IMPROVED FIBRINOGEN-BASED TISSUE ADHESIVE PATCH

Abstract

An improved fibrinogen-based tissue sealing patch having a degradation time of less than two weeks is disclosed. The patch comprises a polyethylene glycol-caprolactone-lactide (PEG-CL-LA) triblock copolymer film into which a fibrinogen-based sealant comprising less than 8 mg/cm.sup.2 fibrinogen and less than 10 IU/cm.sup.2 thrombin has been incorporated. In preferred embodiments, the polymer film comprises PEG having a molecular weight of between 3000 and 3500 and a CL:LA:PEG ratio of 34:2:1. Methods of production and use of the patch are also disclosed.

Claims

1. A fibrinogen-based tissue adhesive patch, wherein said adhesive patch comprises: a backing made from a film made of a biocompatible polyethylene glycol-caprolactone-lactide (PEG-CL-LA) triblock copolymer (PECALA); and, a fibrinogen sealant comprising less than 8 mg/cm.sup.2 fibrinogen and less than 20 IU/cm.sup.2 thrombin incorporated into said biocompatible polymer backing; wherein said PECALA comprises PEG having a molecular weight of between 3000 and 3500 and a CL:LA ratio of 34:2.

2. The fibrinogen-based tissue adhesive patch according to claim 1, wherein said fibrinogen sealant comprises about 2 mg/cm.sup.2 fibrinogen and 10 IU/cm.sup.2 thrombin.

3. The fibrinogen-based tissue adhesive patch according to claim 1, wherein said fibrinogen sealant comprises less than 8 mg/cm.sup.2 fibrinogen, less than 20 IU/cm.sup.2 thrombin, and CaCl.sub.2.

4. The fibrinogen-based tissue adhesive patch according to claim 1, wherein said fibrinogen sealant consists of less than 8 mg/cm.sup.2 fibrinogen, less than 20 IU/cm.sup.2 thrombin, and CaCl.sub.2.

5. The fibrinogen-based tissue adhesive patch according to claim 4, wherein said fibrinogen sealant consists of about 2 mg/cm.sup.2 fibrinogen, about 10 IU/cm.sup.2 thrombin, and CaCl.sub.2.

6. The fibrinogen-based tissue adhesive patch according to claim 1, wherein at least one parameter characterizing said PECALA is chosen so as to provide said patch with a predetermined degradation time.

7. (canceled)

8. The fibrinogen-based tissue adhesive patch according to claim 6, wherein said at least one parameter is selected from the group consisting of PEG molecular weight; ratio of hydrophilic to hydrophobic components; CL:LA ratio; and crystallinity.

9. The fibrinogen-based tissue adhesive patch according to claim 6, wherein said predetermined degradation time is no more than two weeks.

10. The fibrinogen-based tissue adhesive patch according to claim 6, wherein said predetermined degradation time is between 10 and 14 days.

11. The fibrinogen-based tissue adhesive patch according to claim 1, wherein said patch is characterized by a thickness of about 200 ?m.

12. The fibrinogen-based tissue adhesive patch according to claim 1, wherein said fibrinogen sealant additionally comprises at least one additive.

13. The fibrinogen-based tissue adhesive patch according to claim 11, wherein said additive is selected from the group consisting of additives for extending the adhesion half-life of said film, pharmaceutically active agents, and analgesics.

14. The fibrinogen-based tissue adhesive patch according to claim 12, wherein said additive is a plasmin inhibitor for extending the adhesion half-life of said film.

15. The fibrinogen-based tissue adhesive patch according to claim 12, wherein said additive is a pharmaceutically active agent for targeted or controlled release.

16. A method for producing a fibrinogen-based tissue adhesive patch, comprising: casting a polymer film from PECALA, thereby creating a polymer film characterized by a thickness; softening said polymer film; placing a fibrinogen sealant comprising less than 8 mg/cm.sup.2 fibrinogen and less than 20 IU/cm.sup.2 thrombin on at least one surface of said polymer film; and, pressing said polymer film until at least a portion of said fibrinogen sealant is incorporated into the surface of said polymer film; wherein said PECALA comprises PEG having a molecular weight of between 3000 and 3500 and a CL:LA ratio of 34:2.

17. A method for preparing a fibrinogen-based tissue adhesive patch, comprising: heating to a predetermined temperature a work surface in connection with a source of vacuum; engaging said vacuum to said work surface; applying a solution of PECALA to said work surface; adjusting a polymer blade to a predetermined height above said work surface; spreading said solution of PECALA over said work surface with said polymer blade; evaporating said solvent, thereby creating a non-permeable biocompatible polymer film characterized by a thickness; heating said work surface above said softening temperature; spreading over said polymer film a powder comprising a fibrinogen sealant, said fibrinogen sealant comprising less than 8 mg/cm.sup.2 fibrinogen and less than 20 IU/cm.sup.2 thrombin; placing over said polymer film a top release sheet over said powder and polymer film; applying pressure to said top release sheet so as to at least partially incorporate said powder into said polymer film, thereby forming a film of adhesive patch material; removing said top release sheet from said film of adhesive patch material; releasing said vacuum; cooling said work surface to room temperature; and, removing said adhesive patch material from said work surface; wherein said PECALA comprises PEG having a molecular weight of between 3000 and 3500 and a CL:LA ratio of 34:2.

18. The method according to claim 17, wherein said fibrinogen sealant comprises less than 8 mg/cm.sup.2 fibrinogen, less than 20 IU/cm.sup.2 thrombin, and CaCl.sub.2.

19. The method according to claim 17, wherein said thickness is about 200 ?m.

20. The use of a tissue adhesive patch according to claim 1 in the treatment of a leak of fluid into or out of a body part, wherein said treatment comprises applying said adhesive patch to said body part, thereby causing said tissue adhesive patch to adhere to said body part, thereby sealing said body part.

21. The use according to claim 20, wherein said body part is an artery or organ.

22. The use according to claim 20, wherein said leak of fluid is selected from the group consisting of arterial bleeding; organ tissue bleeding; bile anastomosis; cerebrospinal fluid leak; dura leak; and air leak in damaged lung tissue.

23. The use according to claim 20, wherein said treatment comprises applying a tissue adhesive patch by manually pressing said patch on the surface of said body part.

24. A method for treating a leak of fluid from a body part, comprising applying a tissue adhesive patch according to claim 1 to said body part, thereby causing said tissue adhesive patch to adhere to said body part, thereby sealing said body part.

25. The method according to claim 16, wherein said fibrinogen sealant comprises less than 8 mg/cm.sup.2 fibrinogen, less than 20 IU/cm.sup.2 thrombin, and CaCl.sub.2.

26. The method according to claim 16, wherein said thickness is about 200 ?m.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The invention will now be described with reference to the drawings, in which

[0023] FIG. 1 contrasts the failure mode of the patches of the present invention with that of patches known in the art;

[0024] FIG. 2 presents a graph illustrating the adhesive strength of the patches of the present invention as a function of concentration of fibrin sealant; and,

[0025] FIG. 3 presents a graph illustrating the degradation times of patches of the present invention made with different formulations of the polymer film.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] In the following description, various aspects of the invention will be described. For the purposes of explanation, specific details are set forth in order to provide a thorough understanding of the invention. It will be apparent to one skilled in the art that there are other embodiments of the invention that differ in details without affecting the essential nature thereof. Therefore the invention is not limited by that which is illustrated in the figure and described in the specification, but only as indicated in the accompanying claims, with the proper scope determined only by the broadest interpretation of said claims.

[0027] The following abbreviations are used throughout this application:

[0028] PEG is used to refer to polyethylene glycol.

[0029] CL is used to refer to caprolactone.

[0030] LA is used to refer to lactide.

[0031] PECALA is used to refer to a triblock copolymer comprising polyethylene glycol (PEG), caprolactone (CL), and lactide (LA) components. When the term PECALA is followed by two numbers, the first indicates the ratio of hydrophilic (PEG) to hydrophobic (CL and LA) repeat units, and the second to the number of lactide units per triblock flank.

[0032] As used herein, the term about, when applied to numerical quantities, refers to a range of ?25% of the nominal value.

[0033] As used herein, with reference to a polymer film or hemostatic patch attached to tissue, the terms degrade and degradation refer to the breakup of the polymer film or hemostatic patch into smaller pieces.

[0034] In '509, the present inventors disclosed hemostatic patches that contain a fibrinogen component that acts to attach the polymer film to the tissue and in which the polymer film itself rather than the fibrinogen component acts to seal the tissue. In contrast to hemostatic patches and dressings known in the art, these patches do not include a mesh or woven component, woven or non-woven fabrics, or materials made by techniques known in paper-making technology. Rather, these patches comprise a single layer of polymer film into which fibrinogen and thrombin are incorporated, in contrast to multilayer hemostatic dressings known in the art (although embodiments in which additional layers are added for ease of handling or storage are not excluded from the scope of the present invention). Furthermore, the fibrinogen sealant component is physically incorporated into the polymer film to form a single integrated unit, in contrast to those hemostatic patches and dressings known in the art in which the coagulant is present as a free powder.

[0035] The patches disclosed in '509 generally retain their mechanical integrity for a period of several weeks following their attachment to the tissue. For some uses, however, the patch would ideally degrade on a faster time scale. For example, in the case of bleeding, the patch might not need to remain in place for more than a few days. Ideally, the patch would retain its mechanical integrity just long enough to complete the necessary treatment and would then degrade within a few days thereafter in order to minimize the possibility of negative interactions between the patch and the patient's body.

[0036] The present inventors have discovered, surprisingly, that for PECALA-based patches, several parameters can be varied in order to set a desired degradation time, and that patches with degradation times of on the order of two weeks can easily be produced. One important parameter is the ratio of the components of the triblock copolymer (e.g. the CL:LA ratio or ratio of hydrophobic to hydrophilic components). In general, the more CL units per PEG unit, the longer the degradation time, while the more CA units per PEG unit, the shorter degradation time (see the Example below). The degradation time is also apparently controlled by the crystallinity of the polymer; without wishing to be bound by theory, it appears that small amounts of LA prevent the CL from crystallizing, but too high a fraction of LA will itself crystallize, changing the degradation time. The molecular weight of the PEG used can also affect the degradation time. Thus, by proper control of the relative amounts of the components of the PECALA, it is possible to fine-tune the degradation time to the desired length.

[0037] Typical embodiments of the invention comprise a PECALA film comprising PEG of MW between 3000 and 3500 and a CL:LA ratio of 34:2 (i.e. 4 LA units and 68 CL units per PEG) into which a fibrinogen sealant comprising fibrinogen (?8 mg/cm.sup.2, preferably about 2 mg/cm.sup.2) and thrombin (?20 IU/cm.sup.2, preferably about 10 mg/cm.sup.2) has been incorporated. In preferred embodiments, the fibrinogen sealant also comprises CaCl.sub.2. It may also include additives such as additives for extending the adhesion half-life of said film, pharmaceutically active agents, and analgesics.

[0038] In some embodiments, the patch thickness is about 200 ?m; in preferred embodiments, the patches are about an order of magnitude thinner (typically 130-170 nm).

[0039] The patches may be prepared according to any method known in the art. For example, they can be prepared by the method disclosed in '509. In this method, a PECALA film is cast on a surface such as a glass slide from a solution of PECALA in a volatile organic solvent. The film is then heated to its softening point, and a powdered fibrin sealant mixture containing fibrinogen, thrombin, and CaCl.sub.2 sprinkled onto the surface of the softened polymer film. In typical embodiments, the fibrin sealant mixture has been micronized to a particle size of 25-75 nm. The sealant mixture is then pressed into the surface of the softened polymer film and allowed to cool to room temperature. The film is then optionally placed in a freezer (typically at about ?20? C.) to aid in removing it from the surface on which it was prepared. Excess powder is removed from the patch by shaking and the patch then removed from the surface on which it was prepared.

[0040] The inventors have recently developed a second process for manufacture of the patches. This method uses a specially modified drawdown coater, and comprises: (a) heating to a predetermined temperature a work surface in connection with a source of vacuum; (b) engaging said vacuum to said work surface; (c) applying a solution to said work surface, said solution comprising a biocompatible polymer characterized by a softening temperature dissolved in a solvent; (d) adjusting a polymer blade to a predetermined height above said work surface; (e) spreading said solution over said work surface with said polymer blade; (f) evaporating said solvent, thereby creating a non-permeable biocompatible polymer film; (g) heating said work surface above said softening temperature; (h) spreading a powder comprising a fibrinogen sealant over said polymer film; (i) placing over said polymer film a top release sheet over said powder and polymer film; (j) applying pressure to said top release sheet so as to at least partially incorporate said powder into said polymer film, thereby forming a film of adhesive patch material; (k) removing said top release sheet from said film of adhesive patch material; (l) releasing said vacuum; (m) cooling said work surface to room temperature; and, (n) removing said adhesive patch material from said work surface.

[0041] In typical embodiments of the patch, a force of about 5-7 N is required in order to detach it from tissue. Reference is now made to FIG. 1, which illustrates the failure mode of the patches of the present invention. FIG. 1A illustrates a mesh embedded with fibrin of a type known in the art. When a detachment force is applied, the mesh is detached from the tissue and only residues of fibrin remain on the mesh, with no evidence of tissue fragments seen on the mesh. This behavior indicates that hemostatic patches known in the art undergo cohesive failure, i.e. the adhesive itself loses its structural integrity, fragments, and breaks.

[0042] In contrast, as shown in FIG. 1B, when a detachment force is applied to the patches of the present invention, the film detaches with fragments of tissue remaining on the film, indicating that the tissue itself rather than the adhesive underwent mechanical failure. That is, in contrast to hemostatic patches known in the art, the patches of the present invention undergo adhesive failure along the interface between the adhesive and the substrate. Thus, the instant invention comprises patches in which the main contribution to the sealing ability arises from the adhesive strength of the polymer film rather than the rather weak internal strength of fibrin.

[0043] Reference is now made to FIG. 2, which presents a graph showing the adhesive strength of the patches of the present invention as a function of the concentration of fibrin sealant. As can be seen from the figure, the adhesive strength is essentially independent of the amount of fibrin present. Thus, the patches of the present invention are effective with significantly less fibrin sealant than is used in patches known in the art. In preferred embodiments of the present invention, the fibrin sealant comprises about 2 mg/cm.sup.2 fibrin and 10 IU/cm.sup.2 thrombin.

Example

[0044] The following example provides an illustration of a preferred embodiment of the present invention in order to assist one of ordinary skill in the art to make and use the invention, and is not intended to be limiting in any way.

[0045] A series of hemostatic patches of the present invention were prepared with different PECALA formulations. The PECALA was prepared according to standard literature procedures. The degradation time of the patches was measured for a minimum of five independent samples. The results of the experiments are summarized in Table 1, and illustrated graphically in FIG. 3.

TABLE-US-00001 TABLE 1 Mean degradation time Sample PEG MW CL:LA ratio (days) 1 3350 34:2 12.5 2 3350 44:3 3.8 3 3350 44:4 7.0 4 3350 34:1 47.8 5 6000 34:2 9.2 6 3000 34:2 13.4 7 3350 40:2 21.7

[0046] In the table, the CL:LA ratio is given relative to the number of PEG units; that is, a CL:LA ratio of n:m indicates that for each PEG unit in the polymer, there were 2n CL units and 2m LA units.

[0047] As can be seen from the table, in general, the degradation time tended to decrease with increasing PEG molecular weight, decreasing CL:LA ratio, increasing number of CL units per PEG unit, and decreasing number of LA units per PEG unit. Because the degradation time appears to be a function of polymer crystallinity as well, these general rules are only valid within limits; for example, increasing the number of CL units per LA unit will increase the crystallinity of the polymer.