acid and/or a sodium salt thereof.
14 . The process of claim 1 , wherein after crosslinking the container insert is removed from the container body.
15 . The process of claim 1 , 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.
16 . The process of claim 15 , wherein the crosslinked hydrogel is blended with a further polymer and/or at least one further component.
17 . The process of claim 15 , 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.
18 . The process of claim 16 , 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.
19 . A composition comprising a crosslinked hydrogel obtained by a process of claim 1 .
20 . A method for treating a subject in need thereof, comprising applying the composition of claim 19 in a cosmetic application or as a dermatological filler to the subject.

Description

The invention relates to a process for producing a composition comprising a crosslinked hydrogel, wherein a container is provided, the container is filled with a fluid, the fluid is agitated and then crosslinked. Further aspects relate to a composition obtained by this process and the use of the obtained composition. STATE OF THE ART It is known in the art to use gels such as hydrogels based on polysaccharides and water as dermatological fillers. Hydrogels are networks of polymer chains that are hydrophilic. The hydrophilic polymer chains are held together by crosslinks. Such gels are generally prepared by methods comprising the chemical crosslinking of the respective polysaccharides in an aqueous medium. Suitable polysaccharides are e.g. based on hyaluronic. Hyaluronic acid is a polymer natural to the body, which since some time is employed in medicine in different fields such as in orthopedics and in ophthalmology. Nowadays, hyaluronic acid is increasingly used in aesthetic medicine and in plastic surgery. The broad application of hyaluronic acid is particularly due to its very high binding capability of water. In aqueous medium, even at low concentration of hyaluronic acid, viscoelastic gels are formed, which are biologically degradable, and which have advantageous properties. In the production of hyaluronic acid hydrogels, the precursors are first mixed in a mixing vessel and are then usually bottled in glass bottles for crosslinking of the hydrogel. For the process of crosslinking, the bottles are placed into a climate chamber so that the process may be carried out at constant temperature. Processes for preparing hydrogels, in particular hydrogels based on hyaluronic acid, are known in the art. WO2013/185934 A1 discloses a method of preparing a composition comprising a crosslinked first polymer and optionally a second polymer, which may be crosslinked-or non-crosslinked. The polymers are selected from a polysaccharide and the method comprises crosslinking of a mixture comprising at least the first polymer and water, terminating the crosslinking, optionally blending with the second polymer and subjecting the obtained product to dialysis. U.S. Pat. No. 8,052,990 B2 discloses a process for the production of a biocompatible crosslinked polydensified monophasic gel, comprising a crosslinking reaction of a predetermined quantity of at least one biocompatible polymer in solution by the addition of a quantity of crosslinking agent in a first volume of a reaction mixture and adding a supplemental quantity of polymer of a molecular weight higher than 500 000 Da in solution with dilution of the reaction mixture so as to decrease an overall concentration of the polymer in a second volume of the reaction mixture, continuing the crosslinking in the second volume and stopping the crosslinking reaction a drastic reduction of pH and temperature. In order to increase throughput in the production of the hydrogels, it would be advantageous to carry out the step of crosslinking within the mixing vessel. For temperature control, the mixing vessel may be used to heat the contained product during crosslinking. Vessels for mixing and tempering of products are known in the art. Such vessels comprise an agitator for mixing of the contained product and further comprise means for heating or cooling of the product. A machine for mixing and homogenizing of products is known from DE 102 02 084 A1. The machine has a mixing vessel which is heated or cooled by means of a double wall. A homogenizer is arranged at the lowest point of the vessel together with an additional chopper which also mixes the contents of the vessel. DE 198 48 780 C1 discloses a homogenization and tempering container for homogenizing and tempering of a liquid. The container comprises a heat exchanger arranged at a distance from the container walls which is surrounded by at least one partition wall dividing the container into concentric annular chambers. A recirculation pump is used for recirculating a partial volume of the liquid charge of the container from an outlet of the container to an inlet of the container. The concentric annular chambers are divided in in such a way that a flow path of the recirculated partial liquid runs in countercurrent direction through the heat exchanger and the annular chambers. The circulated liquid is both tempered and homogenized. However, when the crosslinking of a hydrogel is performed within a mixing vessel, it has been observed that undesired solid particles form during the step of crosslinking, especially during the crosslinking of hyaluronic acid. This problem becomes worse when the size of the mixing vessel is increased, making it difficult to scale up the crosslinking process from a laboratory to a production scale. It is an object of the present invention to provide a process which may be carried out in a container assembly for mixing and tempering of a fluid which overcomes the limitations of the known processes for the p