METHOD FOR PREPARING AN ANTI-ADHESION BARRIER FILM

Abstract

The present invention relates to a method for preparing a surgical anti-adhesion barrier film comprising the following steps: a°) a first solution, comprising an oxidized collagen is prepared, b) a polyphosphate compound is added to the solution of a) in a quantity so as to obtain a concentration of polyphosphate ranging from 0.007 to 0.7%, by weight, with respect to the total weight of the solution, c) the pH of the solution obtained in b) is adjusted to about 9 by addition of a base or to about 5.1 by addition of an acid, d) a diluted solution is prepared by adding water to solution of c), e) a first layer of solution obtained in c) is casted on an inert support, f) before complete gelation of the layer obtained in d), a second layer, of diluted solution obtained in d) is applied on top of said first layer and let to gelify, g) the gelified first and second layers are dried to obtain a film. The invention further relates to a film obtainable by such a method and to a surgical implant comprising a prosthetic fabric and such a film.

Claims

1-11. (canceled)

12. A method for preparing a surgical anti-adhesion barrier film comprising a) preparing a first solution comprising oxidized collagen at a concentration ranging from 0.5% to 6% by weight, with respect to a total weight of the first solution, b) adding a polyphosphate compound to the first solution in a quantity so as to obtain a concentration of polyphosphate ranging from 0.007 to 0.7% by weight, with respect to the total weight of the first solution, c) adjusting a pH of the first solution obtained in b) to about 9 by adding a base or to about 5.1 by adding an acid, d) adding water to the first solution of c) to form a diluted solution having a concentration of oxidized collagen ranging from 0.1% to 2.7% by weight, with respect to the diluted solution, e) casting a first layer of the first solution obtained in c) at a basis weight ranging from 0.03 to 0.4 g/cm.sup.2, f) applying a second layer of the diluted solution obtained in d) on top of the first layer at a basis weight ranging from 0.03 to 0.4g/cm.sup.2 before complete gelation of the first layer obtained in e), and let gelify, g) drying the first and second layers to obtain a film.

13. The method of claim 12, wherein the concentration of oxidized collagen of the first solution of a) is 2.7% by weight, with respect to a total weight of the first solution.

14. The method of claim 12, wherein the concentration of oxidized collagen of the diluted solution of d) is 1.75% by weight, with respect to the diluted solution.

15. The method of claim 12, wherein the basis weight of e) is about 0.11 g/cm.sup.2.

16. The method of claim 12, wherein the basis weight of f) is about 0.064 g/cm.sup.2.

17. The method of claim 12, further comprising adding glycerol to the first solution of step a) at a concentration ranging from 0.1% to 1.5% by weight, with respect to the total weight of the first solution.

18. The method of claim 12, further comprising adding glycerol to the first solution of step a) at a concentration ranging from 0.9% by weight, with respect to the total weight of the first solution.

19. The method of claim 12, further comprising adding polyethylene glycol to the first solution of step a) at a concentration ranging from 0.1% to 1.5% by weight, with respect to the total weight of the first solution.

20. The method of claim 12, further comprising adding polyethylene glycol to the first solution of step a) at a concentration ranging from 0.9% by weight, with respect to the total weight of the first solution.

21. The method of claim 12, further comprising adding glycerol to the first solution of step a) ata concentration ranging from 0.1% to 1.0% by weight, with respect to the total weight of the solution, and adding polyethylene glycol to the first solution of step a) at a concentration ranging from 0.1% to 1.5% by weight, with respect to the total weight of the solution.

22. The method of claim 12, further comprising adding glycerol to the first solution of step a) at a concentration ranging from 0.1% to 1.0% by weight, with respect to the total weight of the solution, and adding polyethylene glycol to the first solution of step a) at a concentration ranging from 0.9% by weight, with respect to the total weight of the solution.

23. The method of claim 12, wherein the polyphosphate compound of b) comprises sodium polyphosphate.

24. The method of claim 23, wherein the sodium polyphosphate has a degree of polymerization (n) varying from 2 to 100.

25. The method of claim 23, wherein the sodium polyphosphate has a degree of polymerization (n) varying from 2 to 25.

26. The method of claim 23, wherein the sodium polyphosphate has a degree of polymerization (n) varying from 5 to 25.

27. The method of claim 12, wherein adjusting the pH in c) comprises adjusting the pH to about 9 and the method further comprises sterilizing the film obtained in g) by gamma radiation to form a sterilized film.

28. The method of claim 27, further comprising curing the sterilized film at 40° C. for 48 hours.

29. The method of claim 12, wherein adjusting the pH in c) comprises adjusting the pH to about 5.1 and the method further comprises sterilizing the film obtained at g) by ethylene oxide to form a sterilized film.

30. The method of claim 29, further comprising curing the sterilized film at 40° C. for 48 hours.

31. A surgical anti-adhesion barrier film obtainable by the method of claim 12.

32. A surgical implant comprising a biocompatible prosthetic fabric, wherein the prosthetic fabric is at least partially coated with a film obtained according to the method of claim 12.

Description

EXAMPLES

[0077] In the examples below, parts and percentages are by weight unless otherwise indicated.

Example 1

[0078] In the present example, films of the invention comprising oxidized collagen and a polyphosphate at various concentrations are prepared. The influence of the type of sterilization (either by ethylene oxide or by gamma radiation) on the elongation at break of the resulting films is studied.

[0079] 1°) Preparation of the Solutions:

[0080] A solution of oxidized collagen is prepared according to example 4 of U.S. Pat. No. 6,706,684 with a final concentration of oxidized collagen of 4.1%. The solution is heated at 37° C. A glycerol solution in water is prepared at 10%. The oxidized collagen solution is diluted with the glycerol solution at a proportion of 88/12. Initial pH is around 3.3 and is then adjusted to 8.94 with a NaOH solution (1N). The solution of oxidized collagen/glycerol is diluted with water to obtain a final concentration of oxidized collagen equal to 2.7% and a final concentration of glycerol equal to 0.9%.

[0081] Solutions S1-S5 are then prepared by adding to the solution above sodium hexametaphosphate with a degree of polymerization equal to 13 ((NaPO.sub.3).sub.13) in various concentrations, so as to obtain the final concentrations of (NaPO.sub.3).sub.13 in the solution as shown in the table below:

TABLE-US-00001 Solution Final concentration of (NaPO.sub.3).sub.13 in % S1 0.007 S2 0.07 S3 0.11 S4 0.22 S5 0.7

[0082] It is known that the extractible pH after sterilization of the films is dependent on the type of sterilization used. In this view, when it is intended to sterilize the film by ethylene oxide, it is advised to set the pH of the solution at pH 5.1 in order to obtain a pH around 7 after sterilization. On the contrary, when it is intended to sterilize the film by gamma radiation, it is advised to set the pH of the solution at pH 9 in order to obtain a pH around 7 after sterilization.

[0083] In this view, depending on the intended type of sterilization, solutions S1-S5 were readjusted either to pH 9 with addition of NaOH solution (1N), or to pH 5.1 by addition of HCl (1N) and are respectively referred to as S′1, S′2, S′3, S′4 and S′5. For each of these solutions, diluted solutions at 1.75% of oxidized collagen by addition of water are prepared and respectively referred to as S″1, S″2, S″3, S″4 and S″5.

[0084] 2°) Manufacture of the Films:

[0085] A film F1 is prepared according to the following method: a first layer of solution S′1 is casted on an inert support at a basis weight of 0.11 g/cm.sup.2. Before complete gelation of this first layer, for example after 45 min, a second layer, of diluted solution S″1, is applied on top of the first layer at a basis weight of 0.064 g/cm.sup.2.

[0086] After gelation of the two layers, the whole is dried under laminated flow at 20° C., hygrometric degree of 40% for 20 hours. A film F1 is obtained.

[0087] Films F2, F3, F4 and F5 are prepared in the same manner with respectively solutions S′2-S′5 and S″2-S″5.

[0088] 3°) Sterilization and Curing:

[0089] Sterilization by Ethylene Oxide:

[0090] Films F1-F5 obtained at step 2°) from solutions of pH 5.1 were sterilized by ethylene oxide at 30° C. for 12 hours. The films are then cured at 40° C. for 48 hours.

[0091] Sterilization by Gamma Radiation

[0092] Films F1-F5 obtained at step 2°) from solutions of pH 9 were sterilized by gamma radiation with a dose of 25 kGy. The films are then cured at 40° C. for 48 hours.

[0093] 4°) Mechanical Tests:

[0094] The tensile strength and elongation at break of the above films were evaluated according to the following protocol: for each film, dogbone shaped samples are prepared. Samples are hydrated with a saline solution of NaCl at 0.9% for 5 minutes. Each sample is placed between the jaws (one fixed, one mobile) of a traction machine Tinius Olsen (model Benchtop Tester). The distance between the two jaws is calibrated at 9 cm. The cell measurement limit is 5 N. The preload is fixed at 0.005 N. A constant extension speed of 50 mm/min is then applied to the mobile jaw until the sample breaks.

[0095] The tensile strength is the measured force F necessary to achieve breaking of the sample.

[0096] The elongation at break is the deformation in percentage of the length of the sample when it breaks.

[0097] The results are collated in the table below, in which the values indicated for the elongation at break in percentage correspond to the mean of 20 tests for each film.

TABLE-US-00002 Elongation at break in % Film Sterilized by EtO Sterilized by γ radiation F1 95.50 65.25 F2 103.28 75.62 F3 110.12 78.45 F4 118.95 77.34 F5 139.54 93.19

[0098] These results show that the elongation at break is greater for the films which have been sterilized by ethylene oxide. Therefore sterilization by ethylene oxide may be preferred when films having a greater elongation are needed, depending on the function desired for the film.

[0099] Films of the invention prepared in the present example may be used on their own as an anti-adhesive barrier to be implanted in a patient for preventing post-surgical adhesions. Alternatively, these films may be used in combination with a prosthetic fabric in order to manufacture a composite surgical implant. For example, surgical implants for the treatment of hernia may be prepared by coating one face of a prosthetic fabric, such as a mesh, with a film of the present example. The coated film therefore serves as an anti-adhesive barrier for preventing post-surgical adhesions after implantation of the surgical implant.

Example 2

[0100] In the present example, comparative films comprising a non oxidized collagen and the same polyphosphate as in Example 1 at various concentrations are prepared and sterilized either by ethylene oxide or by gamma radiation.

[0101] The respective tensile strengths of the comparative films and of the films of the invention are compared.

[0102] Comparative films are prepared from solutions comprising a polyphosphate and non oxidized collagen.

[0103] Solutions of collagen and glycerol with a final concentration of collagen equal to 2.7% and a final concentration of glycerol equal to 0.9% are prepared in the same manner as in Example 1, except for the fact that the oxidized collagen of Example 1 is replaced by a non oxidized collagen. The non oxidized collagen used is a collagen which has been heated to 60° C. but which has not been modified.

[0104] Solutions C1-C3 are then prepared by adding to the solution above sodium hexametaphosphate with a degree of polymerization equal to 13 ((NaPO.sub.3).sub.13) in various concentrations, so as to obtain the final concentrations of (NaPO.sub.3).sub.13 in the solution as shown in the table below:

TABLE-US-00003 Solution Final concentration of (NaPO.sub.3).sub.13 in % C1 0.007 C2 0.07 C3 0.7

[0105] Like in Example 1, solutions C1-C3 were readjusted to specific pHs depending on the intended type of sterilization and are respectively referred to hereinafter as C′1, C′2, and C′3. Because the non oxidized collagen of the present example is unstable and degrades at pH 9, solutions C1-C3 intended to be used for films intended to be sterilized by gamma radiation were readjusted to pH 7 with addition of NaOH solution (1N). Solutions C1-C3 intended to be used for films intended to be sterilized by ethylene oxide were readjusted to pH 5.1 by addition of HCl (1N). For each of solutions C′1, C′2, and C′3, diluted solutions at 1.75% of non oxidized collagen by addition of water are prepared and respectively referred to as C″1, C″2, and C″3.

[0106] Films were prepared in the same manner as in Example 1 from respectively solutions C′1-C′3 and C″1-C″3.

[0107] The obtained films are referred to as FC1, FC2 and FC3.

[0108] Films FC1, FC2 and FC3 obtained from solutions of pH 5.1 were sterilized by ethylene oxide at 30° C. for 12 hours. The films were then cured at 40° C. for 48 hours.

[0109] Films FC1, FC2 and FC3 obtained from solutions of pH 7 were sterilized by gamma radiation with a dose of 25 kGy. The films were then cured at 40° C. for 48 hours.

[0110] Mechanical tests were performed on Films FC1-FC3 in the same manner as in Example 1.

[0111] The table below compares the results obtained for the tensile strength of films F1, F2 and F5 of the invention of Example 1 and of films FC1, FC2 and FC3 (comparative), for ethylene oxide sterilization on one hand and for gamma radiation sterilization on the other hand. The values indicated for the tensile strength correspond to the mean of 20 tests for each film.

[0112] In this table, F1 is to be compared to FC1, F2 is to be compared to FC2 and F5 is to be compared to FC3.

TABLE-US-00004 Tensile strength (N) Film Sterilized by EtO Sterilized by γ radiation F1 (invention) 1.309 1.787 FC1 (comparative) 0.979 0.776 F2 (invention) 1.531 1.541 FC2 (comparative) 0.281 0.804 F5 (invention) 1.651 1.925 FC3 (comparative) 0.098 0.769

[0113] These results show that the tensile strength of the films of the invention is much greater than that of comparative films prepared from non oxidized collagen, independently from the fact that the films have been sterilized by ethylene oxide or by gamma radiations.

Example 3

[0114] In the present example, films of the invention comprising oxidized collagen and phosphate/polyphosphates of various degrees of polymerization and at various concentrations are prepared and further sterilized either by ethylene oxide or by gamma radiation. The influence of the degree of polymerization on the elongation at break of the resulting films is studied.

[0115] The films are prepared in the same manner as in Example 1, by varying the phosphate/polyphosphate used. The following phosphate/polyphosphates are used: [0116] Disodium hydrogenophosphate: Na.sub.2HPO.sub.4 [0117] Pentasodium tripolyphosphate: Na.sub.5P.sub.3O.sub.10 [0118] Sodium hexametaphosphate of degree of polymerization 13: (NaPO.sub.3).sub.13 [0119] Sodium hexametaphosphate of degree of polymerization 25 (NaPO.sub.3).sub.25

[0120] For each phosphate/polyphosphate used, two concentrations in the final solution are tested: 0.11% and 0.22%. In addition, in order to optimize the comparison between the types of phosphate/polyphosphates, the same corresponding concentrations in orthophosphates (PO.sub.4) were kept for each phosphate/polyphosphate from concentration 0.11% to concentration 0.22%/

[0121] Films prepared from (NaPO.sub.3).sub.13 are films F3 and F4. The other films prepared are referred to as films F6-F11. The elongations at break of the resulting films are measured in the same manner as described in Example 1. The results are collected in the following table:

TABLE-US-00005 Concentration of Phosphate/ phosphate/ Elongation at break in % Polyphosphate polyphosphate in Sterilized by Sterilized by γ Film used % EtO radiations F6 Na.sub.2HPO.sub.4 0.11 105.53 67.03 F7 Na.sub.2HPO.sub.4 0.22 97.7 53.90 F8 Na.sub.5P.sub.3O.sub.10 0.11 112.52 84.16 F9 Na.sub.5P.sub.3O.sub.10 0.22 109.44 79.19 F3 (NaPO.sub.3).sub.13 0.11 110.12 78.45 F4 (NaPO.sub.3).sub.13 0.22 118.95 72.34 F10 (NaPO.sub.3).sub.25 0.11 116.27 77.66 F11 (NaPO.sub.3).sub.25 0.22 212.46 68.93

[0122] These results show that films of the invention prepared from polyphosphates having a degree of polymerization ranging from 5 to 25 show an improved elongation at break with respect to films prepared from Na.sub.2HPO.sub.4.

[0123] Films of the invention prepared in the present example may be used on their own as an anti-adhesive barrier to be implanted in a patient for preventing post-surgical adhesions. Alternatively, these films may be used in combination with a prosthetic fabric in order to manufacture a composite surgical implant. For example, surgical implants for the treatment of hernia may be prepared by coating one face of a prosthetic fabric, such as a mesh, with a film of the present example. The coated film therefore serves as an anti-adhesive barrier for preventing post-surgical adhesions after implantation of the surgical implant.