Foam and use thereof

Abstract

The invention provides a method of producing a gelled foam comprising the steps of:

Description

EXAMPLES

Glossary

• • Sodium alginate PRONOVA® MVG; batch: 701-256-11, viscosity (1 wt % aqueous solution at 20° C.)=385 mPas (FMC BioPolymer, Philadelphia Pa.)
  • Sorbitol Sorbitol special; SPI Polyols, New Castle, USA
  • Glycerine Glycerol, Ph. Eur; VWR Prolabo, Leuven, Belgium
  • HMPC Hypromellose USP; Substitution type 2910, Pharmacoat 603, Shin-Etsu Chemical Co. Ltd., Japan

Example 1

33% saturated foam prepared using 100% saturated Sr-alginate particles (FP-502-02, particle size <75 μm, M content about 53%.)

100 g of a 4% alginate solution made from MQ-water and sodium alginate was added to a mixing bowl. Then 18.0 g sorbitol special, 6.0 g glycerine, 3.0 g HPMC and 51.0 g MQ-water were added to the same mixing bowl. The ingredients were blended with use of a wire whisk and a Hobart mixer at medium speed for two minutes to ensure homogeneity. Then the mixing and aeration continued for six minutes at high speed. 2.0 g Sr-alginate (particle size <75 microns) dispersed in 20.0 g MQ-water was then added to the bowl with the foam, and mixing continued at high speed for another 20 seconds. The resulting foam had a wet density of 0.25 g/ml. The foam was immediately transferred to a 4 mm deep mold and the foam was kept uncovered at the laboratory bench for one hour to allow ion diffusion. Finally the foam was dried in an air forced drying oven at 80° C. for one hour. The amount of strontium ion added was sufficient to saturate 33% of the alginate in the foam (alginate from both Na-alginate and Sr-alginate).

The dried foam sheet was soft, flexible and granulated. While some cracking was seen, generally the dry foam was integral with no holes. The foam swelled fast when water was added, then it fast lost its integrity.

Example 2

33% saturated foam prepared using a 100% saturated Sr-alginate particles (J74-037, 20 g Sr-alginate particles suspended in 450 ml water), dp₅₀˜1 μm after milling with use of an agitated ball mill. The M content of the Sr-alginate was about 41%.

100 g of a 4% alginate solution made from MQ-water and sodium alginate was added to a mixing bowl. Then 18.0 g sorbitol special, 6.0 g glycerine, 3.0 g HPMC and 26.0 g MQ-water were added to the same mixing bowl. The ingredients were blended with use of a wire whisk and a Hobart mixer at medium speed for two minutes to ensure homogeneity. Then the mixing and aeration continued for seven minutes at high speed. 47.0 g of the Sr-alginate dispersion was added the mixing bowl and mixing were continued at high speed for 25 seconds. The resulting foam had a wet density of 0.31 g/ml. Molding, gelling and drying were as described in Example 1. The Strontium added was sufficient to saturate 33% of the total alginate in the foam.

The Sr-alginate particles were visible in the wet alginate foam as gelled small fibers. The dried foam had a very coarse structure, and an open structure with holes through the foam was seen. The foam absorbed water and kept some integrity, but it was very weak.

Example 3

25% saturated foam prepared using a 50% saturated Sr-alginate particles (FP-411-06, with a M content of about 46%), particle size: <0.25 μm.

100 g of a 4% alginate solution made from MQ-water and sodium alginate was added to a mixing bowl. Then 18.0 g sorbitol special, 6.0 g glycerine, 3.0 g HPMC and 39.0 g MQ-water were added to the same mixing bowl. The ingredients were blended with use of a wire whisk and a Hobart mixer at medium speed for two minutes to ensure homogeneity. Then the mixing and aeration continued for six minutes at high speed. 4.0 g Sr-alginate were suspended in 300 g MQ-water and added to the bowl. Mixing continued at high speed for 1 minute and 15 seconds. The wet foam gelled very fast and it was difficult to transfer the foam to the tray and get a smooth surface on the top. Molding, gelling and drying steps were as in Example 1. The Strontium added was sufficient to saturate 25% of the alginate.

The dried foam had collapsed a lot due to the large amount of water and it was somewhat less pliable than the other foams. The hydration rate of the dried foam was somewhat slower than for the other foams and it lost its integrity short time after hydration.

Example 4

50% saturated foam using 100% saturated calcium alginate particles (FP-502-01, from the same source of sodium alginate as in example 1), particle size: >75 μm.

100 g of an alginate 4% solution made from MQ-water and sodium alginate was added to a mixing bowl. Then 18.0 g sorbitol special, 3.0 g HPMC and 69.0 g MQ-water were added to the same mixing bowl. The ingredients were blended with use of a wire whisk and a Hobart mixer at medium speed for two minutes to ensure homogeneity. Then the mixing and aeration continued for five minutes and 30 seconds at high speed. 4.0 g Ca-alginate was suspended in 9.0 g glycerine and 10.0 g water and added to the bowl. The suspension was further mixed for 30 seconds. The resulting foam had a wet density of 0.22 g/ml. Molding, gelling and drying are as in Example 1. The calcium added was sufficient to saturate 50% of the alginate.

The dried foam sheet was soft, flexible and granulated, but more homogeneous than the foams made in the previous examples. It swelled fast and then the weak wet foam disintegrated.

Claims

1. A method of producing a gelled foam comprising the steps of: (a) forming a dispersion by mixing i) a solution comprising a soluble polysaccharide and a plasticizer and adding a polysaccharide/gel-forming ion particles or ii) a soluble, preferably immediately soluble, polysaccharide, preferably an alginate, a polysaccharide/gel-forming ion particles, and adding a solvent, said dispersion (ii) further comprising a water soluble plasticizer;(b) aerating the dispersion in (a), said dispersion optionally further comprising a foaming agent;(c) optionally dispensing the wet foam; and(d) optionally drying the wet foam.

2. A method according to claim 1 in which the plasticizer is selected from glycerin, sorbitol, or a mixture thereof.

3. A method according to claim 1 in which the foaming agent is selected from an ionic surfactant, a non ionic surfactant, a foam stabilizing hydrocolloid.

4. A method according to claim 3 in which the foaming agent selected from hydroxylpropylmethylcellulose, methyl cellulose and albumin.

5. A method according to claim 1 in which the foaming agent is polymeric and biologically-acceptable and substantially free of a non-polymeric surfactant.

6. A method according to claim 1 in which the foaming agent is present in the aqueous dispersion at a level of about 0.5 wt % to about 5 wt %.

7. A method according to claim 1 in which the gel-forming ion in the polysaccharide/gel-forming ion particles comprises calcium ion, strontium ion, barium ion or mixtures thereof.

8. A method according to claim 7 in which the ion is calcium ion.

9. A method according to claim 1 in which the soluble polysaccharide and the polysaccharide in the polysaccharide/gel-forming ion are independently selected from alginates, pectins, carrageenans, chitosan, hyaluronates.

10. A method according to claim 9 in which the soluble polysaccharide is an alginate.

11. A method according to claim 10 or claim 9 in which the polysaccharide in the polysaccharide/gel-forming ion is an alginate

12. A method according to claim 1 in which the gel-forming ion from the polysaccharide/gel-forming ion particles is present at a level sufficient to saturate from about 10% to about 90% and preferably from 25 to 75% of the gelling sites of the total polysaccharide in the dispersion.

13. A method according to claim 1 in which the particle size of the polysaccharide/gel-forming ion particles is from about 500 μm to about 0.001 μm, preferably from about 100 μm to about 0.01 μm and more preferably from about 50 μm to about 0.1 μm.

14. A method according to claim 1 in which the aqueous solution in i) comprises from about 0.1 wt % to about 10 wt %, preferably 0.5 to 8% of the soluble polysaccharide.

15. A method according to claim 1 in which the dispersion comprises from about 0.5 wt % to about 10 wt %, preferably 1 to 5% of the polysaccharide/gel-forming ion particles.

16. A method according to claim 1 in which the dispersion comprises from about 2 wt % to about 25 wt %, preferably 5 to 20 wt %, more preferably 7 wt % to about 15 wt % of plasticizer.

17. A method according to claim 1 in which the soluble polysaccharide is alginate and has a G-content of greater than 50% and a molecular weight from about 10,000 Daltons to about 500,000 Daltons.

18. A method according to claim 1 in which the polysaccharide in the polysaccharide/gel-forming ion particles is alginate and has a G-content from about 30% to about 80% and a molecular weight from about 100 Daltons to about 300,000 Daltons.

19. A foam obtainable by the method according to claim 1 having an endotoxin content of less than 500 EU/gram.

20. A foam according to claim 19 having an endotoxin content of less than 100 EU/gram.

21. A foam according to claim 19 having an endotoxin content suitable for implantation into living organisms.

22. A foam according to claim 19 further comprising one or more cell growth promoting substance.

23. A foam according to claim 19 further comprising one or more cell growth inhibiting substance.

24. A foam according to claim 19 further comprising hydroxyapatite, tricalcium phosphate, demineralized bone and/or organic bone components, bone morphogenic protein, or both.

25. A foam according to claim 19 in which the soluble polysaccharide from the solution and the polysaccharide of the particle are non-uniformly distributed through the foam.

26. A foam according to claim 19 having a inhomogeneous structure.

27. An in vitro cell culture matrix or an in vivo tissue engineering scaffold comprising a self-gelling foam according to claim 19 and cells.

28. A topical wound healing bandage, a structure for treatment of burns or an anti-adhesion barrier comprising a foam according to claim 19.

29. A pharmaceutical delivery device comprising a foam according to claim 19 and a pharmaceutical to be delivered.

30. A method of pharmaceutical delivery comprising applying topically to an external or internal membrane or implanting a structure comprising the pharmaceutical to be delivered and a foam according to claim 19 and optionally dissolving the said foam an aqueous solution of citrate, EDTA or hexametaphosphate or other chelating agents for divalent ions.