WO2001030410A1

WO2001030410A1 - Medical use

Info

Publication number: WO2001030410A1
Application number: PCT/GB2000/004154
Authority: WO
Inventors: Peter Edwardson; Jose Velada
Original assignee: Tissuemed Ltd.
Priority date: 1999-10-28
Filing date: 2000-10-27
Publication date: 2001-05-03
Also published as: AU1043601A; GB9925379D0

Abstract

There is described the use of tissue bonding materials, i.e. materials by which body tissues can be caused to adhere together, to prevent the undesired formation of connective tissue between adjacent tissues following surgery (post-surgical adhesion). The tissue bonding material is preferably a protein or the like, most preferably albumin, and is formulated as either a liquid or gel, or as a flexible sheet which can be applied to the tissues and caused to cure.

Description

Title: Medical Use

This invention relates to a novel use of tissue bonding material, in particular to the use of such material for the prevention or inhibition of the formation of undesired connective tissue following surgery.

Post-surgical adhesion, the formation of undesired connective tissue between adjacent tissues, is a serious problem which can give rise to major post-surgical complications. It is a particular problem in bowel surgery where it can cause, for instance, twisting of the bowel which may then necessitate further surgical intervention. Clearly, it would be beneficial for the occurrence of such adhesion to be avoided.

The use of tissue bonding material as an adhesive to bond tissues together after surgery or to repair wounds, eg in place of suturing or the like, is known. Such material commonly comprises proteinaceous material which is applied to the tissues to be joined and then subjected to curing by the action of heat or light. This causes the material to crosslink to itself and to the tissues, thereby creating a bond.

It has now surprisingly been found that the application of material known for use as a tissue bonding material or adhesive to tissues exposed in a surgical procedure can be effective in preventing post-surgical adhesions between that tissue and neighbouring tissues.

Thus, according to a first aspect of the invention there is provided a method for the prevention or inhibition of post-surgical adhesion, which method comprises coating one or more tissues exposed in a surgical procedure with a tissue bonding material, and causing or allowing that material to cure.

According to another aspect of the invention, there is provided the use of a tissue bonding material in the manufacture of a composition for the prevention or inhibition of post-surgical adhesion. By a "tissue bonding material" is meant a material which when applied to body tissues is capable of binding to those tissues and of causing the tissues to adhere to each other. The mechanism of such adhesion will normally involve curing by which the tissue bonding material molecules covalently bond to each other (cross- linking) and to the tissues.

The tissue bonding material will most commonly be a crosslinkable proteinaceous or other peptide material. The material may be selected from natural and synthetic peptides, enzymatically cleaved or shortened variants thereof and crosslinked derivatives thereof, as well as mixtures of any of the above. Included among the peptides are structural proteins and serum proteins. Examples of proteins are albumin, α-globulins, β-globulins, γ-globulins, transthyretin, collagen, elastin and fibronectin and coagulation factors including fibrinogen, fibrin and thrombin.

The invention more specifically provides the use of such materials in the prevention or inhibition of post-surgical adhesion, and in the manufacture of a composition for that purpose.

The tissue bonding material may be formulated in any suitable form for application to the tissues which are to be protected from post-surgical adhesion. For instance, the formulation may be a liquid or low viscosity gel which may be applied by spraying or any other suitable means of application. A certain degree of viscosity may be desirable in order to aid retention of the material at the locus to which it is applied. The material may therefore be thixotropic such that it is readily dispensed, eg from a spray pump or other applicator, but is viscous when not subjected to shear force. Viscosity-modifying components which may be incorporated into the composition include hyaluronic acid and salts thereof such as sodium hyaluronate, hydroxypropylmethylcellulose, polyethylene glycol, glycerine, dextrans, honey, sodium chondroitin sulphate and mixtures thereof.

Formulations in the form of liquids or gels may be prepared by mixing the various components in appropriate proportions. The tissue bonding material may for example be dispersed or dissolved in water, together with any additional components such as viscosity-modifying agents.

The liquid or gel formulation most preferably also comprises a plasticiser to confer sufficient flexibility on the formulation after curing. Suitable plasticisers include polyalcohols, eg glycerol, sorbitol etc.

The tissue bonding material may alternatively be incorporated into a flexible sheet which can be applied to the tissue and then cured, or allowed to cure, such that it bonds to the tissue. A sheet of this kind may be formed with a degree of flexibility to suit the application for which it is intended, eg by the incorporation of suitable additives and/or controlling the degree of cross-linking. Such a sheet may comprise a single layer of the tissue bonding material. Alternatively, especially where a thin layer is used and/or the material has insufficient integrity for the desired purpose, a carrier layer may be provided. Suitable materials for the carrier layer are biocompatible materials, eg polybutyrate, polysaccharides, polytetrafluoroethylene, polyesters, glycoproteins, polymer composites, collagen (including cross-linked collagen), pericardium, ethacrylate, polyurethane and derivatives thereof. Other materials include absorbable and non-absorbable suture materials, eg polypropylene, polyglactin, polylactic acid, polyglycolic acid, polydioxanone and polyglyconate.

As for liquid formulations, the sheet formulation preferably further comprises a plasticiser in order to ensure that the sheet has sufficient flexibility, even after polymerisation or cross-linking. Suitable plasticisers include polyalcohols, eg glycerol, sorbitol etc.

The sheet preferably also comprises a synthetic structural polymer to confer strength and elasticity on the sheet. Suitable such polymers include water-soluble thermoplastic polymers, in particular selected from the group consisting of poly(vinyl alcohol), poly(ethylene glycol), poly(vinyl pyrrolidone), poly(acrylic acid), poly(acrylamide), copolymers of methylvinyl ether with maleic anhydride in the anhydride, acid, ester or mixed salt form, and similar materials. A relatively small proportion of surfactant, most preferably a non-ionic surfactant, will generally be incorporated into the sheet, though normally to facilitate manufacture (prevention of foaming etc) rather than to confer any beneficial property on the finished product. Suitable surfactants include block copolymers of ethylene oxide and propylene oxide, such as those sold under the trade mark Pluronic^® by BASF.

The sheet may be manufactured by mixing the different components in aqueous solution as follows:

i) tissue-bonding material: 5 - 80%, more preferably 10 - 60 %, and most preferably 15 to 40%. ii) structural polymer : 0.01 - 20%, more preferably 1 - 10% , and most preferably 2 - 8%. iii) surfactant : 0.001 - 10%, more preferably 0.01 - 5%, and most preferably 0.1

- 2%. iv) plasticiser : 0.01 - 60%, more preferably 1 - 50%, and most preferably 10 -

40%

The sheet may be prepared by casting the above solution into a suitable non-stick mould (e.g. of PTFE), and allowing it to set through evaporation.

The casting process used to achieve the desired thickness of the sheet may involve pouring, manual spreading or spraying of the component solutions.

For most applications, the sheet according to the invention may be 20 - 200 μm in thickness, and typically approximately 100 μm in thickness.

The sheet will typically contain between 10% and 50% water by weight, and most preferably between 20% and 40%. The sheet may be partially or totally hydrated with a suitable aqueous medium at or following implantation (eg a body fluid or saline solution). The preferred tissue bonding material for use in the present invention is a soluble protein which is not part of the clotting cascade. Porcine albumin or porcine pericardium or any abundant non-thrombogenic protein, ie excluding collagen, may be used. Genetically or chemically modified versions of such proteins may also be suitable.

Particularly preferred formulations for use in the method of the invention are formulations comprising albumin. Mammalian albumin is preferred, particularly porcine albumin. The formulation most preferably further comprises glycerol as plasticiser.

The tissue bonding material may, or may not, contain a thermochromic compound (which undergoes a colour change on the application of heat) and/or a photochromic compound (which undergoes a colour change on the application of light). For example, the material may include a chromophore, such as methylene blue, which will change colour when the end point (when light activated) has been reached, as described in WO 96/22797. Such a visual colour change may provide the user with an indication that sufficient energy has been applied to ensure that curing of the tissue bonding material has occurred. In addition, when curing is complete the resultant colour change ensures that the material will absorb no further radiant energy. This provides protection against excess energy input.

If a light activated chromophore is present it provides the user, ie normally a surgeon or veterinary surgeon, with means to determine whether or not adequate energy has been provided in the desired area, thereby preventing thermal damage as a result of the application of excessive energy.

As an alternative to heat or light, curing may be brought about using a chemical activator such as a crosslinking agent, eg hexamethylenediisocyanate, which may be applied by spraying or wetting. In some circumstances the tissue bonding material may cure spontaneously. However, it is generally preferred that curing be brought about by the application of heat or, or most preferably, light.

The invention will now be described in greater detail, for illustrative purposes only, with reference to the following Examples.

Example 1 - Viscous Liquid Formulation

Porcine albumin 41% w/w

Methylene blue 0.24% w/w

Glycerol 2% w/w

Water for injection q.s.

The composition was made up by dissolving/dispersing the albumin, methylene blue and glycerol in the water for injection. The resulting viscous solution can be applied to exposed tissues by spraying, and cured by the application of laser or polychromatic light. On completion of curing the colour changes from blue to colourless.

Example 2 - Sheet Formulation

0.9g porcine albumin (Sigma) was dissolved in 2.5ml water for injection (Phoenix Pharmaceuticals pH 7.7) and 0.5ml of 1% w/v methylene blue for injection. To this solution, 0.585g D-sorbitol was added and dissolved. Heating of this solution in a thermostatted water bath at 59°C increases the film rehydration time from 50 seconds (if left at room temperature) to 140 seconds. This solution was left to cool for 30 minutes and then cast on a level PTFE-coated surface. The film was left to dry at room temperature for 20 hours.

The sheet is cut into rectangles approximately 40mm by 30mm in dimension. Such sheets may be applied to exposed tissues, and cured by the application of light as for Example 1. Example 3 - Sheet Formulation

0.9g porcine albumin (Sigma) was dissolved in 4.5ml of water for injection (Phoenix Pharmaceuticals, pH 7.7) and 0.5ml of 1% w/v methylene blue for injection. To this solution, 0.5 glycerol was added and dissolved. This solution was then cast on a level PTFE-coated surface. The film was left to dry at room temperature for 20 hours.

Cut to size and used as for Example 2.

Example 4 -Sheet Formulation

1.51g of porcine albumin, 0.1g of 80% hydrolysed polyvinyl alcohol, 1.42g of glycerol and 0.01 g of Pluronic 25R2 were dissolved in 2.02g of water for injection. 0.1 ml of this solution was poured onto a level PTFE surface, and spread to a thickness of approximately 50μm. The solution was heated to 120°C for 10 minutes to evaporate off water and allowed to cool.

Cut to size and used as for Example 2.

Example 5 - Sheet Formulation

3.03g of porcine albumin, 0.5g of 80% hydrolysed polyvinyl alcohol, 3.00g of glycerol and 0.02g of Pluronic 25R2 were dissolved in 3.53g of water for injection. 0.1 ml of this solution was poured onto a level PTFE surface, and spread to approximately 30μm thick. The sheet was heated at 120°C for 20 minutes and allowed to cool.

Cut to size and used as for Example 2.

Example 6 - Sheet Formulation 9.00g of porcine albumin, 1.53g of 80% hydrolysed polyvinyl alcohol, 8.98g of glycerol and 0.06g of Pluronic 25R2 were dissolved in 10.56g of water for injection. 0.3 ml of this solution was poured onto a level PTFE surface, and spread to a thickness of approximately 50μm, and left at room temperature for 1 hour.

Cut to size and used as for Example 2.

Claims

1. A method for the prevention or inhibition of post-surgical adhesion, which method comprises coating one or more tissues exposed in a surgical procedure with a tissue bonding material, and causing or allowing that material to cure.

2. The use of a tissue bonding material in the manufacture of a composition for the prevention or inhibition of post-surgical adhesion.

3. A method or use as claimed in Claim 1 or Claim 2, wherein the tissue bonding material is a crosslinkable proteinaceous or other peptide material.

4. A method or use as claimed in Claim 3, wherein the tissue bonding material is selected from the group consisting of natural and synthetic peptides, enzymatically cleaved or shortened variants thereof and crosslinked derivatives thereof, and mixtures of any thereof.

5. A method or use as claimed in any preceding claim, wherein the tissue bonding material is incorporated into a formulation in the form of a liquid or gel.

6. A method or use as claimed in Claim 5, wherein the tissue bonding material is formulated as a gel, and further comprises a viscosity-modifying agent selected from the group consisting of hyaluronic acid and salts thereof, hydroxypropylmethylcellulose, polyethylene glycol, glycerine, dextrans, honey, sodium chondroitin sulphate, and mixtures thereof.

7. A method or use as claimed in any one of Claims 1 to 4, wherein the tissue bonding material is incorporated into a formulation in the form of a flexible sheet .

8. A method or use as claimed in any one of Claims 5 to 7, wherein the formulation further comprises a plasticiser.

9. A method or use as claimed in Claim 8, wherein the plasticiser is a polyalcohol.

10. A method or use as claimed in Claim 7, wherein the sheet further comprises a synthetic structural polymer selected from the group consisting of poly(vinyl alcohol), poly(ethylene glycol), poly(vinyl pyrrolidone), poly(acrylic acid), poly(acrylamide), and copolymers of methylvinyl ether with maleic anhydride in the anhydride, acid, ester or mixed salt form.

11. A method or use as claimed in Claim 7, wherein the sheet further incorporates a surfactant.

12. A method or use as claimed in any one of Claims 7, 10 and 11 , wherein the sheet has a thickness of 20 - 200 μm.

13. A method or use as claimed in any one of Claims 7, 10, 11 , and 12, wherein the sheet contains between 10% and 50% water by weight.

14. A method or use as claimed in any one of the preceding claims, wherein the tissue bonding material is albumin.

15. A method or use as claimed in Claim 14, wherein the albumin is porcine albumin.

16. A method or use as claimed in Claim 14 or Claim 15, wherein the albumin is present in admixture with glycerol.

17. A method or use as claimed in any preceding claim, wherein the tissue bonding material is present in admixture with a thermochromic compound (which undergoes a colour change on the application of heat) and/or a photochromic compound (which undergoes a colour change on the application of light).

18. A method or use as claimed in Claim 17, wherein the tissue bonding material is present in admixture with methylene blue.

19. A method or use as claimed in any preceding claim, wherein curing of the tissue bonding material is brought about by the application of heat or light.