阅读说明：本技术 用于减少粘连的方法和产品 (Method and product for reducing blocking ) 是由 莎拉·弗鲁德 彼得·约翰·沃马尔德 于 2018-02-27 设计创作，主要内容包括：本公开涉及用于减少粘连的方法和产品。在某些实施方案中,本公开提供了一种减少受试者中粘连的方法,所述方法包括将受试者中易于形成粘连的区域暴露于具有铁螯合活性和/或抗氧化剂活性的试剂,从而减少受试者中的粘连。(The present disclosure relates to methods and products for reducing blocking. In certain embodiments, the present disclosure provides a method of reducing adhesions in a subject, the method comprising exposing a region of the subject susceptible to adhesion formation to an agent having iron-chelating activity and/or antioxidant activity, thereby reducing adhesions in the subject.)

1. A method of reducing adhesions in a subject, the method comprising exposing a region of the subject susceptible to adhesion formation to an agent having iron-chelating activity and/or antioxidant activity, thereby reducing adhesions in the subject.

2. The method of claim 1, wherein the method comprises administering a composition comprising the agent to an area in a subject prone to adhesion formation.

3. The method of claim 2, wherein the composition comprises any one or more of a gel, a solution, an emulsion, a paste, a nanoparticle, a microparticle, and/or a liposome.

4. A method according to claim 2 or 3, wherein the composition comprises a hydrogel.

5. the method of claim 2 or 3, wherein the gel comprises one or more of chitosan, dextran, carbohydrate polymers, hyaluronic acid and/or salts thereof, collagen, carboxymethyl cellulose, gelatin, polyimide, and alginate.

6. the method of any one of claims 2 to 5, wherein the composition provides greater than 90% release of the agent within 96 hours, greater than 90% release of the agent within 72 hours, greater than 90% release of the agent within 48 hours, or greater than 80% release of the agent within 24 hours.

7. The method of any one of claims 2 to 5, wherein the composition provides sustained release of the agent over a period of 3 to 14 days.

8. The method of any one of claims 1 to 7, wherein the agent comprises a reactive oxygen species inhibitor.

9. the method of claim 8, wherein the reactive oxygen species inhibitor comprises a scavenger of reactive oxygen species and/or an inhibitor of the generation of reactive oxygen species.

10. The method of any one of claims 1 to 9, wherein the agent comprises deferiprone.

11. The method of any one of claims 2 to 10, wherein the reagent comprises deferiprone and the composition comprises a deferiprone concentration of 80mM or less.

12. The method of any one of claims 2 to 11, wherein the reagent comprises deferiprone and the composition comprises a deferiprone concentration of 20mM or less.

13. The method of any one of claims 1-12, wherein the adhesions are surgically-induced adhesions.

14. The method of any one of claims 1-13, wherein the adhesions are adhesions resulting from spinal surgery, abdominal surgery, pelvic surgery, cardiac surgery, joint and tendon surgery, sinus surgery, or plastic surgery.

15. The method of claim 14, wherein the spinal surgery comprises one of a laminectomy, a discoectomy, a hemilaminectomy, a arthrodesis, a microdiscectomy, a discectomy, a laminoplasty, a radio frequency nerve block, and a spinal tumor resection.

16. The method of claim 14, wherein the abdominal or pelvic surgery comprises one of gastrointestinal surgery, vascular surgery, renal surgery, urinary surgery, gynecological surgery, intestinal surgery, liver transplantation, appendectomy, laparoscopy, laparotomy, gynecological appendage surgery, endometriosis surgery, ovarian surgery, fallopian tube surgery, and cilial surgery.

17. The method of claim 14, wherein the cardiac procedure comprises one of a heart valve procedure, a coronary bypass procedure, an angioplasty procedure, an atherectomy procedure, a cardiomyoplasty procedure, and a heart transplant procedure.

18. The method of claim 14, wherein the joint and tendon surgery comprises joint replacement or arthroplasty.

19. The method of claim 14, wherein the sinus surgery comprises one of a paranasal sinus surgery, a skull base surgery, and a skull base surgery involving tumor removal, a lacrimal surgery, and an orbital surgery.

20. The method of claim 14, wherein the orthopedic procedure comprises a surgical procedure involving preventing shrinkage of a fibrous capsule on an implant, such as a breast implant.

21. The method of any one of claims 1-20, wherein the subject is a subject with an existing adhesion.

22. The method of claim 21, wherein the method comprises: the subject is subjected to an adhesion breakdown procedure to treat existing adhesions, and then the agent is administered to an area susceptible to adhesion formation.

23. The method of any one of claims 1 to 22, wherein the area susceptible to adhesion formation in a subject comprises a surgical site and/or an area overlapping and/or adjacent to the surgical site.

24. A method of reducing adhesions in a subject, the method comprising administering a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area in the subject prone to form adhesions, thereby reducing adhesions in the subject.

25. A method of reducing surgical adhesions in a subject, the method comprising administering a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area in a subject prone to surgical adhesions, thereby reducing surgical adhesions in a subject.

26. A method of reducing post-operative adhesions in a subject, the method comprising administering a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area in a subject prone to post-operative adhesions, thereby reducing post-operative adhesions in a subject.

27. A method of preventing and/or treating an adhesion in a subject, the method comprising administering a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area of the subject prone to form an adhesion, thereby preventing and/or treating an adhesion in the subject.

28. A method of treating adhesions in a subject, the method comprising:

(i) Performing an adhesion breakdown procedure on the subject; and

(ii) Applying a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area susceptible to adhesion formation after an adhesion breakdown procedure to reduce the formation of new adhesions in a subject,

Thereby treating the adhesion in the subject.

29. Use of an agent having iron-chelating activity and/or antioxidant activity to reduce adhesions in a subject.

30. An anti-blocking composition comprising an agent having iron chelating activity and/or antioxidant activity.

31. An anti-adhesion composition as claimed in claim 30 wherein the composition comprises any one or more of a gel, solution, emulsion, paste, nanoparticle, microparticle and/or liposome.

32. An anti-blocking composition according to claim 30 or 31 wherein the composition comprises a hydrogel.

33. An anti-adhesion composition as claimed in claim 31 or 32 wherein the gel comprises one or more of chitosan, dextran, carbohydrate polymers, hyaluronic acid and/or salts thereof, collagen, carboxymethyl cellulose, gelatin, polyimides and alginates.

34. the anti-blocking composition of any one of claims 30 to 33, wherein the composition provides greater than 90% release of the agent within 96 hours, greater than 90% release of the agent within 72 hours, greater than 90% release of the agent within 48 hours, or greater than 80% release of the agent within 24 hours.

35. The anti-blocking composition of any one of claims 30 to 33, wherein the composition provides for sustained release of the agent over a period of 3 to 14 days.

36. An anti-blocking composition according to any one of claims 30 to 35 wherein the agent comprises a reactive oxygen species inhibitor.

37. an anti-blocking composition according to claim 36 wherein the reactive oxygen species inhibitor comprises a scavenger of reactive oxygen species and/or an inhibitor of the generation of reactive oxygen species.

38. An anti-blocking composition according to any one of claims 30 to 37 wherein the composition is a salt solution.

39. An anti-blocking composition according to any one of claims 30 to 38 wherein the agent includes deferiprone.

40. The anti-adhesion composition of claim 39, wherein the composition includes a deferiprone concentration of 80mM or less.

41. An anti-adhesion composition according to claim 39 or 40, wherein the composition includes a deferiprone concentration of 20mM or less.

42. A nasal and/or sinus irrigation composition comprising an agent having iron chelating activity and/or antioxidant activity and a liquid carrier.

43. A method of reducing post-operative sinus adhesions in a subject, the method comprising flushing a sinus of the subject with a nasal and/or sinus irrigation composition of claim 42, thereby reducing post-operative sinus adhesions in the subject.

44. An anti-blocking composition comprising a chitosan-based gel and an agent having iron-chelating activity and/or antioxidant activity.

45. A method of reducing adhesions in a subject, the method comprising administering a composition of any of claims 30 to 44 to an area in a subject prone to adhesion formation, thereby reducing adhesions in the subject.

46. A product for reducing adhesions in a subject, the product comprising the following ingredients:

(i) An agent having iron-chelating activity and/or antioxidant activity; and/or

(ii) One or more components for forming a gel comprising an agent having iron chelating activity and/or antioxidant activity, the gel being suitable for application to a surgical site; and/or

(iii) a preformed gel comprising an agent having iron chelating activity and/or antioxidant activity, wherein the gel is suitable for application to a surgical site;

And optionally

(a) An applicator for dispensing a gel containing the agent to a surgical site; and/or

(b) Instructions for forming a gel and/or dispensing the gel to a surgical site.

47. A chitosan-based gel comprising an agent having iron-chelating activity and/or antioxidant activity.

48. A method of producing a product for reducing adhesions in a subject, the method comprising forming a gel comprising an agent having iron-chelating activity and/or antioxidant activity, wherein the gel is suitable for application to a surgical site.

49. A method of identifying an agent for reducing adhesions, the method comprising determining the ability of an agent having iron-chelating activity and/or antioxidant activity to reduce adhesions in a subject, thereby identifying the agent as an agent for reducing adhesions.

50. An anti-blocking agent identified according to the method of claim 49.

Technical Field

The present disclosure relates to methods and products for reducing blocking.

Background

Adhesions are the formation of fibrous bands between tissues and organs that are not normally joined. They are typically formed when two or more surfaces (e.g., surfaces of discrete tissue) are adhered together following a surgical-related injury. Adhesions are a common complication of surgery and their formation is difficult to avoid.

Although normal wound healing is a highly regulated and coordinated process, the causes of adhesion formation are complex and not fully understood. In addition, many pathological processes exacerbate adhesion formation. The critical time interval to prevent the formation of multiple types of adhesions appears to be within the first 48 hours after the initial injury, and the extent of adhesion formation appears to depend at least in part on the inhibition of fibroblast proliferation and/or migration during this time.

Adhesions can occur after almost all types of surgery and can form in most anatomical locations. For example, an enterotomy in the abdominal cavity may result in adhesions between the intestine and the abdominal wall. Adhesions can cause pain and discomfort to the patient, impair the function of the affected organ, and prevent subsequent surgery in the same anatomical area. Adhesions are also a common complication of spinal surgery, and even after success, are a major cause of post-operative pain.

The formation of adhesions may lead to increased medical costs. These costs include subsequent surgery to remove or separate the adhesion, additional visits by the physician, pain medications, and lost productivity. In addition, existing adhesions can complicate surgery if the patient performs subsequent surgery at the same surgical site. The surgeon may have to spend additional time removing the existing adhesions before starting a new procedure.

therefore, reduction of adhesions remains an important goal of surgical practice. Various approaches have been taken to treat adhesions, but they generally do not withstand rigorous clinical testing, or they have significant practical limitations.

For example, one such method is to perform further surgery to remove existing adhesions. However, many times these procedures are ineffective because the adhesions simply reform. Another method of preventing adhesions is the use of agents such as anti-inflammatory agents, anticoagulants, and fibrinolytic agents. However, this method is not particularly encouraging.

Another approach is to develop barriers for surgical procedures, the purpose of which is to physically separate the tissues. Liquid barriers and gels generally do not work well and the clinical effectiveness of structural barriers has been found to be less than desirable.

Thus, new methods and products are needed that reduce the formation of blocking.

Disclosure of Invention

The present disclosure relates to methods and products for reducing blocking.

Certain embodiments of the present disclosure provide a method of reducing adhesions in a subject, the method comprising exposing a region of the subject susceptible to adhesion formation to an agent having iron-chelating activity and/or antioxidant activity, thereby reducing adhesions in the subject.

Certain embodiments of the present disclosure provide a method of reducing adhesions in a subject, the method comprising administering a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area of the subject prone to form adhesions, thereby reducing adhesions in the subject.

Certain embodiments of the present disclosure provide a method of reducing surgical adhesions in a subject, the method including administering a composition including an agent having iron-chelating activity and/or antioxidant activity to an area in the subject prone to surgical adhesions, thereby reducing surgical adhesions in the subject.

Certain embodiments of the present disclosure provide a method of reducing post-operative adhesions in a subject, the method comprising administering a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area of the subject prone to post-operative adhesions, thereby reducing post-operative adhesions in the subject.

Certain embodiments of the present disclosure provide a method of preventing and/or treating adhesions in a subject, the method comprising administering a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area in the subject prone to form adhesions, thereby preventing and/or treating adhesions in the subject.

Certain embodiments of the present disclosure provide a method of treating an adhesion in a subject, the method comprising:

(i) Subjecting the subject to an adhesion breakdown procedure (acquired procedure); and

(ii) Applying a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area susceptible to adhesion formation after an adhesion breakdown procedure to reduce the formation of new adhesions in a subject,

Thereby treating the adhesion in the subject.

Certain embodiments of the present disclosure provide for the use of an agent having iron-chelating activity and/or antioxidant activity in reducing adhesions in a subject.

Certain embodiments of the present disclosure provide agents having iron chelating activity and/or antioxidant activity for use in treating adhesions.

Certain embodiments of the present disclosure provide an anti-blocking composition comprising an agent having iron chelating activity and/or antioxidant activity.

Certain embodiments of the present disclosure provide a product for reducing adhesions in a subject, the product comprising the following components:

(i) An agent having iron-chelating activity and/or antioxidant activity; and/or

(ii) One or more components for forming a gel comprising an agent having iron-chelating activity and/or antioxidant activity, the gel being suitable for application to a surgical site; and/or

(iii) A preformed gel comprising an agent having iron chelating activity and/or antioxidant activity, wherein the gel is suitable for application to a surgical site;

And optionally:

(a) an applicator for dispensing a gel containing the agent to a surgical site; and/or

(b) instructions for forming the gel and/or dispensing the gel to a surgical site.

Certain embodiments of the present disclosure provide nasal and/or sinus irrigation compositions comprising an agent having iron chelating activity and/or antioxidant activity and a liquid carrier.

Certain embodiments of the present disclosure provide chitosan-based gels comprising an agent having iron-chelating activity and/or antioxidant activity.

certain embodiments of the present disclosure provide an anti-blocking composition comprising a chitosan-based gel and an agent having iron-chelating activity and/or antioxidant activity.

Certain embodiments of the present disclosure provide a method of producing a product for reducing adhesions in a subject, the method comprising forming a gel comprising an agent having iron-chelating activity and/or antioxidant activity, wherein the gel is suitable for application to a surgical site.

Certain embodiments of the present disclosure provide a method of identifying an agent for reducing adhesions, the method comprising determining the ability of an agent having iron-chelating activity and/or antioxidant activity to reduce adhesions in a subject, thereby identifying the agent as an agent that reduces adhesions.

Other embodiments are disclosed herein.

Drawings

Certain embodiments are illustrated by the following figures. It is to be understood that the following description is for the purpose of describing particular embodiments only and is not intended to be limiting.

Fig. 1 shows fibroblast Proliferation measured using the Alamar Blue Proliferation assay (which was normalized to control untreated primary fibroblasts), indicating a dose and time dependent significant reduction in fibroblast Proliferation treated with deferiprone (Def). P <0.05, p <0.01, p <0.001, p < 0.0001.

FIG. 2 shows the dose and time dependent effect of Def on primary fibroblast proliferation over 48-72 hours. Primary fibroblasts were stained with CytoX-Violet migration and after 48 hours in control cells (first column, 0mM Def) the voids in the fibroblasts were blocked, while in 20mM Def treated fibroblasts (last column, 20mM Def) minimal blocking was up to 48 hours.

FIG. 3 shows the release profile of a gel loaded with 20mM deferiprone (Def). Data are mean ± SD of 3 replicates.

Figure 4 shows that deferiprone gel is effective in reducing adhesion formation after spinal surgery in vivo compared to untreated controls or gels containing corticosteroids.

Figure 5 shows cell viability (cell viability) of HNEC and human nasal fibroblast monolayers from CRS patients. Survival of hnec (a) and primary human nasal fibroblasts from CRS patients (B) as determined by LDH assay relative to untreated control cells 1 hour, 2 hours, 3 hours, 4 hours, 5 hours and 6 hours after application of deferiprone (1mM, 5mM, 10mM, 20mM), negative control (medium) and positive control (0.5% Triton X-100). Cell viability was calculated relative to untreated cells as a negative control. Values are shown as mean ± SEM, n ═ 3. ANOVA, followed by Tukey HSD post hoc testing (post hoc test). (. p < 0.05).

Fig. 6 shows scratch tests of primary human nasal epithelial cells and primary fibroblasts over time in the presence of different concentrations of deferiprone. Average percentage of wound area over time in scratch tests of primary human nasal epithelial cells (a) and sinus fibroblasts (B) in the presence of different deferiprone concentrations (1mM, 5mM, 10mM, 20mM) or negative (medium) controls. Values are shown as mean ± SEM, n ═ 3. ANOVA followed by Tukey HSD post hoc testing. P < 0.05.

FIG. 7 shows measurement of IL-6 production by ELISA on human nasal epithelial cells (A) or nasal fibroblasts (B) in the presence or absence of the pro-inflammatory agents polyinosinic acid (Poly (I: C)) or IL-I β, respectively. Budesonide was used as an anti-inflammatory standard for the care control and medium as a negative control. ANOVA followed by Tukey HSD post hoc testing. (p <0.05, p <0.001, p < 0.0001); values are shown as mean ± SEM.

Fig. 8 shows collagen release in de-ferrone treated primary nasal fibroblasts measured by ELISA in the absence (a) or presence of L-ascorbic acid-2 phosphate (ASC) (B). Primary human nasal fibroblasts were treated with 1mM, 5mM, 10mM and 20mM deferiprone for 48 hours. Medium only and L-ascorbic acid 2 phosphate (ASC) were used as negative and positive controls, respectively. Bars represent mean ± standard deviation (n ═ 4). (p <0.001 (p <0.0001) ANOVA, followed by Tukey HSD post hoc testing.

Detailed Description

The present disclosure relates to methods and products for reducing blocking.

The present disclosure is based, at least in part, on the recognition that: an agent having iron-chelating activity and/or antioxidant activity is effective in reducing adhesions in a subject. Without being bound by theory, the antioxidants and iron chelator deferiprone have been shown to inhibit fibroblast proliferation and migration in vitro. Additionally, it has been found that gel-based systems can be used to provide maximum delivery of agents to the surgical site within 48 hours, consistent with a critical period to prevent adhesion formation. This deferiprone-containing gel system reduces adhesions in vivo in large animal laminectomy models.

Certain embodiments of the present disclosure provide methods of reducing adhesions in a subject.

In certain embodiments, the present disclosure provides methods of reducing adhesions in a subject, the methods comprising exposing a region of the subject susceptible to adhesion formation to an agent having iron-chelating activity and/or antioxidant activity, thereby reducing adhesions in the subject.

In certain embodiments, the subject is a human subject. For example, a human patient undergoing surgery may be treated to expose areas susceptible to adhesion formation to an agent having iron-chelating activity and/or antioxidant activity.

In certain embodiments, the subject is an animal subject, a mammalian subject, a livestock animal (e.g., horses, cattle, sheep, goats, pigs), a livestock animal (e.g., dogs or cats) and other types of animals, such as monkeys, rabbits, mice, rats, and laboratory animals. Veterinary applications of the present disclosure are contemplated. For example, in horses, post-operative abdominal adhesions are a significant problem.

In certain embodiments, the subject is susceptible to forming adhesions.

In certain embodiments, the subject is suitable for treatment to reduce the formation of adhesions.

in certain embodiments, the subject has an increased risk or likelihood of suffering from adhesions. For example, a subject may have one or more risk factors associated with increased risk of postoperative adhesion formation, such as certain genetic polymorphisms, increased estrogen exposure, endometriosis, diabetes, metabolic syndrome, hyperglycemia, obesity, alcohol consumption, treatment with certain drugs, hormonal therapy, pregnancy, and cancer.

In certain embodiments, the subject suffers from an existing adhesion. In certain embodiments, the subject suffers from an existing adhesion and is adapted to remove the existing adhesion by an adhesion breakdown procedure and subsequently treated to reduce the formation of new adhesions.

In certain embodiments, the area of the subject prone to adhesion formation includes the surgical site and/or a site that overlaps, is adjacent to, or is proximate to the surgical site.

In certain embodiments, the area in the subject prone to adhesion formation comprises a non-surgical site. In certain embodiments, the area in the subject prone to adhesion formation is a site of inflammation.

In certain embodiments, the area in the subject prone to adhesion formation includes a site that has removed an existing adhesion or has undergone an adhesion breakdown procedure.

In certain embodiments, the methods comprise reducing adhesions at the surgical site, adhesions formed at a non-surgical site, or adhesions formed after dissolution of a previous adhesion.

In certain embodiments, the adhesions are adhesions resulting from surgery.

Examples of procedures that may form adhesions after surgery include spinal procedures such as laminectomy, disc decompression, hemilaminectomy, arthrodesis, microdiscectomy, discectomy, laminoplasty, radio frequency nerve dissection, and spinal tumor resection; abdominal or pelvic surgery, such as gastrointestinal, vascular, renal, urinary, gynecological, intestinal, liver transplantation, appendectomy, laparoscopy, laparotomy, gynecological adnexal, endometriosis, ovarian, fallopian tube, and cilial surgery; cardiac surgery, such as heart valve surgery, coronary bypass surgery, angioplasty, atherectomy, cardiomyoplasty and heart transplantation; joint and tendon surgery, such as joint replacement or arthroplasty; sinus surgery, such as paranasal sinus surgery, cranial base surgery, and cranial base surgery involving tumor removal, lacrimal passage, and orbital surgery; orthopedic surgery, for example, involves surgical procedures that prevent shrinkage of fibrous capsules on implants (e.g., breast implants).

In certain embodiments, the adhesions are adhesions resulting from spinal surgery, abdominal surgery, pelvic surgery, cardiac surgery, joint and tendon surgery, sinus surgery, or plastic surgery. Other types of surgery that cause adhesions are also contemplated.

In certain embodiments, the spinal procedure comprises one of a laminectomy, a discoectomy, a hemilaminectomy, a arthrodesis, a microdiscectomy, a discectomy, a laminoplasty, a radio frequency nerve block, and a spinal tumor resection.

In certain embodiments, the abdominal or pelvic surgery comprises one of gastrointestinal surgery, vascular surgery, renal surgery, urinary surgery, gynecological surgery, intestinal surgery, liver transplantation, appendectomy, laparoscopy, laparotomy, gynecological attachment surgery, endometriosis surgery, ovarian surgery, fallopian tube surgery, and cilial surgery.

In certain embodiments, the cardiac procedure comprises one of a heart valve procedure, a coronary bypass procedure, an angioplasty procedure, an atherectomy procedure, a cardiomyoplasty procedure, and a heart transplant procedure.

in certain embodiments, joint and tendon surgery includes joint replacement or arthroplasty.

In certain embodiments, the sinus surgery comprises one of a paranasal sinus surgery, a skull base surgery, and a skull base surgery involving removal of a tumor, a lacrimal surgery, and an orbital surgery.

In certain embodiments, the orthopedic procedure comprises a surgical procedure involving preventing shrinkage of a fibrous capsule on an implant (e.g., a breast implant).

In certain embodiments, the method reduces the formation, rate, amount, or incidence of blocking.

In certain embodiments, the method reduces the formation or amount of blocking by at least 10%, 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%. In certain embodiments, the method reduces the formation or number of adhesions by 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or more than 90%.

In certain embodiments, the methods reduce the characteristics of the adhesion, such as the strength, thickness, extent, severity, and/or vascularization of the adhesion.

In certain embodiments, the method reduces the incidence of blocking. For example, adhesions can be classified as membranous adhesions, strong adhesions, or very strong vascularized adhesions.

For abdominal adhesions, a standardized grading system is as follows: 0-no adhesion; 1-film adhesion; 2-more than one such adhesion; 3-thick adhesion with focus; 4-thick adhesion with planar attachment; 5-very thick vascularized adhesions or adhesions with more than one plane.

In certain embodiments, the method prevents the formation of adhesions.

Methods of assessing blocking are known in the art, for example using the grading system described herein.

In certain embodiments, the agent has iron-chelating activity.

Methods for determining iron-chelating activity are known in the art, for example, in vitro methods for assessing the ability of an agent to bind iron, or methods for assessing the ability of an agent to bind iron in vivo. Iron chelators for use in therapy are described, for example, in "iron chelation therapy" (2012) in experimental Medicine and Biology, vol 509; the CaimHersko edition; published by Springer, Kluwer Academic/plenum Publishers, USA.

Examples of agents having iron-chelating activity include deferiprone, deferoxamine, deferasirox, kojic acid, tetramic acid, deferthiocin, 8-hydroxyquinoline analogue, clioquinol, O-treslox (tris-N- (2-aminoethyl- [ 8-hydroxyquinoline 5-sulfo-7-amido)]Amine), tacrine (N, N' -tris (2-picolyl) -cis, cis-1, 3, 5-triaminocyclohexane), Dexrazone, thiosemicarbazone, and mixtures thereof,(3-aminopyridine-2-carboxaldehyde thiosemicarbazone [ 3-AP)]) Pyridoxal Isonicotinyl Hydrazone (PIH) and its analogs, phytochemicals, proanthocyanidins, epicatechin, flavonols and anthocyanins, curcumin, vanillyl ketone (apocynin), Kolavonone (kolaviron), fluoroalcohol (florano)l), nitrilotriacetate (nitrilotriacetate), pycnogenol (pycnogenol), procyanidins (procyanidins), baicalein (baicalein), baicalin (baicalin), quercetin, tetramethylpyrazine, ferulic acid, ligustrazine, quercetin, chrysin, 3-hydroxyflavone, 3', 4' -dihydroxyflavone, rutin and flavone, iron triazine, gallic acid, catechin, epigallocatechin gallate (EGCG) and proanthocyanidins, green tea catechin, black tea theaflavin, ethylenediaminetetraacetic acid/ethylenediaminetetraacetic acid salts (EDTA), citric acid, phosphonic acid/phosphonate and analogs thereof, aminophosphonate and analogs, bisphosphonate and analogs; and/or an acceptable salt, derivative (e.g., a chemically substituted form), solvate, hydrate, tautomer, prodrug, or stereoisomer of any of the foregoing. Other iron chelators are also contemplated.

Iron chelators are commercially available or synthesized by methods known in the art.

In certain embodiments, the agent has antioxidant activity.

Methods for determining antioxidant activity are known in the art, for example, methods for assessing the ability of an agent to inhibit oxidation and/or to assess the ability of an agent to remove oxidizing agents or free radicals (e.g., reactive oxygen species).

Examples of agents having antioxidant activity include small molecule compounds such as glutathione, bilirubin, ubiquinone, vitamin C, vitamin E, carotenoids, phytic acid, oxalic acid, tannins, beta-carotene (beta-caroten), eugenol, retinol, cannabinoids, dithiol-containing antioxidants, lipoic acid, DTT (dithiothreitol), aspirin, salicylic acid, glutathione, egg thiol (ovothiol), and phenolic compounds, and enzymes such as SOD, GPX, PRDX, and catalase. Other agents having antioxidant activity are also contemplated.

Antioxidants are commercially available or can be synthesized by methods known in the art.

In certain embodiments, the agent has iron-chelating activity and antioxidant activity.

In certain embodiments, the agent having iron-chelating activity and/or antioxidant activity comprises a reactive oxygen species inhibitor. In certain embodiments, the reactive oxygen species inhibitor comprises a scavenger of reactive oxygen species and/or an inhibitor of reactive oxygen species generation. Methods for determining the ability of agents to act as ROS inhibitors are known in the art, for example, as described in Pavelescu et al (2015) J.Med.Life 8:38-42 and Woolley et al (2013) Tends Biochem Sci (11): 556-565.

in certain embodiments, the agent comprises one or more of deferiprone, deferoxamine, and deferoxamine, or any combination thereof. These reagents are commercially available or synthesized by methods known in the art. For example, deferiprone is available from Apotex Pty Ltd or Selleckchem. com (product # S4067) and deferoxamine (as the mesylate salt) is available from Merck (formerly Sigma-Aldrich; product # D9533).

In certain embodiments, the agent comprises deferiprone.

As used herein, the term "exposed" and related terms such as its modified forms refer to the area susceptible to adhesion formation being contacted directly and/or indirectly with and/or treated with an agent having iron-chelating activity and/or antioxidant activity.

The agent may be exposed to the area of the subject in a suitable form. In this regard, the agent may also be a precursor form of the agent, or a derivative that will form a therapeutically effective form of the agent when exposed to a subject.

In certain embodiments, the method comprises contacting the region with the agent. In certain embodiments, the method comprises applying the agent to the area, for example by coating the area with the agent, spraying the area with the agent or by applying a composition comprising the agent to the area. For example, in the case of sinus surgery, the composition may be applied to the surgical site and/or the composition may be used to post-operatively cleanse the sinuses.

In certain embodiments, the exposing utilizes a therapeutically effective amount of the agent. The term "therapeutically effective amount" as used herein refers to an amount of an agent sufficient to reduce adhesions or to prevent and/or treat adhesions. The therapeutically effective amount will vary depending on a number of factors including, for example, the specific activity of the agent used, the clinical characteristics, age, physical condition, presence of other disease states, and the nutritional status of the subject. Examples of therapeutic amounts are described herein.

Formulations for delivering agents with iron-chelating activity and/or antioxidant activity are described, for example, in ramington: pharmaceutical Science and Practice (Remington: The Science and Practice of Pharmacy), edited by DavidB&Wilkins and Tiwari G et al edit (2012) int.j.phar,. Investig2(1):2-11；

In certain embodiments, the amount of agent delivered is an amount in one of the following selected ranges: 1 μ g to 100 mg; 1 μ g to 10 mg; 1 μ g to 1 mg; 1 to 100 mug; 1 to 10 mug; 10 mug to 100 mg; 10 μ g to 10 mg; 10 μ g to 1 mg; 10 to 100 mug; 100 μ g to 100 mg; 100 μ g to 10 mg; 100 μ g to 1 mg; 1mg to 10 mg; 1mg to 100mg and 10mg to 100 mg. The dose and frequency of delivery can be determined by one skilled in the art.

In certain embodiments, the amount of agent delivered is 1mg to 100 mg.

In certain embodiments, the exposure to an agent is prophylactic exposure. In certain embodiments, exposing to the agent comprises exposing to the agent prior to and/or during formation of the adhesion.

in certain embodiments, the agent exposure area comprises delivery of the agent by a gel, ointment, cream, lotion, foam, emulsion, suspension, spray, aerosol, solution, liquid, powder, semisolid, gel, solid, paste, or tincture.

In certain embodiments, the exposing of the agent comprises delivering the agent via a particle, such as a microparticle or nanoparticle, or delivering the agent via a liposome.

Other forms of delivery of the agent include delivery through a scaffold, such as a biomaterial scaffold, including scaffolds produced from collagen, hydroxyapatite, β -tricalcium phosphate, or a combination thereof. Methods of incorporating reagents into such matrices are known in the art.

In certain embodiments, the methods comprise administering a composition, formulation, or medicament comprising an agent described herein to a region in a subject susceptible to adhesion formation. The composition, formulation or medicament may include other various excipients, dosage forms and other ingredients suitable for use in connection with the delivery of the agent, and may be in, for example, a solid form, a semi-solid form, a liquid form or a foam form.

In certain embodiments, the methods comprise administering a composition comprising the agent to an area of the subject prone to adhesion formation. Methods of producing compositions are known in the art, for example, in remington: pharmaceutical science and practice, edited by David B.Troy and Paul Beringer (2006) Lipincott Williams&Wilkins and Tiwari G et al edit (2012) int.j.phar,. Investig2(1)2-11;

In certain embodiments, the composition comprises one or more of a gel, solution, rinse, emulsion, cream, spray, nanoparticle, microparticle, liposome, ointment, cream, lotion, foam, suspension, aerosol, liquid, powder, semi-solid, paste, or tincture.

Gels are semisolid systems and are typically composed of a dispersion of molecules in a liquid carrier, jellified by the addition of a gelling agent.

A solution is a liquid formulation of a soluble chemical dissolved in a solvent such as water, alcohol, or propylene glycol. For example, a nasal rinse comprising the agent may be used to reduce inflammation or adhesions of the sinuses.

Emulsions are two-phase formulations in which one phase (the dispersed or internal phase) is finely dispersed in the other phase (the continuous or external phase). The dispersed phase may be hydrophobic (oil-in-water) or water-based (water-in-oil). The emulsion may comprise a water-in-oil emulsion or an oil-in-water emulsion.

Ointments are drugs dissolved or suspended in a water removable or emollient base. Ointments are generally classified as either water-in-oil or oil-in-water. Lotions are typically clear/translucent solutions. Lotions typically contain 25% to 50% alcohol and may also contain preservatives, emollients and hemostatic materials. Ointments are semi-solid formulations. Water-soluble ointments may be formulated, for example, with polyethylene glycol. Pastes are ointments to which a high percentage (typically up to 50% by weight) of insoluble solids has been added.

Powders typically utilize small particle sizes with large surface areas per unit weight.

Foams typically utilize entrapped gas in a liquid, semi-solid, or solid matrix.

In certain embodiments, the composition is a gel. Examples of gel compositions include fibrin gels, polysaccharide gels (e.g., alginate, agarose, chitosan, or pectate salts), polymer gels (e.g., polyvinyl alcohol polymers), and protein gels (e.g., gelatin or collagen). Methods of producing gels are known in the art.

In certain embodiments, the composition comprises a hydrogel. Methods for producing Hydrogels are known in the art, for example, from Gulrez et al (2011) "Hydrogels: Methods of Preparation, edited by Characteriission and applications" Angelo Carpi, ISBN 978-.

In certain embodiments, the gel comprises one or more of chitosan, dextran, carbohydrate polymers, hyaluronic acid and/or salts thereof, collagen, carboxymethyl cellulose, gelatin, polyimides, and alginates.

In certain embodiments, the composition comprises a chitosan-based gel. Chitosan-based gels are known in the art, for example, as described in International patent application WO/2009028965 and Ahmad et al (2015) Res Pharm Sci 10(1): 1-16.

In certain embodiments, the agent is exposed to the area by administering the agent to the subject.

The agents described herein may be administered to a subject in a suitable form. In this regard, the terms "administering" or "providing" encompass the administration of one or more agents, or the administration of a prodrug of such an agent or a derivative of such an agent, which prodrug or derivative will form a therapeutically effective amount of the agent in the subject. The term includes, for example, systemic routes of administration (e.g., by injection, e.g., intravenous injection, oral in tablets, pills, capsules, or other dosage forms for systemic administration of the drug) and topical routes of administration (e.g., ointments, solutions, gels, etc., as well as solutions such as mouthwashes, lotions for topical oral administration, etc.).

Methods of administering agents are known in the art.

The agents may be administered alone or may be delivered in admixture with other therapeutic substances and/or other substances that enhance, stabilize or maintain the activity of the agent. In certain embodiments, the administration vehicle (e.g., pill, tablet, implant, injectable solution, etc.) comprises one or more agents and/or one or more other substances.

When administered to a subject, the effective dosage may vary depending on the particular agent used, the mode of administration, and various physical factors associated with the subject being treated. It is contemplated that the daily dosage will vary with the route of administration and the nature of the agent being administered.

In certain embodiments, one or more agents are administered orally. In certain embodiments, the one or more agents are administered topically. In certain embodiments, the one or more agents are administered by injection, e.g., intravenous injection. In certain embodiments, the one or more agents are administered parenterally. In certain embodiments, the one or more agents are administered by direct introduction into the lung, such as by aerosol administration, by nebulization, and by infusion into the lung. In certain embodiments, the one or more agents are administered via an implant. In certain embodiments, the one or more agents are administered by subcutaneous injection, intraarticular, rectal, intranasal, intraocular, vaginal, or transdermal administration. In certain embodiments, the one or more agents are administered via a biological or non-biological implant.

"intravenous administration" is the administration of a substance directly into a vein. In certain embodiments, the agent may also be administered intravenously. Compositions comprising an agent described herein suitable for intravenous administration may be formulated by the skilled person and will generally comprise a carrier or excipient, for example isotonic saline.

"oral administration" is the route of administration by oral ingestion of a substance and includes buccal, sublabial and sublingual administration, as well as enteral administration, and administration through the respiratory tract, except through a tube so that the drug does not come into direct contact with any oral mucosa. Typical forms of orally administering therapeutic substances include the use of tablets or capsules.

In certain embodiments, it may be desirable to administer one or more agents directly to the airway in the form of an aerosol. Formulations for aerosol administration are known.

In certain embodiments, the agent may also be administered parenterally (e.g., directly into the joint space) or intraperitoneally. For example, a solution or suspension of the agent in a non-ionized form or as a pharmacologically acceptable salt may be prepared by suitably mixing a surfactant such as hydroxypropylcellulose in water. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations usually contain a preservative to prevent the growth of microorganisms.

In certain embodiments, the one or more agents may also be administered by injection. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

For example, a pharmaceutical composition for intravenous use of an iron chelator may be as follows: 10-500mg deferiprone in isotonic saline, optionally containing one or more pharmaceutically acceptable additives and/or excipients.

In certain embodiments, the one or more agents may also be administered transdermally. Transdermal administration is understood to mean all administration via the surface of the body and the inner layers of body passages, including epithelial and mucosal tissues. Such administration can be carried out using the agents described herein, or pharmaceutically acceptable salts thereof, in the form of lotions, ointments, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

Transdermal administration can also be accomplished by using a transdermal patch containing the active compound and a carrier that is inert to the active compound, non-toxic to the skin, and allows delivery of the agent for systemic absorption through the skin into the bloodstream. The carrier may take a wide variety of forms such as pastes and ointments, pastes, gels, and occlusive devices. Ointments and creams may be viscous liquid or semisolid emulsions of the oil-in-water or water-in-oil type. Pastes comprised of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient are also suitable. A variety of occlusive devices can be used to release the active ingredient into the bloodstream, such as a semi-permeable membrane covering a reservoir containing the active ingredient (with or without a carrier) or a matrix containing the active ingredient.

In certain embodiments, the one or more agents may also be administered by suppository. Suppositories may be made of conventional materials, including cocoa butter with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.

In certain embodiments, the one or more agents may be administered or delivered via a solid or semi-solid substrate, e.g., incorporated into a matrix, scaffold, or carrier, e.g., a biodegradable matrix or carrier. Methods of delivering agents through stents are known in the art. For example, a biomaterial scaffold including a scaffold produced from collagen, hydroxyapatite, β -tricalcium phosphate, or a combination thereof may be used to deliver the agent. Methods for incorporating reagents into such substrates are known in the art.

In certain embodiments, the one or more agents may be administered or delivered by an implantable composition. Methods of preparing implantable compositions are known in the art.

Additional excipients, dosage forms, dispersants, and the like are contemplated and are suitable for administration of the agents and/or administration in formulated compositions, medicaments, or pharmaceutical compositions.

Formulations are known and described, for example, in Remington's Pharmaceutical Sciences, 17 th edition, Mack Publishing Company, Easton, Pa,1985, which is incorporated herein by reference in its entirety.

In certain embodiments, the compositions described herein comprise a desired release profile.

Formulations for Controlled Release of active agents, such as immediate Release, sustained Release and delayed Release formulations, are known in the art, for example, as described in "Handbook of Controlled drug Release Technology" edited by Donald L Wise (2000) Marcel Dekker inc.,270Madison Avenue New York, NY 10016. For example, immediate release formulations may provide for immediate release of an agent in a disintegrant such as cross-linked carboxymethylcellulose, sodium starch glycolate, or polyvinylpyrrolidone, which provides for rapid disintegration of the tablet, and delayed release formulations may provide for delayed release of an agent (e.g., a non-ferrous metalloporphyrin) in a pH-dependent agent coating using an acrylic-based resin such as Eudragit S (methacrylic acid copolymer B, NF) and/or Eudragit L (methacrylic acid copolymer a, NF).

In certain embodiments, the composition comprises an agent in an amount in one of the following selected ranges: 1 mug/ml to 100 mg/ml; 1 mug/ml to 10 mg/ml; 1 mug/ml to 1 mg/ml; 1 to 100 mug/ml; 1 to 10 mug/ml; 10 mug to 100 mg/ml; 10 mug/ml to 10 mg/ml; 10 mug/ml to 1 mg/ml; 10 to 100 mug/ml; 100 mug/ml to 100 mg/ml; 100 mu g/ml to 10 mg/ml; 100 mug/ml to 1 mg/ml; 1mg/ml to 10 mg/ml; 1mg/ml to 100mg/ml and 10/mlmg to 100 mg/ml. Other ranges are also contemplated.

In certain embodiments, the composition comprises an agent in an amount ranging from 1mg/ml to 100 mg/ml.

In certain embodiments, the composition comprises deferiprone in an amount ranging from 1mg/ml to 100 mg/ml.

In certain embodiments, the composition comprises the agent in a concentration range selected from one of the following ranges: 1 μ M to 1M; 1 μ M to 100 mM; 1 μ M to 10 mM; 1 μ M to 1 mM; 1 μ M to 100 μ M; 10 μ M to 10 μ M; 10 μ M to 1M; 10 μ M to 100 mM; 10 μ M to 10 mM; 10 μ M to 1 mM; 10 to 100. mu.M; 100 μ M to 1M; 100 μ M to 100 mM; 100 μ M to 10 mM; 100 μ M to 1 mM; 1mM to 1M; 1mM to 100 mM; 1mM to 10 mM; 10mM to 1M; 10mM to 100 mM; and 100mM to 1M. Other ranges are also contemplated.

In some cases, the composition comprises deferiprone in a concentration range selected from one of the following ranges: 1mM to 1M, 1mM to 100mM, 1mM to 10mM, 10mM to 1M, 10mM to 100mM, or 100mM to 1M.

In certain embodiments, the agent is one or more of deferiprone, deferoxamine, and/or deferoxamine, or any combination thereof. Other agents are described herein.

In certain embodiments, the composition comprises deferiprone at a concentration of 1mM or greater, 2mM or greater, 3mM or greater, 4mM or greater, 5mM or greater, 10mM or greater, 20mM or greater, 30mM or greater, 40mM or greater, 50mM or greater, 100mM or greater, 250mM or greater, or 500mM or greater.

In certain embodiments, the composition comprises deferiprone at a concentration of 1mM or less, 2mM or less, 3mM or less, 4mM or less, 5mM or less, 10mM or less, 20mM or less, 30mM or less, 40mM or less, 50mM or less, 100mM or less, 250mM or less, 500mM or less, or 1M or less.

In certain embodiments, the composition comprises deferiprone at a concentration of 200mM or less.

In certain embodiments, the composition comprises deferiprone at a concentration of 80mM or less.

In certain embodiments, the composition comprises deferiprone at a concentration of 50mM or less. In certain embodiments, the composition comprises deferiprone at a concentration of 20mM or less. In certain embodiments, the composition comprises deferiprone at a concentration of 10mM or less.

In certain embodiments, the composition provides greater than 90% release of the agent within 96 hours. In certain embodiments, the composition provides greater than 90% release of the agent within 72 hours. In certain embodiments, the composition provides greater than 90% release of the agent within 48 hours. In certain embodiments, the composition provides greater than 80% release of the agent within 24 hours.

Methods for determining the release rate of an agent are known in the art.

In certain embodiments, the composition provides for release of the agent for up to 14 days, up to 7 days, up to 3 days, up to 2 days, or up to 1 day.

In certain embodiments, the composition provides for at least 14 days, at least 7 days, at least 3 days, at least 2 days, or at least 1 day of release of the agent.

In certain embodiments, the composition provides for release of the agent over a period of 1 to 14 days, 1 to 7 days, 1 to 3 days, or 1 to 2 days.

In certain embodiments, the composition provides sustained release of the agent over a period of 0 to 14 days, 1 to 14 days, 2 to 14 days, 3 to 14 days, or 7 to 14 days. In certain embodiments, the composition provides sustained release of the agent over a period of 3 to 14 days.

In certain embodiments, the composition is an immediate release composition. In certain embodiments, the composition is a sustained release composition. In certain embodiments, the composition is a controlled release composition. In certain embodiments, the composition is a delayed release composition. In certain embodiments, the composition is a slow release composition.

Formulations for controlled release of active agents, such as immediate release formulations, sustained release formulations, slow release and delayed release formulations are known in the art, for example, as described in "Handbook of Pharmaceutical controlled release Technology" Donald L Wise edition (2000) Marcel Dekker Inc.,270Madison Avenue New York, N.Y.10016.

In certain embodiments, an active agent may be incorporated into the particles, which provides for sustained release of the agent. For example, the sustained release particles can comprise PLGA (poly lactic glycolic acid).

In certain embodiments, the method comprises further exposing the region susceptible to formation to an antibiotic. The method of exposure is as described herein.

Examples of antibiotics include aminoglycosides, carbapenems, cephalosporins, glycopeptides, lincosamides (lincosamides), lipopeptides, macrolides, monobactams (monobactams), nitrofurans, oxazolidinones, penicillins (penicillins), polypeptides (peopypeptides), quinolones, fluoroquinones (fluoroquinolones), sulfonamides, and tetracyclines. Antibiotics are commercially available and methods of their use are known in the art, for example, as described in the "Therapeutic guide-Antibiotic", 15 th edition, 2014, eTG complete publication.

For example, specific antibiotics include mupirocin (mupirocin), ciprofloxacin (ciprofloxacin), ampicillin (ampicilin), amoxicillin (amoxicillin), gentamicin (gentamicin), clavulanic acid (clavulanate), clindamycin (clindamycin), trimethoprim-sulfamethoxazole (trimethoprim-sulfamethoxazole), doxycycline (doxycycline), minocycline (minocycline), rifampin (rifampin), linezolid (linezolid), flucloxacillin (flucloxacillin), dicloxacillin (dicloxacillin), cefazolin (cefazolin), cephalosporin (cefalothrin) and cephalexin (cefalexin), clindamycin (clindamycin), lincomomycin (comomycin), erythromycin (erythromycin), doxycycline (amoxicillin), doxycycline (amoxicillin), levofloxacin (amoxicillin), doxycycline (amoxicillin (doxycycline), doxycycline (doxycycline), doxycycline (, One or more of ticarcillin (ticarcillin) and piperacillin (piperacillin), or in combination with a beta lactamase inhibitor, such as clavulanic acid, sulbactam or tazobactam (azobactam). Other types of antibiotics are also contemplated.

In certain embodiments, the antibiotic comprises one or more of mupirocin, gentamicin, doxycycline, metronidazole, amoxicillin, piperacillin, ciprofloxacin, trimethoprim-sulfamethoxazole (norgestimate (Bactrim)), or any combination thereof.

In certain embodiments, the method comprises reducing adhesions caused by abdominal surgery and further exposing the area to one or more antibiotics described herein.

In certain embodiments, the method comprises reducing adhesions caused by sinus surgery and further exposing the area to one or more antibiotics described herein.

In certain embodiments, the compositions described herein further comprise an antibiotic. In certain embodiments, the gel compositions described herein further comprise an antibiotic. The antibiotic is as described herein.

In certain embodiments, the composition for reducing adhesions resulting from abdominal surgery further comprises one or more antibiotics described herein.

In certain embodiments, the composition for reducing adhesions resulting from sinus surgery further comprises one or more antibiotics described herein.

In certain embodiments, the method comprises further exposing the region to an anti-inflammatory agent. Methods of use of anti-inflammatory agents are known in the art. Anti-inflammatory agents are commercially available or can be synthesized by methods known in the art.

In certain embodiments, the method further comprises exposing the area to a non-steroidal anti-inflammatory drug/agent.

Examples of non-steroidal anti-inflammatory drugs include agents such as retinoic acid, quinacrine (quinacrine), dipyridamole (dipyridamole), aspirin (e.g., diprin (Disprin)), ibuprofen (e.g., noufeen (Nurofen)), naproxen (e.g., methoxymethylnaphthylacetic acid (Naprosyn)), diclofenac (e.g., nataline tablets (Voltaren)) and celecoxib (e.g., celecoxib (Celebrex)), indomethacin (indomethacin), oxaprozin (oxaprozin), and piroxicam (piroxicam).

In certain embodiments, the method further comprises exposing the region to a corticosteroid.

Examples of corticosteroids include fluticasone propionate (fluticasone propionate), fluticasone furoate (fluticasone furoate), mometasone furoate (mometasone furoate), ciclesonide triamcinolone acetonide (ciclesonide triamcinolone acetonide), flunisolide (flutolide), beclomethasone (beclomethasone), budesonide (budesonide), and dexamethasone (dexamethasone).

In certain embodiments, the method comprises further exposing the region to budesonide. For example, the method may further comprise exposing the region to budesonide in the gel composition.

In certain embodiments, the compositions described herein further comprise an anti-inflammatory agent, such as a corticosteroid.

In certain embodiments, the gel compositions described herein further comprise an anti-inflammatory agent.

In certain embodiments, the method comprises further exposing the region to an iron mimetic and/or a hemoglobin mimetic. The term "iron mimetic" refers to an agent that: it is an analogue of iron and interferes with the action of iron in the cell, including interfering with iron-utilizing enzymes (e.g., oxidoreductases) or with iron metabolism. The term "hemoglobin mimetic" refers to an agent that: it is an analog of heme and interferes with heme activity, heme synthesis, or heme metabolism. Such compounds may be produced by methods known in the art or may be commercially available.

In certain embodiments, the agent that is an iron mimetic and/or a hemoglobin mimetic includes a non-iron porphyrin.

The term "porphyrin" as used herein refers to molecules based on the porphyrin structure and includes derivatives thereof.

In certain embodiments, the non-ferrous porphyrin comprises a non-ferrous metalloporphyrin. In certain embodiments, the non-ferrous porphyrin comprises a non-ferrous metal protoporphyrin.

The term "non-ferrous metalloporphyrin" refers to a non-ferrous reagent having a porphyrin group coordinated to a metal ion (M), as follows:

Wherein M is a metal ion and any one or more of R1 to R4 and/or any one or more of R1 'to R4' are the same or different groups.

In certain embodiments, the non-ferric porphyrin comprises one or more of gallium protoporphyrin, manganese protoporphyrin, zinc protoporphyrin, indium protoporphyrin, cobalt protoporphyrin, ruthenium protoporphyrin, silver protoporphyrin, or copper protoporphyrin, or any combination thereof.

In certain embodiments, the non-ferriporphyrin comprises gallium protoporphyrin.

In certain embodiments, the non-ferriporphyrin comprises a compound having the structure:

Wherein Me is selected from the group consisting of gallium, manganese, zinc, indium, cobalt, ruthenium, silver and copper; and/or an acceptable salt, substituted derivative, solvate, tautomer or stereoisomer thereof. In certain embodiments, Me is gallium.

In certain embodiments, the method comprises exposing the region to the following concentrations of agents that are iron mimetics and/or hemoglobin mimetics: 100mM or less, 50mM or less, 20mM or less, 10mM less than or equal to 5mM or less, 4mM or less, 3mM or less, 2mM or less, 1.5mM or less deferiprone, 1mM or less, 0.5mM or less, 0.4mM or less, 0.3mM or less, 0.2mM or less, or 0.1mM or less.

In certain embodiments, the method comprises exposing the region to the following concentrations of agents that are iron mimetics and/or hemoglobin mimetics: 1mg/ml or less, 500. mu.g/ml or less, 200. mu.g/ml or less, 100. mu.g/ml or less, 50. mu.g/ml or less, 25. mu.g/ml or less, 10. mu.g/ml or less, 5. mu.g/ml or less, or 1. mu.g/ml or less.

In certain embodiments, the method comprises exposing the region to 200 μ g/ml or less, 100 μ g/ml or less, 50 μ g/ml or less, 25 μ g/ml or less, 10 μ g/ml or less, 5 μ g/ml, or less or 1 μ g/ml or less of a non-ferriporphyrin.

In certain embodiments, the method comprises exposing the region to 200 μ g/ml or less of a non-ferriporphyrin.

In certain embodiments, the method comprises exposing the region to the following concentration ranges of non-ferriporphyrin: 1 to 200. mu.g/ml, 5 to 200. mu.g/ml, 10 to 200. mu.g/ml, 25 to 200. mu.g/ml, 50 to 200. mu.g/ml, 100 to 200. mu.g/ml, 1 to 100. mu.g/ml, 5 to 100. mu.g/ml, 10 to 100. mu.g/ml, 25 to 100. mu.g/ml, 50 to 100. mu.g/ml, 1 to 50. mu.g/ml, 5 to 50. mu.g/ml, 10 to 500. mu.g/ml, 25 to 50. mu.g/ml, 1 to 25. mu.g/ml, 5 to 25. mu.g/ml, 10 to 25. mu.g/ml, 1 to 10. mu.g/ml, 5 to 10. mu.g/ml, or 1 to 5. mu.g/ml.

In certain embodiments, the compositions described herein further comprise a reagent that is an antibiotic to the iron mimetic and/or the hemoglobin mimetic.

In certain embodiments, the gel compositions described herein further comprise a reagent that is an iron mimetic and/or a hemoglobin mimetic.

In certain embodiments, the subject is a subject having an existing adhesion. In certain embodiments, the methods comprise subjecting a subject to an adhesion breakdown procedure to treat an existing adhesion, and then administering the agent to an area susceptible to the formation of a new adhesion.

In certain embodiments, the methods described herein are for reducing adhesions in a subject by administering a composition comprising the agent to an area susceptible to adhesion formation, for reducing surgical adhesions in a subject by administering a composition comprising the agent to an area susceptible to adhesion formation, for reducing post-surgical adhesions in a subject by administering a composition comprising the agent to an area susceptible to adhesion formation, for preventing and/or treating adhesions, and for reducing inflammation associated with adhesions.

In certain embodiments, the present disclosure provides a method of reducing adhesions in a subject, the method comprising administering a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area susceptible to forming an adhesion in a subject, thereby reducing the adhesion in the subject.

In certain embodiments, the present disclosure provides a method of reducing surgical adhesions in a subject, the method including administering a composition including an agent having iron-chelating activity and/or antioxidant activity to an area susceptible to forming surgical adhesions in the subject, thereby reducing surgical adhesions in the subject.

In certain embodiments, the present disclosure provides a method of reducing post-surgical adhesions in a subject, the method including administering a composition including an agent having iron-chelating activity and/or antioxidant activity to an area of the subject prone to post-surgical adhesions, thereby reducing post-surgical adhesions in the subject.

In certain embodiments, the present disclosure provides a method of preventing and/or treating an adhesion in a subject, the method comprising administering a composition comprising an agent having iron chelating activity and/or antioxidant activity to an area susceptible to forming an adhesion in a subject, thereby preventing and/or treating an adhesion in a subject.

As used herein, the term "preventing" and related terms such as "prevention" and variations thereof, refer to obtaining a desired therapeutic and/or physiological effect in preventing or inhibiting the appearance of one or more symptoms in a subject.

As used herein, the term "treating" and related terms such as "treatment" and variations thereof, refer to obtaining a desired therapeutic and/or physiological effect in improving the condition of a subject, ameliorating, arresting, inhibiting, reducing and/or slowing the progression of one or more symptoms in a subject, partially or fully stabilizing a subject, resolving one or more symptoms, or healing a subject.

In certain embodiments, the methods described herein can be used as part of a therapy to treat existing adhesions, as an adjunct to an adhesion breakdown procedure.

In certain embodiments, the present disclosure provides a method of treating an adhesion in a subject, the method comprising:

(i) Performing an adhesion breakdown procedure on the subject; and

(ii) Applying a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area susceptible to adhesion formation to reduce the formation of new adhesions in a subject,

Thereby treating the adhesion in the subject.

It will be appreciated that the administration of the composition may occur at one or more of the following stages: before the adhesion breaking procedure, during the adhesion breaking procedure, and after the adhesion breaking procedure.

In certain embodiments, the application of the composition occurs after an adhesion breaking procedure.

In certain embodiments, the present disclosure provides a method of treating an adhesion in a subject, the method comprising:

(i) Performing an adhesion breakdown procedure on the subject; and

(ii) Applying a composition comprising an agent having iron-chelating activity and/or antioxidant activity to an area susceptible to adhesion formation after an adhesion breakdown procedure to reduce the formation of new adhesions in a subject,

Thereby treating the adhesion in the subject.

Certain embodiments of the present disclosure provide for the use of an agent having iron-chelating activity and/or antioxidant activity.

In certain embodiments, the present disclosure provides the use of an agent having iron-chelating activity and/or antioxidant activity in reducing or preventing and/or treating adhesions in a subject.

Certain embodiments of the present disclosure provide for the use of an agent having iron-chelating activity and/or antioxidant activity in the manufacture of a composition or medicament to prevent and/or treat adhesions in a subject.

Agents having iron-chelating activity and/or antioxidant activity are described herein. The use of the agent for reducing adhesions is described herein.

In certain embodiments, the present disclosure provides the use of an agent having iron-chelating activity and/or antioxidant activity in the manufacture of a composition or medicament to reduce adhesions in a subject.

In certain embodiments, the present disclosure provides the use of an agent having iron-chelating activity and/or antioxidant activity in the manufacture of a composition or medicament for preventing and/or treating adhesions in a subject.

Compositions, formulations, and medicaments containing agents having iron-chelating activity and/or antioxidant activity are described herein.

Certain embodiments of the present disclosure provide agents for reducing adhesions having iron-chelating activity and/or antioxidant activity.

Certain embodiments of the present disclosure provide agents for treating adhesions having iron-chelating activity and/or antioxidant activity.

Certain embodiments of the present disclosure provide a composition.

In certain embodiments, the present disclosure provides an anti-blocking composition comprising an agent having iron chelating activity and/or antioxidant activity.

Agents having iron-chelating activity and/or antioxidant activity are described herein.

The method for evaluating the anti-blocking properties of the compositions is described herein.

Compositions comprising agents having iron-chelating activity and/or antioxidant activity are described herein.

In certain embodiments, the anti-adhesion composition comprises one or more of a gel, a solution, a rinse, an emulsion, a paste, nanoparticles, microparticles, and/or liposomes.

In certain embodiments, the composition comprises a gel. In certain embodiments, the composition comprises a hydrogel.

In certain embodiments, the composition comprises a chitosan-based gel.

in certain embodiments, the gel comprises chitosan, dextran, carbohydrate polymers, hyaluronic acid and/or salts thereof, one or more of collagen, carboxymethylcellulose, gelatin, polyimides, and alginates.

In certain embodiments, the gel comprises a desired release profile. The release profile of the composition is as described herein.

in certain embodiments, the anti-blocking composition provides greater than 90% release of the agent within 96 hours. In certain embodiments, the anti-blocking composition provides greater than 90% release of the agent within 72 hours. In certain embodiments, the anti-blocking composition provides greater than 90% release of the agent within 48 hours. In certain embodiments, the anti-blocking composition provides greater than 80% release of the agent within 24 hours.

In certain embodiments, the anti-blocking composition provides for sustained release of the agent over a period of 3 to 14 days.

In certain embodiments, the agent comprises a reactive oxygen species inhibitor. In certain embodiments, the reactive oxygen species inhibitor comprises a scavenger of reactive oxygen species and/or an inhibitor of reactive oxygen species generation.

In certain embodiments, the agent comprises one or more of deferiprone, deferoxamine, and desferrioxamine, or any combination thereof.

the amount of the agent in the composition is as described herein.

In certain embodiments, the composition comprises a deferiprone concentration of 80mM or less. In certain embodiments, the composition comprises a deferiprone concentration of 50mM or less. In certain embodiments, the composition comprises a deferiprone concentration of 20mM or less. In certain embodiments, the composition comprises a deferiprone concentration of 10mM or less.

In certain embodiments, the anti-adhesion composition further comprises an antibiotic. Examples of antibiotics include aminoglycosides, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidinones, penicillins (e.g., doxorubicin (amoxicillin), amoxicillin, and clavulanic acid), polypeptides, quinolones, fluoroquinones, sulfonamides, and tetracyclines. Antibiotics are commercially available and their methods of use are known in the art, for example, as described in the "therapeutic guidelines-antibiotics", 15 th edition, 2014, eTG complete publication.

Examples of antibiotics include aminoglycosides, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidinones, penicillins, polypeptides, quinolones, fluoroquinones, sulfonamides, and tetracyclines. Antibiotics are commercially available and their methods of use are known in the art, for example, as described in the "therapeutic guidelines-antibiotics", 15 th edition, 2014, eTG complete publication.

For example, specific antibiotics include mupirocin, ciprofloxacin, ampicillin, amoxicillin, gentamicin, clavulanic acid, clindamycin, trimethoprim-sulfamethoxazole, doxycycline, minocycline, rifampin, linezolid, flucloxacillin, dicloxacillin, ceftizolin, cephalosporins and cephalexin, clindamycin, lincomycin, erythromycin, rifaximin, levofloxacin, sulbactam, cefoxitin, levofloxacin gaclindamycin or metronidazole, aztreonam, polymyxin E, metronidazole, ampicillin and amoxicillin, ticarcillin and piperacillin, or in combination with beta lactamase inhibitors such as clavulanic acid, sulbactam or tazobactam.

In certain embodiments, the antibiotic comprises one or more of mupirocin, gentamicin, doxycycline, metronidazole, amoxicillin, piperacillin, ciprofloxacin, trimethoprim-sulfamethoxazole (sulfamethoxazole), or any combination thereof.

In certain embodiments, the anti-adhesion composition is for reducing adhesions resulting from abdominal surgery and the composition comprises one or more antibiotics described herein.

In certain embodiments, the anti-adhesion composition is for reducing adhesions resulting from sinus surgery and the composition comprises one or more antibiotics described herein.

In certain embodiments, the anti-adhesion composition further comprises an anti-inflammatory agent. The anti-inflammatory agent is as described herein. In certain embodiments, the anti-adhesion composition comprises a corticosteroid, such as budesonide.

In certain embodiments, the compositions described herein further comprise an anti-inflammatory agent, such as a corticosteroid.

In certain embodiments, the present disclosure provides nasal and/or sinus irrigation compositions comprising an agent having iron chelating activity and/or antioxidant activity.

The irrigant is as described herein.

In certain embodiments, the present disclosure provides chitosan-based gels comprising an agent having iron-chelating activity and/or antioxidant activity.

Chitosan-based gels are known in the art, for example, in Ahmad et al (2015) Res Pharm Sci10 (1)1-16 are described.

In certain embodiments, the chitosan-based gel further comprises one or more of an iron mimetic, an antibiotic, and/or an anti-inflammatory agent.

In certain embodiments, the present disclosure provides an anti-blocking composition comprising a chitosan-based gel and an agent having iron-chelating activity and/or antioxidant activity.

Agents having iron chelating activity and/or antioxidant activity and their use in gels are described herein. The method of producing the chitosan-based gel is as described herein.

In certain embodiments, the gel further comprises one or more antibiotics, as described herein. For example, the gel composition may comprise ciprofloxacin at 5 μ g/ml.

In certain embodiments, the gel further comprises one or more anti-inflammatory agents, as described herein. For example, the gel composition may comprise budesonide at a concentration of 100 μ g/ml.

In certain embodiments, the gel further comprises a reagent that is an iron mimetic and/or a hemoglobin mimetic. In certain embodiments, the agent that is an iron mimetic or a hemoglobin mimetic is present in the composition in an amount in one of the selected ranges: 1 μ g to 1000mg,1 μ g to 500 mg; 1 μ g to 250 mg; 1 μ g to 100 mg; 1 μ g to 10 mg; 1 μ g to 1 mg; 1 to 100 mug; 1 to 10 mug; 10 μ g to 1000 mg; 10 μ g to 500 mg; 10 μ g to 250mg,10 μ g to 10 mg; 10 μ g to 1 mg; 10 to 100 mug; 100 μ g to 1000mg,100 μ g to 500mg,100 μ g to 250mg,100 μ g to 100 mg; 100 μ g to 10 mg; 100 μ g to 1 mg; 1mg to 1000mg,1mg to 500mg,1mg to 250mg,1mg to 100 mg; 1mg to 10mg,10mg to 1000mg,10mg to 500mg,10mg to 250mg,10mg to 100mg,100mg to 1000mg,100mg to 500mg,100mg to 250mg and 500mg to 1000 mg. Other amounts are also contemplated.

In certain embodiments, the present disclosure provides an anti-adhesion composition comprising an agent having iron-chelating activity and/or antioxidant activity and comprising one or more of an antibiotic, an anti-inflammatory agent, and an iron mimetic.

For example, the composition may be a chitosan-based gel comprising an agent having iron-chelating activity and/or antioxidant activity (e.g., deferiprone) and comprising one or more of an antibiotic (e.g., ciprofloxacin), an anti-inflammatory agent (e.g., budesonide), and an iron mimetic (e.g., gallium protoporphyrin)), or any combination thereof.

Certain embodiments of the present disclosure provide a method of reducing blocking using the compositions described herein.

In certain embodiments, the present disclosure provides a method of reducing adhesions in a subject, the method comprising administering a composition described herein to an area of the subject prone to adhesion formation, thereby reducing adhesions in the subject.

In certain embodiments, the adhesions comprise post-operative sinus adhesions.

In certain embodiments, the present disclosure provides a method of reducing post-operative sinus adhesions in a subject, the method comprising irrigating a sinus of the subject using a nasal and/or sinus irrigation composition described herein, thereby reducing post-operative sinus adhesions in the subject.

Certain embodiments of the present disclosure provide methods of reducing inflammation using the compositions described herein.

Certain embodiments of the present disclosure provide kits or products.

In certain embodiments, a kit or product comprises: (i) an agent having iron-chelating activity and/or antioxidant activity; and/or (ii) one or more components for forming a composition; and/or (iii) one or more other agents described herein; and/or (iv) instructions for performing the methods described herein.

certain embodiments of the present disclosure provide a kit or article of manufacture for performing the methods described herein.

Certain embodiments of the present disclosure provide products for reducing adhesions, or for preventing and/or treating adhesions.

In certain embodiments, the present disclosure provides a product for reducing adhesions in a subject, the product comprising the following components:

(i) An agent having iron-chelating activity and/or antioxidant activity; and/or

(ii) One or more components for forming a gel comprising an agent having iron-chelating activity and/or antioxidant activity, the gel being suitable for application to a surgical site; and/or

(iii) A preformed gel comprising an agent having iron chelating activity and/or antioxidant activity, wherein the gel is suitable for application to a surgical site;

And optionally

(a) An applicator for dispensing a gel containing the agent to a surgical site; and/or

(b) Instructions for forming the gel and/or dispensing the gel to a surgical site.

agents having iron-chelating activity and/or antioxidant activity are described herein.

In certain embodiments, the agent comprises one or more of deferiprone, deferoxamine, and desferrioxamine, or any combination thereof.

The agent may be provided in a suitable form. In certain embodiments, the reagents may be provided in solid or lyophilized form, and may optionally be mixed with one or more other reagents.

In certain embodiments, the reagents may be supplied in liquid form, and may optionally be combined with one or more other reagents (e.g., stabilizers).

For example, the agent having iron-chelating activity and/or antioxidant activity may be in a form suitable for incorporation into one or more other components for forming a gel.

In certain embodiments, the one or more components for forming the gel comprise the following:

(i) One or more base solutions, and optionally one or more of the base solutions may further comprise an agent having chelating activity and/or antioxidant activity; and

(ii) A gelling agent or gelling solution for forming a gel in combination with the base solution.

For example, to form a chitosan dextran gel, the product may comprise a solution of deferiprone (provided at a suitable concentration, which is the concentration at which the gel is formed at the desired final concentration), a chitosan solution and a dextran solution.

An example of a preformed gel is a chitosan-dextran gel containing a suitable concentration of deferiprone. Other types of gels are described herein.

in certain embodiments, the applicator is a syringe. Other types of applicators are also contemplated.

The product may further comprise one or more other components, for example one or more other components for assisting the dispensing of the gel, for example the dispensing tip of a syringe, and/or one or more dyes for visualising the area or site of application of the gel. .

In certain embodiments, the product is a nasal and/or sinus irrigant.

In certain embodiments, the present disclosure provides a nasal and/or sinus irrigation solution comprising an agent having iron chelating activity and/or antioxidant activity and a liquid carrier.

In certain embodiments, the present disclosure provides a nasal and/or sinus irrigation solution comprising an agent having iron chelating activity and/or antioxidant activity and a salt solution.

In certain embodiments, the present disclosure provides a product for reducing post-operative sinus adhesions in a subject, the product comprising the following components:

(i) A solution comprising an agent having iron chelating activity and/or antioxidant activity (typically containing about 1-2% saline);

And optionally

(a) An applicator for delivering the solution to the nasal and/or sinus passages; and/or

(b) instructions for delivering the solution using an applicator.

Certain embodiments of the present disclosure provide a method of producing an anti-blocking product. The method of producing the anti-blocking product is as described herein.

In certain embodiments, the anti-blocking product comprises a gel. In certain embodiments, the anti-adhesion product comprises a solution or a rinse.

In certain embodiments, the present disclosure provides a method of producing a product for reducing adhesions in a subject, the method comprising forming a gel comprising an agent having iron-chelating activity and/or antioxidant activity, wherein the gel is adapted to be applied to an area or site susceptible to adhesion formation.

the method of forming the gel is as described herein.

The areas or regions susceptible to adhesion formation are as described herein. In certain embodiments, the area is a surgical site.

Certain embodiments of the present disclosure provide a method of screening or identifying an agent for reducing adhesions or a method of screening or identifying an agent for preventing and/or treating adhesions.

In certain embodiments, the present disclosure provides a method of identifying an agent for reducing adhesions, the method comprising determining the ability of an agent having iron-chelating activity and/or antioxidant activity to reduce adhesions in a subject, thereby identifying the agent as an agent that reduces adhesions.

In certain embodiments, the present disclosure provides a method of identifying an agent for preventing and/or treating an adhesion, the method comprising determining the ability of an agent having iron-chelating activity and/or antioxidant activity to reduce an adhesion in a subject, and thereby determining the agent as an agent for preventing and/or treating an adhesion.

Methods for determining the ability of an agent to reduce an adhesion or to prevent or treat an adhesion are described herein.

In certain embodiments, the method comprises using an animal model.

In certain embodiments, the method comprises determining the ability of an iron chelator to reduce adhesions in a subject. In certain embodiments, the method comprises determining the ability of the antioxidant to reduce adhesions in the subject. In certain embodiments, the method comprises determining the ability of an agent having both iron-chelating and antioxidant activity to reduce adhesions in a subject.

Certain embodiments of the present disclosure provide anti-blocking agents identified using the screening methods described herein.

As described herein, certain embodiments of the present disclosure provide a method of inhibiting fibroblast proliferation and/or migration by exposing the fibroblast to an agent having iron-chelating activity and/or antioxidant activity.

in certain embodiments, the present disclosure provides a method of inhibiting fibroblast proliferation and/or migration, the method comprising exposing the fibroblast to an agent having iron-chelating activity and/or antioxidant activity, thereby inhibiting proliferation and/or migration of the fibroblast.

Agents having iron-chelating activity and/or antioxidant activity are described herein. In certain embodiments, the agent comprises a reactive oxygen species inhibitor. In certain embodiments, the reactive oxygen species inhibitor comprises a reactive oxygen species scavenger and/or a reactive oxygen species generation inhibitor. In certain embodiments, the agent comprises one or more of deferiprone, deferoxamine, and deferoxamine.

Methods of exposing fibroblasts to the agent are described herein.

In certain embodiments, the method comprises exposing the fibroblast cells to a concentration of deferiprone of 80mM or less. In certain embodiments, the method comprises exposing the fibroblast cells to a concentration of deferiprone of 50mM or less. In certain embodiments, the method comprises exposing the fibroblast cells to a concentration of deferiprone of 20mM or less. In certain embodiments, the method comprises exposing the fibroblast cells to a concentration of deferiprone of 10mM or less.

In certain embodiments, the method comprises inhibiting proliferation of fibroblasts by at least 30% within 48 hours of exposure of the fibroblasts to the agent. In certain embodiments, the method comprises inhibiting proliferation of fibroblasts by at least 50% within 72 hours of exposure of the fibroblasts to the agent.

In certain embodiments, exposing the fibroblast cells to the agent comprises exposing the fibroblast cells to a composition comprising the agent.

Compositions comprising agents having iron-chelating activity and/or antioxidant activity are described herein.

In certain embodiments, the composition comprises one or more of a gel, a solution, a rinse, an emulsion, a paste, a nanoparticle, a microparticle, and/or a liposome.

in certain embodiments, the composition comprises a gel. In certain embodiments, the composition comprises a hydrogel. The gels are as described herein.

In certain embodiments, the gel comprises chitosan, dextran, carbohydrate polymers, hyaluronic acid and/or salts thereof, one or more of collagen, carboxymethyl cellulose, gelatin, polyimide, and alginate. Other agents for forming gels are also contemplated.

In certain embodiments, the composition provides greater than 90% release of the agent within 96 hours. In certain embodiments, the composition provides greater than 90% release of the agent within 72 hours. In certain embodiments, the composition provides greater than 90% release of the agent within 48 hours. In certain embodiments, the composition provides greater than 80% release of the agent within 24 hours.

In certain embodiments, the composition comprises a desired release profile. The release profile of the composition is as described herein.

In certain embodiments, the composition provides sustained release of the agent over a period of 3 to 14 days.

In certain embodiments, the fibroblast is a human fibroblast. In certain embodiments, the fibroblast is an animal fibroblast.

In certain embodiments, the fibroblast is in vitro. For example, the cells may be cultured fibroblasts.

In certain embodiments, the fibroblast is in vivo. Described herein are methods of exposing fibroblasts in vivo to an agent having iron-chelating activity and/or antioxidant activity.

In certain embodiments, fibroblast proliferation and/or migration is associated with the formation of adhesions in a subject.

In certain embodiments, the fibroblasts include fibroblasts at, near, or near the surgical site.

Certain embodiments of the present disclosure provide methods for screening for or identifying inhibitors of fibroblast proliferation and/or migration.

In certain embodiments, the present disclosure provides methods of identifying an inhibitor of fibroblast proliferation and/or migration, the method comprising determining the ability of an agent having iron-chelating activity and/or antioxidant activity to inhibit proliferation and/or migration of fibroblasts, thereby identifying the agent as an inhibitor of fibroblast proliferation and/or migration.

Certain embodiments of the present disclosure provide anti-fibroblast agents identified using the screening methods described herein.

The disclosure is further described by the following examples. It is to be understood that the following description is for the purpose of describing particular embodiments only and is not intended to be limiting of the above description.