Enteral administration of sorbent polymer for treatment and prophylaxis of inflammation

Abstract

The invention provides a method of ameliorating inflammation in a patient involving administering to the patient a therapeutically effective dose of composition including polystyrene divinyl benzene copolymer and a polyvinyl pyrrolidone polymer. More particularly, the method relates to using these polymers as an enteral sorbent preparation to remove inflammatory mediators, such as cytokines, from the intestinal lumen. The polymers can be in the form of a preparation of polystyrene divinyl benzene copolymer beads with a biocompatible polyvinyl pyrrolidone polymer coating.

Claims

1. A method of ameliorating inflammation in a patient suffering from or at risk of inflammation comprising: administering to the patient a therapeutically effective dose of a composition comprising a sorbent, wherein the sorbent comprises both polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer, wherein the administration results in enteral adsorption of an inflammatory mediator.

2. The method of claim 1, wherein an inflammatory mediator is associated with sepsis, surgery, cytotoxic chemotherapy, bone marrow manipulation, major tissue injury, mesenteric hypoperfusion, gut-mucosal injury, malaria, local gastrointestinal inflammatory disease, acute lung inflammation, pancreatitis, rheumatoid arthritis, or collagen vascular diseases.

3. The method of claim 1, wherein the administration is oral or rectal.

4. The method of claim 1, wherein the administration is via feeding tube.

5. The method of claim 1, wherein the patient is human.

6. The method of claim 1, wherein the inflammation is systemic.

7. The method of claim 1, wherein the inflammation is associated with local gastro-intestinal injury or disease.

8. The method of claim 1, wherein the composition consists essentially of the sorbent.

9. The method of claim 1, wherein the sorbent is in the form of beads.

10. The method of claim 9, wherein the beads comprise polystyrene divinyl benzene copolymer with a polyvinyl pyrrolidone polymer coating.

11. The method of claim 9, wherein the beads consist essentially of polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer.

12. The method of claim 9, wherein the bead diameter is about 200 m to about 800 m.

13. The method of claim 9, wherein the beads have pores on the surface of the beads.

14. The method of claim 13, wherein the pores have a diameter of about 10 to about 100 .

15. The method of claim 13, wherein the beads comprise a distribution of pore sizes.

16. The method of claim 13, wherein the pores have a diameter of at least 10 .

17. The method of claim 9, wherein the beads have an internal surface area of about 700 m.sup.2 per gram to about 1000 m.sup.2 per gram of beads.

18. The method of claim 9, wherein the beads adsorb cytokines.

19. The method of claim 9, wherein the beads adsorb one or more molecules selected from the group consisting of tumor necrosis factor (TNF), interleukin (IL)-6, IL-10, high mobility group protein B (HMGB)-1, IL-8, IL-18, monocyte chemotactic protein (MCP)-1, IL-2, IL-1, and S100B.

20. The method of claim 9, wherein composition is in the form of a pill comprising the beads and a pharmaceutically acceptable excipient.

21. The method of claim 9, wherein the beads are administered in the form of a slurry, gel, or powder comprising the beads.

22. The method of claim 9, wherein the beads have a diameter of at least 200 m.

23. The method of claim 9, wherein the beads have an internal surface area of at least 700 m.sup.2 per gram of beads.

24. A method of treating a patient suffering from an inflammatory response comprising: enterally administering to the patient a therapeutically effective dose of a composition consisting essentially of polystyrene divinyl benzene copolymer and a polyvinyl pyrrolidone polymer.

25. The method of claim 24, wherein the composition consisting essentially of the polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer is in the form of beads.

26. The method of claim 25, wherein the beads consist essentially of polystyrene divinyl benzene copolymer with a polyvinyl pyrrolidone polymer coating.

27. The method of claim 24, wherein the composition is administered orally, rectally, or via a feeding tube.

28. The method of claim 24, wherein the patient is human.

29. The method of claim 24, wherein the inflammatory response is systemic.

30. The method of claim 24, wherein the inflammatory response is associated with local gastro-intestinal injury or disease.

31. A method of reducing inflammation in a patient suffering from or at risk of same, comprising: enterally administering to the patient a therapeutically effective dose of a composition comprising beads of a sorbent that adsorbs a mediator of inflammation, wherein the sorbent comprises both polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer.

32. The method of claim 31, wherein the beads comprise polystyrene divinyl benzene copolymer with a polyvinyl pyrrolidone polymer coating.

33. The method of claim 31, wherein the patient is human.

34. The method of claim 31, wherein the inflammation is systemic.

35. The method of claim 31, wherein the inflammation is associated with local gastro-intestinal injury or disease.

36. The method of claim 31, wherein the composition consists essentially of the beads of a sorbent.

37. An orally-admissible pharmaceutical dosage form comprising, as active principal, beads comprising both polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer.

38. The dosage form of claim 37, comprising one or more pharmaceutically acceptable excipients.

39. The dosage form of claim 37, which is in the form of a capsule.

40. The dosage form of claim 37, in the form of a pill, slurry, gel, or powder.

41. The dosage form of claim 37, wherein the beads comprise polystyrene divinyl benzene copolymer coated with a polyvinyl pyrrolidone polymer.

42. The dosage form of claim 37, wherein the beads consist essentially of polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer.

43. The dosage form of claim 37, wherein the bead diameter is at least 200 m.

44. The dosage form of claim 37, wherein the beads have pores on the surface of the beads.

45. The dosage form of claim 44, wherein said pores have a diameter of at least 10 .

46. The dosage form of claim 37, wherein the beads comprise a distribution of pore sizes.

47. The dosage form of claim 37, wherein the beads have an internal surface area of at least 700 m.sup.2 per gram of beads.

Description

BRIEF DESCRIPTION OF THE DRAWING FIGURES

(1) The above and other features and advantages of embodiments of the present invention will become more apparent by describing in detail embodiments thereof with reference to the attached drawings.

(2) FIG. 1 shows in vitro cytokine elimination. Data shown: meansSE for six pools of blood from two animals each. All time points were significantly different form time 0, p<0.001.

(3) FIG. 2 shows immuoblots for HMBG-1 in RAW 264.7. Cells stimulated with LPS in the presence or absence of polymer.

(4) FIG. 3 shows NF.sub.kB DNA-binding in livers of CYTOSORB vs. sham-treated animals at 4 h. Graph depicts mean dataSEM; P<0.05. Right panel depicts representative bands from the electrophoretic mobility shift assay. N=12 animals.

(5) FIG. 4 shows the effect of enteral CYTOSORB on survival in septic rats.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(6) An embodiment of the present invention provides a method for the treatment of systemic inflammation. Also, embodiments of the present invention relate to a method of mitigating the effects of shock and/or to a method of intralumenal adsorption of mediators of inflammation.

(7) In one embodiment, a therapeutically effective dose of a sorbent polymer is administered to a patient in need thereof. Sorbent polymers include polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer. A preferred composition comprises, consists essentially of, or consists of polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer.

(8) In the context of the present invention, the patient is typically a human patient. However, the patent can alternatively be an animal patient (such as domestic animals (e.g., cattle, horses, sheep, goats, cats, dogs, etc.)), an animal used in laboratory research (such as mice, rats, and the like) or an animal of zoological interest (e.g., large cats, ungulates, elephants, etc.).

(9) A composition of polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer can be in the form of beads. For purposes of this disclosure, the term bead refers to any solid three-dimensional particle. The bead shape can be spherical, spheroidal, ellipsoidal, ovoid, rod, or prismatic. As used herein, the term diameter in reference to beads refers to average diameter.

(10) The beads can comprise polystyrene divinyl benzene copolymer, which can be further coated with polyvinyl pyrrolidone polymer. The beads can also consist essentially of, or consist of, polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer. The beads can be fabricated with pores on the outer surface. Molecules can enter the bead's interior via such pores. It is believed that inflammatory mediators are adsorbed within the pores as the beads adsorb the inflammatory mediators from the body of a patient. In one embodiment, the pores have a size of at least 10 , such as at least 20 , at least 30 , at least 40 , at least 50 , at least 60 , at least 70 , at least 80 or at least 90 (or at least about such values). The pores can have a size of as much as 100 , or as much as 90 , or as much as 80 , or as much as 70 , or as much as 60 , or as much as 50 , or as much as 40 , or as much as 30 , or as much as 20 (or as much as about such values). In one embodiment, the beads have a pore size of from 10 to 100 ; in another, from 20 to 50 (or about such values). Beads can be fabricated to have specific pore sizes. The beads can thus be engineered to accommodate and target specific molecules of a particular size for removal. To capture multiple inflammatory mediators, the beads can have a variety of or distribution of pore sizes.

(11) The beads can be of any suitable size and internal surface area. For example, beads can have a diameter of at least 200 m, such as at least 300 m, such as at least 400 m, such as at least 500 m, such as at least 600 m, such as at least 700 m (or at least about such values). The beads can have a diameter of up to 800 m, such as up to 700 m, such as up to 600 m, such as up to 500 m, such as up to 400 m, such as up to 300 m (or up to about such values). A non-limiting example of beads ranges from about 300 to about 800 microns in diameter. The internal surface area of the beads can be at least 700 m.sup.2/gram of beads, such as at least 800 m.sup.2/gram of beads, such as at least 900 m.sup.2/gram of beads (or at least about such values). The internal surface area of the beads can be up to 1000 m.sup.2/gram of beads, such as up to 900 m.sup.2/gram of beads, such as up to 800 m.sup.2/gram of beads (or up to about such values). A non-limiting example of beads has internal surface area of about 700 m.sup.2/gram of beads to about 1000 m.sup.2/gram of beads. In one embodiment, the composition comprises beads having internal surface area of about 850 m.sup.2/gram of beads.

(12) In another embodiment, the invention provides is a method of ameliorating systemic inflammation in a patient comprising identifying a patient suffering from or at risk of systemic inflammation; and administering to the patient a therapeutically effective dose of a composition comprising one or more sorbent polymers that adsorb mediators of inflammation. A preferred administration is via a feeding tube.

(13) The mediators of inflammation can be associated with, for example, sepsis, shock (hemorrhagic, cardiogenic, septic), tissue injury (e.g., surgery, injury to battlefield combatants), ischemia and reperfusion, cytotoxic chemotherapy, chemotherapy using IL-2 or other cytokines, bone marrow manipulation, mesenteric hypoperfusion, gut-mucosal injury, local gastrointestinal inflammatory disease (e.g., inflammatory bowel disease), acute lung inflammation, pancreatitis, malaria or rheumatoid arthritis and other collagen vascular diseases. Thus, for example, the beads can adsorb cytokines. Non-limiting examples of inflammatory mediators that can be adsorbed include tumor necrosis factor (TNF), interleukin (IL)-6, IL-10, high mobility group protein (HMGB)-1, IL-8, IL-18, monocyte chemotactic protein (MCP)-1, IL-2, IL-1, and S100B.

(14) The beads can be administered, e.g., orally, in the form of a pill (e.g., capsules, tablets and the like). Such pills comprise the beads and, optionally, pharmaceutically acceptable excipients such as binders, fillers, buffers, and the like. Such excipients are well known in the art, and suitable excipients can be selected by one of ordinary skill in the art without undue experimentation. In another embodiment, the composition can be administered in the form of a slurry, gel, powder, or other form suitable for oral administration.

(15) Embodiments of sorbent polymers, such as polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer, preferably in bead form, can be administered to a patient in need thereof to adsorb inflammatory mediators. The administration can be prophylactic (e.g., preceding the onset of inflammation), during, or after the cause of the release of the inflammatory mediators.

(16) Administration according to embodiments of the present invention can be any suitable administration that allows a sorbent polymer to be found in the gastrointestinal tract. For example, the administration can be oral, rectal, via a feeding tube, or direct administration into the gastrointestinal tract. A preferred administration is oral or via a feeding tube, though other routes of administration can be used. An oral administration of embodiments of the present invention allows a sorbent polymer, such as a polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer, to pass normally through the gastrointestinal tract of most individuals. Such administration allows a sorbent polymer, such as polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer, to enterally adsorb inflammatory mediators.

(17) The polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer can be in the form of beads, as discussed herein. Such beads can be orally administered in the form of a pill or a slurry. The pill can include the beads and other ingredients, such as fillers. The slurry can include the beads and other ingredients, such as a carrier liquid. A pill or slurry formulation can be prepared similar to an activated charcoal pill or slurry, substituting beads of the embodiments of the present invention for the activated charcoal.

(18) A form of polystyrene divinyl benzene copolymer and polyvinyl pyrrolidone polymer beads is manufactured by RenalTech International LLC, now doing business as MedaSorb Technologies, Inc. (Princeton, N.J.). MedaSorb manufactures polystyrene divinyl benzene copolymer beads with a biocompatible polyvinyl pyrrolidone polymer coating under the tradenames of CYTOSORB and BETASORB. Both CYTOSORB and BETASORB beads are envisioned to fall within the scope of embodiments of the present invention. The CYTOSORB beads are approximately 300-800 m in size and have pores of a size of approximately 20-50 .

(19) Testing has revealed that CYTOSORB beads remove various molecules relevant to inflammation in sepsis, including: TNF, IL-6, IL-10, HMGB-1, IL-8, IL-18, MCP-1, IL-2, IL-1 and S100B. As shown in FIG. 1, CYTOSORB shows in vitro cytokine elimination. The data shown in FIG. 1 is meansSE for six pools of blood from two animals each. All time points were significantly different form time 0, p<0.0001. As shown in FIG. 2, CYTOSORB removes HMGB-1 in RAW 264.7 Cells stimulated with LPS in the presence or absence of polymer.

EXAMPLES

(20) The following examples explain embodiments of the present invention in more detail. However, these examples are given for the purpose of illustration and not limitation.

(21) Briefly, a hemoadsorption device containing CYTOSORB polymer has been tested for the treatment of systemic inflammation due to sepsis, endotoxemia and brain death. CYTOSORB successfully removes circulating inflammatory mediators in a hemoadsorption device, resulting in reduced DNA binding in the liver and improved survival time in animals.

Example 1

Treatment with CYTOSORB Beads and NFkB DNA-Binding

(22) In one set of experiments, 12 animals were studied after intravenous lipopolysaccharide (LPS) injection, six sham and six treated with CYTOSORB using a 10-g device and an aterial-venous circuit. All animals were euthanized after four hours of perfusion so that liver tissue could be obtained for determination of NF.sub.kB DNA-binding. The results, shown in FIG. 3, indicate that NF.sub.kB DNA-binding was significantly lower for CYTOSORB-treated animals as compared to sham-treated animals (p=0.03).

Example 2

Treatment with CYTOSORB Beads and Short-Term Survival

(23) In a separate set of experiments, randomized 40 animals were randomized to receive either hemoadsorption or treatment using a sham circuit for four hours beginning immediately following a lethal LPS infusion. Following the termination of perfusion at four hours, the animals received only fluid resuscitation for the next 8 hours. All animals were sacrificed at 12 hours. Animals treated with CYTOSORB demonstrated a 21% increase in survival time (p>0.01). In the sham-perfusion group, 19 of 20 animals died before 12 hours, while 7 of 20 rats that received hemoperfusion with CYTOSORB were alive at 12 hours, representing an overall improvement in survival (form 5% to 35%, p=0.02). Circulating plasma IL-6, TNF and IL-10 levels for animals treated with CYTOSORB were also significantly lower and their concentrations were inversely correlated with survival time p=0.003.

Example 3

Enteral CYTOSORB Improves Survival in Septic Rats

(24) Preliminary experiments were conducted in 22 rats using an established lethal model of sepsis, cecal ligation and puncture (CLP). Survival was measured with and without enteral CYTOSORB therapy. The results are shown in FIG. 4. Compared to controls, CYTOSORB-treated animals had significantly improved survival (36% vs. 9%), p=0.03. It is important to emphasize that this significant improvement in survival was obtained using only enteral administration of the CYTOSORB beads. Presumably, the presence of these beads within the lumen of gastrointestinal tract acted as a sink for deleterious mediators released into the gut via the bile and/or secreted by immunostimulated enterocytes.

(25) All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

(26) The use of the terms a and an and the and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms comprising, having, including, and containing are to be construed as open-ended terms (i.e., meaning including, but not limited to,) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., such as) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

(27) Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.