WO2003092754A1

WO2003092754A1 - Ionically crosslinked alginate hydrogels, process for their manufacture and their use in medical devices

Info

Publication number: WO2003092754A1
Application number: PCT/GB2003/001919
Authority: WO
Inventors: Hugh Semple Munro; Gareth Charles Jeffrey; Susana Sainz Garcia
Original assignee: First Water Limited
Priority date: 2002-05-03
Filing date: 2003-05-02
Publication date: 2003-11-13
Also published as: GB0210216D0; AU2003224324A1

Abstract

A hydrogel film comprises one or more alkaline and/or alkaline earth metal alginate, the film having a disintegration time of less than about 72 hours in saline solution at room temperature. A process for the preparation of such a hydrogel film comprises: (a) forming a first liquid comprising water and a suitable quantity of alkaline alginate; (b) absorbing on an absorbent web a second liquid comprising one or more alkaline earth metal salt at a concentration of between about 0.1 % and about 50 % by weight; and (c) contacting the absorbent web, wetted in the second liquid, with the first liquid, to form a layer structure comprising the cured first liquid and the absorbent web. The hydrogel film is useful as a coating in wound care device, including devices for repairing damaged body tissue such as hernias and prolapses.

Description

IONICALLY CROSSLINKED ALGINATE HYDROGELS, PROCESS FOR THEIR MANUFACTURE AND THEIR USE IN MEDICAL DEVICES

Field of the Invention

The present invention relates to ionically crosslinked hydrogels, and more particularly to ionically crosslinked alginate hydrogels, to a process for their preparation and to their use in medical devices.

Background of the Invention

Medical devices incorporating hydrogels have been developed for a range of uses, including topical use, for example as wound dressings, use for implantation, for example as stents, catheters, cannulas, plugs and constrictors, use as tissue or biological encapsulants and similar applications.

Typically, many of these devices are made from durable, non-degradable plastic materials such as polyurethanes, polyesters and polyorthoesters which undergo hydrolytic cleavage, such as disclosed in US 5,085,629; crosslinked polysaccharide polymers, such as disclosed in EP-A-0507604; and other ionically crosslinked hydrogels, such as disclosed in US Patent Nos. 4,941,870, 4,286,341 and 4,878,907. The disclosures of these documents are incorporated herein by reference.

EP-A-0645150, the disclosure of which is incorporated herein by reference, describes hydrogel devices prepared from ionically crosslinked polymers e.g. polysaccharides such as calcium alginate These medical devices can be disintegrated in vivo through the exposure of a chemical trigger explicitly introduced to the device at the onset of disintegration.

Hydrogels potentially offer excellent biocompatibility. Unfortunately, however, the use of hydrogels in biomedical applications has often been hindered by poor mechanical stability. US Patent No. 6,184,266 discloses hydrogels that are ionically and covalently crosslinked that have improved mechanical properties. In US Patent No. 5,709,877, highly hydrated alginate hydrogels self-supporting films containing hydrophilic polymers such as hyaluronic acid which are bioreasorbable are disclosed. No disclosure is made with respect to the time taken for disintegration. A process for manufacture involving extrusion into a coagulation bath at line speeds of 0.4m/min is also disclosed. The disclosures of these documents are incorporated herein by reference.

US Patent No. 4,505,935, the disclosure of which is incorporated herein by reference, describes an aqueous skin ointment containing a water soluble salt of alginic acid and hydrophilic lipid crystals dispersed in the aqueous phase. After the ointment has been spread on the skin, and aqueous solution of a water soluble calcium salt is applied to the ointment layer to create in the ointment layer an insoluble calcium salt of alginic acid.

The present invention is based on our surprising finding that certain ionically crosslinked polysaccharides are capable of forming self-supporting films which have relatively fast disintegration times. Such ionically crosslinked hydrogels can be prepared in at least some embodiments using a process that does not necessarily require the use of a coagulation bath and can be capable of making films at speeds of up to 20m/min. Such self-supporting ionically crosslinked polysaccharide films do not necessarily contain additional synthetic or natural polymers in at least some embodiments. ^" Such ionically crosslinked polysaccharide hydrogel films can in at least some embodiments be in the form of a foam, film or perforated film, and may be provided (e.g. cast) on suitable support such as a net or non-woven substrate, or on a web made from natural and/or synthetic materials. The presence of the web can greatly facilitate the conversion of the film into finished products. Such ionically crosslinked polysaccharide hydrogel films can in at least some embodiments partially or totally encapsulate a porous scrim, made from natural or synthetic materials e.g. in the form of a non- woven sheet, a net or a perforated film. The presence of the scrim can enhance the handling properties of the film. In the case where the net material is used as a scaffold in the repair of torn or ruptured body tissues, then it is found that the disintegration properties of the hydrogel can in at least some embodiments lead to a device with practical and superior handling properties. Such properties can in at least some embodiments enable the provision of a wound medication device (e.g. medicated dressing) which: can be removed easily from the wound, sterilizable by heat or radiation; is potentially compatible with a large number of drugs, therefore allowing their incorporation; can be generally permeable to gases but generally not to bacteria; and can be transparent.

Brief Description of the Invention

The present invention provides in a first aspect a hydrogel film comprising one or more ionically crosslinked alkaline and/or alkaline earth metal alginate, the film having a disintegration time of less than about 72 hours in saline solution at room temperature (about 15°C). The hydrogel film may optionally include one or more polyhydric alcohol and/or other ingredients. The film may, for example, be a self- supporting film. The film may be substantially free of any additional polymer component (by which is preferably meant that any additional polymer component that may be present will be at a level less than about 10% by weight of the hydrogel film, more typically less than about 5% by weight, and most preferably absent).

In one embodiment of the invention, a medicament (for example, having antiseptic (e.g. a silver salt, or chlorhexidine gluconate), antibiotic, anti-inflammatory, antihistaminic or other activity, or combinations thereof) is contained within the gel.

The present invention provides in a second aspect a process for the preparation of a hydrogel film comprising one or more ionically crosslinked alkaline and/or alkaline earth metal alginate, the process comprising: (a) forming a first liquid comprising water and a suitable quantity of alkaline alginate; (b) absorbing on an absorbent web a second liquid comprising one or more alkaline earth metal, e.g. calcium, salts at a concentration of between about 0.1% and about 50% by weight; and (c) contacting the absorbent web, wetted in the second liquid, with the first liquid, to cure the first liquid and form a layered structure .comprising the cured first liquid and the absorbent web.

The process according to the second aspect of the present invention can be used to prepare the hydrogel films according to the first aspect of the invention.

The hydrogel film can, if desired, partially or totally encapsulate a foraminous or porous material. In the manufacturing process, the first liquid can, if desired, be provided as a layer, e.g. on a web or infiltrated into the foramina or pores of a foraminous or porous sheet material, e.g. a porous net.

The present invention provides in a further aspect the use of a hydrogel film comprising one or more alkaline and/or alkaline earth metal alginate, and optionally one or more polyhydric alcohol, in wound care. The expression "wound care" used herein includes all forms of repair of torn or ruptured body tissue, e.g. reconstructive repair of hernias and prolapses. In this aspect of the invention, there is provided a wound care device, the device comprising a hydrogel film comprising one or more alkaline and/or alkaline earth metal alginate, and optionally one or more polyhydric alcohol. The device suitably includes a substrate in sheet form, e.g. serving as a backing member for the device, and a peelable release layer to protect the hydrogel film before use. The substrate sheet is preferably foraminous or porous, and the hydrogel film preferably partially or totally encapsulates the foraminous or porous sheet material. The parts of the device are suitably associated with each other in a generally conventional manner, and the hydrogel film suitably includes other optional ingredients as desired.

Detailed Description of the Invention

The hydrogels in film form according to the present invention preferably comprise a quantity between about 0.4% and about 10% and preferably between about 0.5% and about 4% (all percentages are by weight) of one or more alkaline (e.g. alkali metal) alginate, preferably sodium alginate, and between about 0.05% and about 5% alkaline earth (e.g. alkaline earth metal) alginate, preferably calcium alginate; a quantity of between 0 and about 50%, preferably between about 0.05% and about 50%, of a polyhydric alcohol, preferably glycerol or sorbitol; and optionally between about 0.01% and about 10% of one or more medicaments; plus optionally between about 0.01% to about 10% of calcium chelating agents, for example sodium citrate; the remainder being water. Other alkaline alginates, which may be used, include for example potassium and ammonium alginates.

In one embodiment of the invention, the hydrogel may consist essentially of one or more alkaline alginate, one or more alkaline earth alginate, one or more polyhydric alcohol, water, optionally one or more medicament, and optionally one or more calcium chelating agent, with less than about 10% (e.g. less than about 5% or less than about 2%) of other components. Such other components suitably do not include other hydrophilic organic material or other hydrogel matrix components.

In another embodiment of the invention, the hydrogel may consist essentially of one or more alkaline earth alginate, one or more polyhydric alcohol, water, optionally one or more alkaline alginate, optionally one or more medicament, and optionally one or more calcium chelating agent, with less than about 10% (e.g. less than about 5% or less than about 2%) of other components. Such other components suitably do not include other hydrophilic organic material or other hydrogel matrix components.

The film of hydrogel may be in sheet form or in a non-sheet form such as a coating on a net or mesh structure. The net or mesh structure, when coated or encapsulated by the hydrogel film, will typically then be generally in the form of a sheet. The sheet of hydrogel film or the sheet structure including the hydrogel film may suitably have a substantially uniform thickness, which may, for example, be in the range of about 0.5 to about 8mm, more preferably about 0.5 to about 5mm.

The described film is suitably obtained, to provide the required characteristics according to the invention, by preparing (a) a first liquid comprising a suitable quantity (e.g. between about 0.4% and about 10% by weight) of alkaline alginate, preferably sodium alginate, and a suitable quantity (e.g. between 0 and about 50% by weight) of a polyhydric alcohol (preferably glycerol), optionally a calcium chelating agent (suitably 0 to 10% by weight), optionally medicament and the balance water; and (b) a second liquid comprising one or more calcium salts at a concentration of between about 0.1% and about 50% by weight.

The first liquid is suitably formed as a layer (e.g. by being extruded by pumping through a slit of adjustable width and thickness) on a first web (which may for example be made from natural or synthetic polymer or combinations of both). To assist the formation of the layer of the first liquid, the web may suitably (but not essentially) move at a speed of about l-20m/min. An absorbent second web is used to absorb a quantity of the second liquid [e.g. by providing that a moving non-woven second web (or any other web capable of collecting liquid) is passed through a bath containing the calcium salt solution (b)] and the second web is then contacted with the layer of first liquid (e.g. by laying down on top of the layer of first liquid) to form a three-layer structure ("structure No.l") consisting of the first web, the first solution and the second web (e.g. non-woven) wetted in the calcium salt solution. This structure is suitably then wound into a roll.

In another embodiment of the process, the second (e.g. non- woven) web is suitably wetted with the calcium salt solution, laid on to a moving first web and then the first liquid is applied as a layer (e.g. extruded) on top (to form "structure No. 2"), which is then suitably wound into a roll.

In a further embodiment of the process, a further absorbent (e.g. non-woven) web, wetted with the calcium salt solution, can be laid onto structure No. 2 (to form "structure No. 3"), which is then suitably wound into a roll.

In all cases, curing of the gel begins immediately when the first solution contacts a web (e.g. non- woven) wetted by the calcium salt solution.

In another embodiment of the process, the film can be prepared as a partial or total encapsulation of a foraminous or porous material, for example a net made from synthetic or natural polymer or combinations of both (e.g. a polyester). The foraminous or porous material (e.g. net) is suitably contacted with a layer of the first liquid (e.g. a layer of the first liquid which is provided down by extrusion of the first liquid on a substrate we) so that the first liquid infiltrates the foramina or pores of the foraminous or porous material. An absorbent second web (e.g. non- woven) wetted by the calcium salt solution is then contacted with the foraminous or porous material (e.g. by being laid down on top) (to form "structure No. 4"), which can then suitably be wound into a roll. Alternatively the other process embodiments previously described may be employed in connection with this structure No. 4 embodiment.

The present invention also provides hydrogels in film form, prepared by any of the novel processes described herein.

It will be readily apparent to those skilled in the art that the extrusion and other laying down and contacting steps do not need to take place on a moving web. Small-scale or batchwise sheet samples can be made for example by extruding or pouring the first solution on to a static substrate and laying down the wetted non- woven.

The present invention also provides wound care (including medical repair) devices which comprise the hydrogel film according to the present invention in association with one or more suitable substrate in sheet form, as well as methods for wound care (including medical repair) which comprise applying to the wound (including generally torn or ruptured body tissue) the said wound care device. The medical repaire device can, for example, be used to repair hernias or prolapses. A peelable release sheet, e.g. of conventional construction, is suitably provided in contact with the hydrogel film, to protect the hydrogel film prior to use. The device is suitably subjected to conventional sterilisation and sterile-packing procedures for transportation and storage.

It is found that the presence of the hydrogel film in the device enhances the tendency for the damaged body tissue to repair itself around the device, particularly infiltrating foramina or pores of a foraminous or porous sheet of the device which is placed in contact with the damaged body tissue. The relatively fast disintegration time of the hydrogel film appears to assist this infiltrating repair mechanism of the body tissue, with the result that a strong mass of repaired body tissue forms relatively easily and quickly around the substrate sheet, which is thereby embedded in the repaired body tissue and supports the same in a desired configuration.

Examples

The following examples are provided purely for illustration of the present invention, without limitation.

Example 1

lOOg of sodium alginate (LF10/60LS) were dissolved in 7325g of water, to which were added with stirring 150g of glycerol and 75 g of sodium citrate to form a clear solution No. 1. A solution No. 2 was prepared by dissolving lOOg CaCl₂ (Aldrich) into 900g of water. A film was made by passing a polyurethane film (2301 from Rexam Imaging Products) at a speed of 3m/min under a slot die 200mm wide with a slot gap of 175 microns. Solution No. 1 was pumped through the slot die at a rate sufficient to deposit a liquid film of coatweight of 600g per square metre on to the polyurethane web. A non- woven scrim (18 gsm from HDK) was passed through a bath containing Solution No. 2 at a speed of 3m/min and laid on the top of the extruded solution No. 1. The assembled structure was then wound into a roll.

The gel has good mechanical properties and disintegrated within 72 hours on immersion into saline solution.

Example 2

lOOg of sodium alginate (LF10/60LS) were dissolved in 7400g of water, to which were added with stirring 150g of glycerol and to form a clear solution No. 1. A solution No. 2 was prepared by dissolving lOOg CaCl₂into 900g of water.

The film was made as in Example 1.

Example 3

The composition of solutions Nos. 1 and 2 were as in Example 1.

A film part encapsulating a net was made by laying a net (Culzean Fabrics CFL/SBR/1) onto a polyurethane film (2301 from Rexam Imaging Products) which was then passed, at a speed of 3m/min, under a slot die 200mm wide with a slot gap of 175 microns. Solution No. 1 was pumped through the slot die at a rate sufficient to deposit a liquid film of coatweight of 600g per square metre onto the polyurethane web. A non- woven polyester scrim (18gsm, D1451. from HDK) was passed through a bath containing Solution No. 2 at a speed of 3m/min and laid onto the top of the extruded solution No. 1. The assembled structure was then wound into a roll.

Claims

1. A hydrogel film comprising one or more ionically crosslinked alkaline and/or alkaline earth metal alginate, the film having a disintegration time of less than about 72 hours in saline solution at room temperature.

2. A hydrogel film according to claim 1, which includes one or more polyhydric alcohol and/or other ingredients.

3. A hydrogel film according to claim 1 or claim 2, which contains a medicament.

4. A hydrogel film according to claim 3, wherein the medicament has antiseptic, antibiotic, anti-inflammatory and/or antihistaminic activity.

5. A hydrogel film according to any one of the preceding claims, which has a thickness less than about 3mm.

6. A hydrogel film according to any one of the preceding claims, which has a thickness less than about 0.6mm.

7. A hydrogel film according to any one of the preceding claims, when present as a foam.

8. A hydrogel film according to any one of claims 1 to 6, when present as a perforated film.

9. A hydrogel film according to any one of the preceding claims, when present on a suitable support.

10. A hydrogel film according to any claim 9, wherein the support is a net or non-woven substrate.

11. A hydrogel film according to claim 9, wherein the support is a foraminous or porous scrim, net or mesh, which is partially or totally encapsulated by the hydrogel film.

12. A hydrogel film according to any one of claims 1 to 8, which is a self- supporting film.

13. A hydrogel film according to any one of claims 9 to 12, wherein the hydrogel film and any support is present in the form of a sheet having a substantially uniform thickness.

14. A hydrogel film according to claim 13, wherein the thickness of the sheet is less than about 5mm.

15. A hydrogel film comprising one or more ionically crosslinked alkaline and/or alkaline earth alginate, wherein the hydrogel film is present as a coating on a foraminous or porous support and the film is prepared on the support by a process that does not include the use of a coagulation bath.

16. A hydrogel film comprising one or more ionically crosslinked alkaline and/or alkaline earth alginate, wherein the hydrogel film is present as a coating on a support and the film is prepared lengthwise, without the use of a coagulation bath, at a speed of up to 20m/min

17. A hydrogel film according to claim 16, wherein the support is a foraminous or porous support.

18. A process for the preparation of a hydrogel film comprising one or more alkaline and/or alkaline earth metal alginate, the process comprising: (a) forming a first liquid comprising water and a suitable quantity of alkaline alginate; (b) absorbing on all absorbent web a second liquid comprising one or more alkaline earth metal salt at a concentration of between about 0.1% and about 50% by weight; and (c) -contacting the absorbent web, wetted in the second liquid, with the first liquid, to form a layer structure comprising the cured first liquid and the absorbent web.

19. A process according to claim 18, wherein the alkaline earth metal salt is a calcium salt.

20. A process according to claim 18 or claim 19, wherein the first liquid is provided as a layer.

21. A process according to claim 20, wherein the layer is provided at a coatweight up to about 600g per square metre.

22. A process according to any one of claims 18 to 21, wherein the process is performed without the use of a coagulation bath and at a film making speed of up to about 20m/min.

23. A hydrogel film, when prepared by a process according to any one of claims 18 to 22.

24. A hydrogel film according to any one of claims 1 to 17, when prepared by a process according to any one of claims 18 to 22

25. A wound care device comprising a hydrogel film according to any one of claims 1 to 17, 23 or 24.

26. A wound care device according to claim 25, which is a device for repairing damaged body tissue.

27. A wound care device according to claim 26, for repairing hernias or prolapses.