(19)
(11)EP 2 091 567 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
27.05.2020 Bulletin 2020/22

(21)Application number: 07848395.5

(22)Date of filing:  22.11.2007
(51)Int. Cl.: 
A61K 47/18  (2017.01)
A61L 15/28  (2006.01)
C08J 3/09  (2006.01)
A61K 31/717  (2006.01)
C08L 1/28  (2006.01)
(86)International application number:
PCT/GB2007/004488
(87)International publication number:
WO 2008/062209 (29.05.2008 Gazette  2008/22)

(54)

DISSOLUTION AND PROCESSING OF CARBOXYMETHYLCELLULOSE

AUFLÖSUNG UND AUFBEREITUNG VON CARBOXYMETHYLCELLULOSE

DISSOLUTION ET TRAITEMENT DE LA CARBOXYMÉTHYLCELLULOSE


(84)Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

(30)Priority: 24.11.2006 GB 0623473

(43)Date of publication of application:
26.08.2009 Bulletin 2009/35

(73)Proprietor: ConvaTec Technologies Inc.
Reno NV 89511 (US)

(72)Inventors:
  • KERSHAW, David
    Deeside Flintshire CH5 2NU (GB)
  • ADAMS, Simon
    Deeside Flintshire CH5 2NU (GB)

(74)Representative: Wilson Gunn 
Blackfriars House The Parsonage 5th Floor
Manchester M3 2JA
Manchester M3 2JA (GB)


(56)References cited: : 
EP-A- 0 355 536
WO-A-03/022909
WO-A-2007/005388
US-A- 4 246 221
WO-A-93/12275
WO-A-03/029329
WO-A-2008/043837
US-A- 6 075 177
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description


    [0001] This invention relates to chemically modified cellulosic materials and particularly chemically modified cellulosic fibres and preferably those which are gel forming materials. Such materials are of particular use in wound care.

    [0002] Chemically modified cellulose in powder form is well known as a thickener. In particular carboxymethyl cellulose in powder form is produced by the reaction of cellulose pulp with a strong alkali such as sodium hydroxide and monochloroacetic acid or a salt thereof. There have been many suggestions for the production of carboxymethyl cellulose fibres from regenerated cellulose (viscose rayon) fibres or from cotton. There are problems with these methods however in achieving fibres that are suitable for use in wound care because for some applications, highly absorbent fibres which are free of surface stickiness and which are strong enough to be processed on textile machinery are required. Carboxymethyl cellulose fibres suitable for use in wound care have however been produced by the method described in WO 93/12275 which uses solvent spun cellulose fibre as a starting material. This method however has its limitations in that the cellulose has to be chemically converted to the starting material; the carboxymethyl cellulose has to subsequently be converted to a wound care product and the conversion process may not be suitable for all fibre lengths especially short fibres. WO 03/029329 discusses the dissolution and processing of cellulose using ionic liquids. EP 0355536 discloses a process for preparing and the use of a flexible hydrophilic gel film. US 6075177 discloses a wound dressing. WO 03/022909 discloses a method for the production of silk fibroin hydrogels.

    [0003] The use of ionic liquids to dissolve cellulose is known. WO 03/029329 describes the dissolution and processing of cellulose using ionic liquids. Ionic liquids have not however been previously used in the dissolution of gel forming fibres for use in wound care. For instance, for dissolving chemically modified cellulose and particularly water swellable but insoluble carboxymethylcellulose polymers. We have now found that gel forming wound care materials can be produced and modified by using a solvent for the gel forming materials and particularly by dissolving the components that make up the eventual gel forming material in an ionic liquid or other solvent. Surprisingly we have found that when carboxymethyl cellulose polymers are dissolved in an ionic liquid and subsequently regenerated the properties of the modified cellulose are not significantly changed by the process. Accordingly, disclosed herein is a method for dissolving chemically modified cellulose comprising the steps of admixing chemically modified cellulose with an ionic liquid. By the term ionic liquid is meant a liquid ionic compound which is liquid below 150°C.

    [0004] A first aspect of the invention provides a method for producing gel forming materials suitable for use in wound care, comprising the step of admixing carboxymethylcellulose with an ionic liquid comprising cations and anions in the substantial absence of water.

    [0005] A second aspect of the invention provides a solution comprised of a chemically modified cellulose in an ionic liquid characterised in that the chemically modified cellulose is carboxymethylcellulose and the ionic liquid comprises cations and anions in the substantial absence of water.

    [0006] A third aspect of the invention provides a method for producing chemically modified cellulose suitable for use in wound care, that comprises admixing a solution of chemically modified cellulose in an ionic liquid with a liquid non-solvent for the chemically modified cellulose that is miscible with said ionic liquid, said admixing causing the chemically modified cellulose and ionic liquid to form solid and liquid phases, wherein the chemically modified cellulose is a carboxymethycellulose and the ionic liquid comprises cations and anions in the substantial absence of water.

    [0007] The advantage of such methods is that the components of the eventual gel forming material that are admixed with the solvent need not be in a fibrous form. The components could for instance be in the form of a powder prior to dissolution for example a carboxymethylcellulose powder.

    [0008] Additionally in some embodiments the chemically modified cellulose is rendered into a solution which can be directly processed into any form such as but not limited to fibers, nanofibers, films, coatings, foams, and sponges. These forms are all suitable for use in the treatment of wounds.

    [0009] In a preferred embodiment the invention provides a solution comprised of a chemically modified cellulose in an ionic liquid solvent wherein said ionic liquid is comprised of a liquid ionic compound which is liquid below 150°C.

    [0010] In a further preferred embodiment the invention provides a method for regeneration of chemically modified cellulose that comprises admixing a solution of chemically modified cellulose with a liquid non-solvent for the chemically modified cellulose that is miscible with said ionic liquid said admixing causing the cellulose and ionic liquid to form solid and liquid phases.

    [0011] It has been found that chemically modified cellulose can be dissolved in a number of solvents including tertiary amine N-oxides, N,N-dimethyl formamide/nitrogen tetroxide mixtures, dimethyl sulphoxide/paraformaldehyde mixtures and solutions of lithium chloride in N,N-dimethyl acetamide or N-methyl pyrrolidone and solvents that are described as ionic liquids. The ionic liquid comprises cations and anions in the substantial absence of water, which are molten at a temperature of less than 150°C.

    [0012] The cations of an ionic liquid are preferably cyclic and correspond in structure to a formula selected from the group consisting of:









    wherein R1 and R2 are independently a C1-C6 alkyl group or a C1-C6 alkoxyalkyl group, and R3, R4, R5, R6, R7, R8 and R9 (R3-R9), when present, are independently a hydrido, a C1-C6 alkyl, a C1-C6 alkoxyalkyl group or a C1-C6 alkoxy group. The anions of the ionic liquid are halogen, pseudohalogen, or C1-C6 carboxylate. It is to be noted that there are two isomeric 1,2,3-triazoles. It is preferred that all R groups not required for cation formation be hydrido.

    [0013] The anions of an ionic liquid are preferably a halogen ion (chloride, bromide or iodide), perchlorate, a pseudohalogen ion such as thiocyanate and cyanate or C1 to C6 carboxylate. Pseudohalides are monovalent and have properties similar to those of the halides. Pseudohalides include the cyanide, thiocyanate, cyanate, fulminate and azide anions. Carboxylate anions that contain 1 to 6 carbon atoms and are illustrated by formate, acetate, propionate, butyrate, hexanoate, maleate, fumarate, oxalate, lactate, pyruvate and the like.

    [0014] For the dissolution of modified cellulose we have found that the following ionic liquids are particularly preferred:

    butyl-3-methyl imidazolium chloride

    1-butyl-1-methylpyrrolidium dicyanamide

    N-butyl-4-methylpyridinium dicyanamide



    [0015] By gel forming material is meant hygroscopic material which upon the uptake of exudate become moist and slippery or gelatinous and thus reduce the tendancy of the material to adhere to the wound. The gel forming material can be of the type which retain their structural integrity on absorption of exudate or can be of the type which lose their form and become a structureless gel on absorption of exudate.

    [0016] The gel forming materials made by the process of the present invention include chemically modified cellulosic fibres and preferably solvent spun sodium carboxymethyl cellulose fibres, and in particular carboxymethylated cellulose fibres as described in PCT WO/ 9312275. The cellulosic fibres preferably have a degree of substitution of at least 0.05 carboxymethyl groups per glucose unit and a tenacity of at least 10cN/tex.

    [0017] The invention will now be described by way of the following examples:

    Example 1



    [0018] An ionic liquid, 1-butyl-3-methylimidazolium chloride was placed in a 70C water bath to melt. Approximately 0.1 gram of degree of fiber as described in patent WO 93/12275 or Aquasorb (manufactured by Hercules Inc) were weighed out into a 20ml scintillation vial. Sufficient molten ionic liquid was added to the vials to give a final concentration of polymer of 1% by weight. The vials without lids were placed in a microwave oven and heated at maximum power for 5 seconds. The vials were removed and the solution mixed. This was repeated until total dissolution of the polymer was achieved.

    [0019] The solution was spun by extruding a sample of the solution from a syringe with a 21 guage needle into an excess of IMS, a nonsolvent for the polymer. The coagulated fibres were recovered by filtration.

    [0020] It was also found that fibres could be electrospun by feeding a sample of the solution through a flat ended 25 guage needle and applying a positive 20kV charge to the needle. The distance to the ground plate was 15cm.

    [0021] A sample of the extruded fibre was hydrated with solution A (sodium / calcium chloride solution BP) and showed similar properties to the starting polymer.

    Example 2



    [0022] An ionic liquid, 1-ethyl-3-methylimidazolium acetate was used to make a 2% w/w solution of fiber as described in patent WO 93/12275 and sold under the trademark Aquacel ™. The flock of fibres were dispersed in the solvent at ambient temperature but required heating to form a solution. The solution was spun by extruding a sample of the solution through a Spinneret in the form or either a 400 jet 74 micron diameter parallel sided capillary or the same capillary with a straight sided conical inlet, or the same capillary with a hyperbolically curved inlet cone. The dope velocity was 2m/min to 10m/min spun into an excess of ethanol, a non solvent for the polymer. The coagulated fibres were recovered by filtration.

    [0023] The resulting fibres had a dry fibre average diameter of 15 microns and a hydrated average diameter of 38 microns.

    Example 3



    [0024] An ionic liquid, 1-ethyl, 3-methyl imidazolium acetate was used to make a 2% w/w solution of Hercules Aqualon A-500. The powder Was dispersed in the solvent at ambient temperature but required heating to form a solution.

    [0025] The solution was spun by extruding a sample of the solution through a Spinneret in the form or either a 400 jet 74 micrometre (micron) diameter parallel sided capillary or the same capillary with a straight sided conical inlet, or the same capillary with a hyperbolically curved inlet cone. The dope velocity was 2m/min to 10m/min and was spun into an excess of ethanol, a non solvent for the polymer. The coagulated fibres were recovered by filtration.

    [0026] The resulting fibres had a dry fibre average diameter of 29 micrometres (microns) and a hydrated average diameter of 189 micrometres (microns).


    Claims

    1. A method for producing gel forming materials suitable for use in wound care, comprising the step of admixing carboxymethylcellulose with an ionic liquid comprising cations and anions in the substantial absence of water.
     
    2. A method as claimed in claim 1, wherein the ionic liquid is selected from the group of tertiary amine N-oxides, N,N-dimethyl formamide/nitrogen tetroxide mixtures, dimethyl sulphoxide/paraformaldehyde mixtures and solutions of lithium chloride in N,N-dimethyl acetamide or N-methyl pyrrolidone.
     
    3. A method as claimed in any preceding claim, wherein the cations and anions are molten at a temperature of less than 150°C.
     
    4. A method as claimed in any preceding claim, wherein the carboxymethylcellulose is a carboxymethylcellulose powder.
     
    5. A method as claimed in any preceding claim, wherein the carboxymethylcellulose is dissolved in the ionic liquid to form a solution.
     
    6. A method as claimed in claim 5, wherein the solution is processed into a form of carboxymethylcellulose suitable for use in the treatment of wounds.
     
    7. A method as claimed in claim 6, wherein the solution is processed into carboxymethylcellulose fibres.
     
    8. A solution comprised of a chemically modified cellulose in an ionic liquid characterised in that the chemically modified cellulose is carboxymethylcellulose and the ionic liquid comprises cations and anions in the substantial absence of water.
     
    9. A solution as claimed in claim 8 wherein the ionic liquid is selected from the group of tertiary amine N-oxides, N,N-dimethyl formamide/nitrogen tetroxide mixtures, dimethyl sulphoxide/paraformaldehyde mixtures and solutions of lithium chloride in N,N-dimethyl acetamide or N-methyl pyrrolidone.
     
    10. A solution as claimed in claims 8 or 9, wherein the carboxymethylcellulose is in the form of a powder prior to dissolution.
     
    11. A method for producing chemically modified cellulose suitable for use in wound care, that comprises admixing a solution of chemically modified cellulose in an ionic liquid with a liquid non-solvent for the chemically modified cellulose that is miscible with said ionic liquid, said admixing causing the chemically modified cellulose and ionic liquid to form solid and liquid phases, wherein the chemically modified cellulose is a carboxymethycellulose and the ionic liquid comprises cations and anions in the substantial absence of water.
     


    Ansprüche

    1. Verfahren zur Herstellung von gelbildenden Materialien, die zur Verwendung bei der Wundversorgung geeignet sind, umfassend den Schritt des Beimischens von Carboxymethylcellulose mit einer ionischen Flüssigkeit, die Kationen und Anionen im Wesentlichen in Abwesenheit von Wasser enthält.
     
    2. Verfahren nach Anspruch 1, wobei die ionische Flüssigkeit ein tertiäres Amin-N-Oxid, eine N,N-Dimethylformamid/Stickstofftetroxid-Mischungen, eine Dimethylsulfoxid/Paraformaldehyd-Mischungen oder eine Lösung von Lithiumchlorid in N,N-Dimethylacetamid oder N-Methylpyrrolidon ist.
     
    3. Verfahren nach einem der vorstehenden Ansprüche, wobei die Kationen und Anionen bei einer Temperatur von weniger als 150°C geschmolzen werden.
     
    4. Verfahren nach einem der vorstehenden Ansprüche, wobei die Carboxymethylcellulose ein Carboxymethylcellulosepulver ist.
     
    5. Verfahren nach einem der vorhergehenden Ansprüche, wobei die Carboxymethylcellulose in der ionischen Flüssigkeit gelöst wird, um eine Lösung zu bilden.
     
    6. Verfahren nach Anspruch 5, wobei die Lösung zu einer Form von Carboxymethylcellulose verarbeitet wird, die zur Verwendung bei der Behandlung von Wunden geeignet ist.
     
    7. Verfahren nach Anspruch 6, wobei die Lösung zu Carboxymethylcellulosefasern verarbeitet wird.
     
    8. Eine Lösung, die eine chemisch modifizierte Cellulose in einer ionischen Flüssigkeit enthält, dadurch gekennzeichnet, dass die chemisch modifizierte Cellulose Carboxymethylcellulose ist und die ionische Flüssigkeit Kationen und Anionen im Wesentlichen in Abwesenheit von Wasser enthält.
     
    9. Lösung nach Anspruch 8, wobei die ionische Flüssigkeit ein tertiäres Amin-N-Oxid, eine N,N-Dimethylformamid/Stickstofftetroxid-Mischungen, eine Dimethylsulfoxid/Paraformaldehyd-Mischungen oder eine Lösung von Lithiumchlorid in N,N-Dimethylacetamid oder N-Methylpyrrolidon ist.
     
    10. Lösung nach Anspruch 8 oder 9, wobei die Carboxymethylcellulose vor der Auflösung in Form eines Pulvers vorliegt.
     
    11. Verfahren zur Herstellung von chemisch modifizierter Cellulose, die zur Verwendung bei der Wundversorgung geeignet ist, umfassend das Beimischen einer Lösung von chemisch modifizierter Cellulose in einer ionischen Flüssigkeit mit einem flüssigen Nichtlösungsmittel für die chemisch modifizierte Cellulose, das mit der ionischen Flüssigkeit mischbar ist, wobei das Beimischen bewirkt, dass die chemisch modifizierte Cellulose und die ionische Flüssigkeit feste und flüssige Phasen bilden, wobei die chemisch modifizierte Cellulose eine Carboxymethylcellulose ist und die ionische Flüssigkeit Kationen und Anionen im Wesentlichen in Abwesenheit von Wasser enthält.
     


    Revendications

    1. Procédé de production de matière formant du gel propre à être utilisée dans le soin des blessures, comprenant le stade de mélange de la carboxyméthylcellulose à un liquide ionique, comprenant des cations et des anions en l'absence substantielle d'eau.
     
    2. Procédé suivant la revendication 1, dans lequel le liquide ionique est choisi dans le groupe des N-oxides d'amine tertiaire, des mélanges de N,N-diméthyle formamide/tétroxide d'azote, des mélanges de diméthyle sulphoxide/paraformaldéhyde et des solutions de chlorure de lithium dans le N,N-diméthyle acétamide ou dans la N-méthyle pyrrolidone.
     
    3. Procédé suivant l'une quelconque des revendications précédentes, dans lequel on fait fondre les cations et les anions à une température de moins de 150°C.
     
    4. Procédé suivant l'une quelconque des revendications précédentes, dans lequel la carboxyméthylcellulose est une poudre de carboxyméthylcellulose.
     
    5. Procédé suivant l'une quelconque des revendications précédentes, dans lequel on dissout la carboxyméthylcellulose dans le liquide ionique pour former une solution.
     
    6. Procédé suivant la revendication 5, dans lequel on transforme la solution en une carboxyméthylcellulose propre à être utilisée dans le traitement de blessures.
     
    7. Procédé suivant la revendication 6, dans lequel on transforme la solution en fibres de carboxyméthylcellulose.
     
    8. Solution comprenant une cellulose modifiée chimiquement dans un liquide ionique, caractérisée en ce que la cellulose modifiée chimiquement est de la carboxyméthylcellulose et le liquide ionique comprend des cations et des anions en l'absence substantielle d'eau.
     
    9. Solution suivant la revendication 8, dans laquelle le liquide ionique est choisi dans le groupe des N-oxides d'amine tertiaire, des mélanges de N,N-diméthyle formamide/tétroxide d'azote, des mélanges de diméthyle sulphoxide/paraformaldéhyde et des solutions de chlorure de lithium dans le N,N-diméthyle acétamide ou dans la N-méthyle pyrrolidone.
     
    10. Solution suivant les revendications 8 ou 9, dans laquelle la carboxyméthylcellulose est sous la forme d'une poudre avant dissolution.
     
    11. Solution de production de cellulose modifiée chimiquement propre à être utilisée dans le soin de blessures, qui comprend mélanger une solution de cellulose modifiée chimiquement dans un liquide ionique à un non-solvant liquide de la cellulose modifiée chimiquement, qui est miscible au liquide ionique, le mélange faisant que la cellulose modifiée chimiquement et le liquide ionique forment des phases solide et liquide, la cellulose modifiée chimiquement étant une carboxyméthylcellulose et le liquide ionique comprenant des cations et des anions en l'absence substantielle d'eau.
     




    REFERENCES CITED IN THE DESCRIPTION



    This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

    Patent documents cited in the description