WO2018119320A1

WO2018119320A1 - Hemostatic compositions with antifibrinolytic agents

Info

Publication number: WO2018119320A1
Application number: PCT/US2017/068033
Authority: WO
Inventors: Omar M. Ahmad; Joseph A. Landolina; Yulia Sapir LEKHOVITSER; Jonathan Lee; Wenjie Luo
Original assignee: Cresilon Inc
Current assignee: Cresilon Inc
Priority date: 2016-12-21
Filing date: 2017-12-21
Publication date: 2018-06-28
Anticipated expiration: 2019-06-21

Abstract

This disclosure relates to a biocompatible polymer composition useful in facilitating and maintaining hemostasis.

Description

HEMOSTATIC COMPOSITIONS WITH ANTIFIBRINOLYTIC AGENTS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 62/437,631, filed on December 21, 2016, the entirety of which is incorporated herein by reference.

FIELD

This disclosure relates to biocompatible polymer compositions useful in facilitating and maintaining hemostasis.

BACKGROUND

Hemostasis is a complex, multi-stage mechanism involving an orchestrated effort on the part of many cell types and scaffold formations to begin production of an initial platelet plug at the site of a wound and then develop a fully mature clot capable of arresting blood flow. Hemostasis is usually divided into three phases: primary hemostasis, the coagulation cascade, and fibrinolysis. Initially, a platelet plug is formed as a response to exposed endothelial cells at a compromised surface, after platelets adhere to collagen fibers surrounding said surface. Exposure to collagen "activates" the platelets, prompting them to release coagulation factors that allow for the coagulation cascade to progress. The process ends in the cleavage of fibrinogen by thrombin to form the foundational material for a clot, known as fibrin.

A notable challenge in the treatment of bleeding wound surfaces is presented by the adhesive properties of the physical barrier component of a given hemostatic device. If sustained blood flow is particularly strong, hemostasis can be disrupted as premature platelet plugs and fibrin clots may be ruptured in the process. This difficulty can be exacerbated if a hemostatic device lacks sufficient adhesion and a partially formed plug or clot disengages prematurely from a wound site. Various hemostatic devices seek to increase adhesive strength by utilizing dry devices to dehydrate the wound site. Such devices retard epithelialization and, in turn, slow wound healing substantially. SUMMARY

Uncontrolled bleeding is difficult to treat in surgery and trauma victims, and can often lead to death. Antifibrinolytic agents (such as aprotinin, tranexamic acid (TXA) and epsilon- aminocaproic acid) have been shown to reduce blood loss following surgery and may also be effective in reducing blood loss following trauma. However, administration of these

antifibrinolytic agents may be time sensitive.

Provided herein is a biocompatible polymeric composition which adheres to a wound site, effectively creating a physical barrier component, and also administers a antifibrinolytic agent which strengthens the blood clot, therefore providing an effective topical wound closure composition for treating wounds, particularly traumatic wounds. It is contemplated that the clot formed upon the addition of the biocompatible polymeric composition described herein will be stable for longer (i.e., reduced fibrinolysis) as compared to a composition which does not comprise antifibrinolytic agent. The biocompatible polymeric composition interacts with the red blood cells leading to the blood clotting and effective wound closure. The clot is formed and the bleeding is stopped without the need to apply pressure. Further, the material conforms to the injury being treated, with the ability to deliver the antifibrinolytic agent uniformly throughout the area despite potentially complex wound geometries. Over the course of wound treatment, the antifibrinolytic agent is gradually being absorbed into local coagulated blood, allowing for a delayed clot breakdown time and thus a higher likelihood to maintain clot strength during patient transport or while awaiting follow-on treatment.

In particular, provided herein is a biocompatible polymeric composition comprising (a) at least one polyanionic polymer, (b) at least one polycationic polymer, and (c) at least one

antifibrinolytic agent. In certain embodiments, the biocompatible polymeric composition further comprises a solvent. Also provided is a viscous composition comprising at least one

antifibrinolytic agent (e.g., tranexamic acid) for topical administration, and optionally comprising at least one thickening agent.

Also provided are methods of making the biocompatible polymeric composition. Also provided are methods of treating a wound in a patient in need thereof, comprising administering a biocompatible polymeric composition comprising (a) at least one polyanionic polymer, (b) at least one polycationic polymer, and (c) at least one antifibrinolytic agent. Also provided are methods of treating a wound in a patient in need thereof, comprising administering a

biocompatible polymeric composition comprising (a) at least one polyanionic polymer and (b) at least one polycationic polymer, and topically administering (c) a viscous composition comprising at least one antifibrinolytic agent. In certain embodiments, the wound is a traumatic wound. In certain embodiments, the wound is the result of surgery.

DETAILED DESCRIPTION

Described herein is a biocompatible polymer gel composition for facilitating and maintaining hemostasis. The biocompatible polymeric gel composition generally comprises (a) at least one polyanionic polymer, (b) at least one polycationic polymer, and (c) at least one antifibrinolytic agent. In certain embodiments, the biocompatible polymeric composition further comprises a solvent. Various properties associated with each component of the biocompatible polymeric compositions may impact the properties of the final product. Properties associated with the selection of a particular polyanionic polymer include chain length, molecular weight, viscosity in solution, particle size and morphology. Properties associated with the selection of a particular polycationic polymer include chain length, molecular weight, degree of deacetylation, viscosity in solution, particle size and morphology.

Biocompatible Polymer Composition

In certain embodiments, the biocompatible polymeric composition may be a gel that comprises about 0.1% to about 5% by weight polyanionic polymer; about 5% to about 40% by weight polycationic polymer; at least about 1% by weight antifibrinolytic agent; and optionally about 50%) to about 94%) by weight solvent. In certain embodiments, the composition does not comprise hyaluronic acid.

The biocompatible polymeric composition is able to clot blood rapidly while maintaining a stable clot (i.e., exhibits reduced fibrinolysis). It is contemplated that incorporation of the antifibrinolytic agent will enhance the strength of a blood clot formed upon administration of the biocompatible polymeric composition compared to a composition which does not comprise antifibrinolytic agent. It is contemplated that the clot formed upon the addition of the biocompatible polymeric composition described herein will be stable for longer (i.e., reduced fibrinolysis) as compared to a composition which does not comprise antifibrinolytic agent, although, in certain embodiments, the strength may not necessarily be greater.

Clot strength is a primary metric of the utility of a biocompatible polymeric composition. A Sonoclot coagulation analyzer (marketed by Sienco as Sonoclot Analyzer) is recognized as a suitable method for testing efficacy of hemostatic devices. Clot strength of a formed clot increases over time, depending upon the activator it is exposed to. The clot strength of a clot on a wound exposed to a biocompatible polymeric compositions may be at least 50% higher than the strength of a clot formed without exposure to the biocompatible polymeric composition. In certain embodiments, the clot strength of a clot on a wound exposed to the biocompatible polymeric compositions is from about 90 to about 200 clot strength units (CSU) at t = 15 minutes.

Time to clot is another primary metric of the utility of a biocompatible polymeric composition. Clot strength (and clot strength units) increase over time. Hemostasis of a wound should be achieved rapidly to minimize blood loss. The biocompatible polymeric composition facilitates hemostasis when applied to a wound, and in certain embodiments, the time to clot is achieved in 120 seconds or less, or 90 seconds or less, or 60 seconds or less, or 30 seconds or less, or 15 seconds or less. The time to clot of a wound exposed to the biocompatible polymeric

compositions is about 190% faster than the time to clot of a wound without exposure to the biocompatible polymeric composition. In certain embodiments, the biocompatible polymeric composition clots blood in vitro in 120 seconds or less, or 90 seconds or less, or 60 seconds or less, or 30 seconds or less, or 15 seconds or less. The time to clot blood exposed to the biocompatible polymeric composition {in vitro) is about 190%) faster than the time to clot without exposure to the biocompatible polymeric composition {in vitro). In one embodiment, about 13 mg or more of the biocompatible polymeric composition coagulates about 0.34 mL of blood in vitro.

Adhesive strength is yet another metric of the utility of a biocompatible polymeric gel composition. The biocompatible polymeric compositions should demonstrate sufficient adhesion to a wound to keep the biocompatible polymeric composition at the site of the wound but without the permanence of adhesives such as cyanoacrylate glues. In certain embodiments, the biocompatible polymeric composition withstands a vertical strain of up to 0.5 Newtons per square millimeter without fracture between two samples of tissue. In one embodiment, 1 mL of a biocompatible polymeric gel is placed between two pieces of chicken liver (20 mm x 20 mm x 5 mm) and compressed, and the gel withstands a vertical strain of about 0.5 Newtons per square millimeter without fracture when then the tissue samples are pulled apart vertically.

The biocompatible polymeric gel composition may be characterized by various methods including viscosity, pH, Fourier Transform Infrared (FTIR) spectroscopy, and chemical analysis.

In certain embodiments, the biocompatible polymeric composition has a viscosity between about 145,000 (centipoise) cP and about 250,000 cP at about 25°C. In certain embodiments, the biocompatible polymeric composition has a viscosity of between about 165,000 cP and about 174,000 cP at about 25°C. In certain embodiments, the biocompatible polymeric composition has a viscosity of between about 169,000 cP and about 170,000 cP at about 25°C. In certain embodiments, the biocompatible polymeric composition has a viscosity of about 169,500 cP at about 25°C. It is contemplated that the viscosity allows for maximum adhesion capabilities which, in turn, affects performance. Subtle alterations in viscosity can have a substantial impact on product efficacy. In certain embodiments, the biocompatible polymeric composition may have a viscosity of about 145,000 cP, about 145,500 cP, about 146,000 cP, about 146,500 cP, about 147,000 cP, about 147,500 cP, about 148,000 cP, about 148,500 cP, about 149,000 cP, about 149,500 cP, about 150,000 cP, about 150,500 cP, about 151,000 cP, about 151,500 cP, about 152,000 cP, about 152,500 cP, about 153,000 cP, about 153,500 cP, about 154,000 cP, about 154,500 cP, 155,000 cP, about 155,500 cP, about 156,000 cP, about 156,500 cP, about 157,000 cP, about 157,500 cP, about 158,000 cP, about 158,500 cP, about 159,000 cP, about 159,500 cP, about 160,000 cP, about 160,500 cP, about 161,000 cP, about 161,500 cP, about 162,000 cP, about 162,500 cP, about 163,000 cP, about 163,500 cP, about 164,000 cP, about 164,500 cP, 165,000 cP, about 165,500 cP, about 166,000 cP, about 166,500 cP, about 167,000 cP, about 167,500 cP, about 168,000 cP, about 168,500 cP, about 169,000 cP, about 169,500 cP, about 170,000 cP, about 170,500 cP, about 171,000 cP, about 171,500 cP, about 172,000 cP, about 172,500 cP, about 173,000 cP, about 173,500 cP, about 174,000 cP, about 174,500 cP, 175,000 cP, about 175,500 cP, about 176,000 cP, about 176,500 cP, about 177,000 cP, about 177,500 cP, about 178,000 cP, about 178,500 cP, about 179,000 cP, about 179,500 cP, about 180,000 cP, about 180,500 cP, about 181,000 cP, about 181,500 cP, about 182,000 cP, about 182,500 cP, about 183,000 cP, about 183,500 cP, about 184,000 cP, about 184,500 cP, 185,000 cP, about 185,500 cP, about 186,000 cP, about 186,500 cP, about 187,000 cP, about 187,500 cP, about 188,000 cP, about 188,500 cP, about 189,000 cP, about 189,500 cP, about 190,000 cP, about 190,500 cP, about 191,000 cP, about 191,500 cP, about 192,000 cP, about 192,500 cP, about 193,000 cP, about 193,500 cP, about 194,000 cP, about 194,500 cP, 195,000 cP, about 195,500 cP, about 196,000 cP, about 196,500 cP, about 197,000 cP, about 197,500 cP, about 198,000 cP, about 198,500 cP, about 199,000 cP, about 199,500 cP, about 200,000 cP, about 200,500 cP, about 201,000 cP, about 201,500 cP, about 202,000 cP, about 202,500 cP, about 203,000 cP, about 203,500 cP, about 204,000 cP, about 204,500 cP, 205,000 cP, about 205,500 cP, about 206,000 cP, about 206,500 cP, about 207,000 cP, about 207,500 cP, about 208,000 cP, about 208,500 cP, about 209,000 cP, about 209,500 cP, about 210,000 cP, about 210,500 cP, about 211,000 cP, about 211,500 cP, about 212,000 cP, about 212,500 cP, about 213,000 cP, about 213,500 cP, about 214,000 cP, about 214,500 cP, 215,000 cP, about 215,500 cP, about 216,000 cP, about 216,500 cP, about 217,000 cP, about 217,500 cP, about 218,000 cP, about 218,500 cP, about 219,000 cP, about 219,500 cP, about 220,000 cP, about 220,500 cP, about 221,000 cP, about 221,500 cP, about 222,000 cP, about 222,500 cP, about 223,000 cP, about 223,500 cP, about 224,000 cP, about 224,500 cP, 225,000 cP, about 225,500 cP, about 226,000 cP, about 226,500 cP, about 227,000 cP, about 227,500 cP, about 228,000 cP, about 228,500 cP, about 229,000 cP, about 229,500 cP, about 230,000 cP, about 230,500 cP, about 231,000 cP, about 231,500 cP, about 232,000 cP, about 232,500 cP, about 233,000 cP, about 233,500 cP, about 234,000 cP, about 234,500 cP, 235,000 cP, about 235,500 cP, about 236,000 cP, about 236,500 cP, about 237,000 cP, about 237,500 cP, about 238,000 cP, about 238,500 cP, about 239,000 cP, about 239,500 cP, about 240,000 cP, about 240,500 cP, about 241,000 cP, about 241,500 cP, about 242,000 cP, about 242,500 cP, about 243,000 cP, about 243,500 cP, about 244,000 cP, about 244,500 cP, 245,000 cP, about 245,500 cP, about 246,000 cP, about 246,500 cP, about 247,000 cP, about 247,500 cP, about 248,000 cP, about 248,500 cP, about 249,000 cP, about 249,500 cP or about 250,000 cP at about 25°C. In certain embodiments, the biocompatible polymeric composition has a pH between about 6 and about 8, between about 6.5 and about 7.5, between about 6.8 and about 7.2, or about 7. The biocompatible polymeric compositions are intended to be stored at about 25°C. In one embodiment, the biocompatible polymeric compositions have a density of between about 1.00 and 1.40 g/mL at about 25°C. In one embodiment, the biocompatible polymeric compositions have a density of between about 1.10 and 1.30 g/mL at about 25°C. In one embodiment, the biocompatible polymeric compositions have a density of between about 1.20 and 1.22 g/mL at about 25°C. In certain embodiments, the biocompatible polymeric composition has a density of about 1.21 g/mL at about 25°C. The biocompatible polymeric composition may have density of about 1.00 g/mL, about 1.01 g/mL, about 1.02 g/mL, about 1.03 g/mL, about 1.04 g/mL, about 1.05 g/mL, about 1.06 g/mL, about 1.07 g/mL, about 1.08 g/mL, about 1.09 g/mL, about 1.10 g/mL, about 1.11 g/mL, about 1.12 g/mL, about 1.13 g/mL, about 1.14 g/mL, about 1.15 g/mL, about 1.16 g/mL, about 1.17 g/mL, about 1.18 g/mL, about 1.19 g/mL, about 1.20 g/mL, about 1.21 g/mL, about 1.22 g/mL, about 1.23 g/mL, about 1.24 g/mL, about 1.25 g/mL, about 1.26 g/mL, about 1.27 g/mL, about 1.28 g/mL, about 1.29 g/mL, about 1.30 g/mL, about 1.31 g/mL, about 1.32 g/mL, about 1.33 g/mL, about 1.34 g/mL, about 1.35 g/mL, about 1.36 g/mL, about 1.37 g/mL, about 1.38 g/mL, about 1.39 g/mL or about 1.40 g/mL at about 25°C.

The biocompatible polymeric composition has a storage modulus of between about 6 kPa to about 30 kPa. The biocompatible polymeric composition has a storage modulus of between about 20 kPa to about 30 kPa. The biocompatible polymeric composition has a storage modulus of between about 8 kPa to about 15 kPa. The biocompatible polymeric composition has a storage modulus of between about 6 kPa to about 23 kPa. In one embodiment the biocompatible polymeric composition has a storage modulus of about 16 kPa. The biocompatible polymeric composition may have a storage modulus of about 6 kPa, about 7 kPa, about 8 kPa, about 9 kPa, about 10 kPa, about 11 kPa, about 12 kPa, about 13 kPa, about 14 kPa, about 15 kPa, about 16 kPa, about 17 kPa, about 18 kPa, about 19 kPa, about 20 kPa, about 21 kPa, about 22 kPa, - about 23 kPa or about 25 kPa. The biocompatible polymeric composition has a storage modulus of about 12 kPa.

Storage media containers for the biocompatible polymeric composition may include syringes, packets, sachets, tubes, tubs, pumps, bottles and bags. In certain embodiments, the polymeric composition is sterile and suitable for application to humans and animals. One exemplary storage media is a 5 mL syringe (sterile); or a 10 mL syringe (sterile). The biocompatible polymeric composition may further include optional components such as antimicrobial, preservative or therapeutic agents. The biocompatible polymeric composition may include silver salts, metal or carbon nanoparticles, antibiotics, hormones, proteins (such as calreticulin, thrombin, prothrombin, Factor VIII), methylparaben, chlorocresol, cetrimide and iodine, and combinations thereof. In one embodiment the biocompatible polymeric composition further includes iodine. In one embodiment, the biocompatible polymeric composition further includes silver nitrate. In one embodiment, the biocompatible polymeric composition further includes methylparaben.

In certain embodiments, this disclosure provides a syringe, a packet, a sachet, a tube, a tub, a pump, a bottle or a bag comprising the biocompatible polymeric composition as described herein.

Polyanionic Polymer

In certain embodiments, the polymeric gel composition comprises about 0.1% to about 5.0% by weight of polyanionic polymer (or more than one polyanionic polymer). In certain

embodiments, the polymeric gel composition comprises about 1.0% to about 4.0% by weight of a polyanionic polymer; or about 2.0% to about 3.0%> by weight of a polyanionic polymer. In certain embodiments, the polymeric gel composition may comprise about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0. .30%, about 0.35%, about 0. .40%, about 0. .45%, about 0.50%, about 0.55%, about 0.60%, about 0. .65%, about 0.70%, about 0. .75%, about 0. .80%, about 0.85%, about 0.90%, about 0.95%, about 1. .00%, about 1.05%, about 1. .10%, about 1. .15%, about 1.20%_: about 1.25%, about 1.30%, about 1. .35%, about 1.40%, about 1. .45%, about 1. .50%, about 1.55%, about 1.60%, about 1.65%, about 1. .70%, about 1.75%, about 1. .80%, about 1. .85%, about 1.90%, about 1.95%, about 2.00%, about 2. .05%, about 2.10%, about 2. .15%, about 2. .20%, about 2.25%, about 2.30%, about 2.35%, about 2. .40%, about 2.45%, about 2. .50%, about 2. .55%, about 2.60%, about 2.65%, about 2.70%, about 2. .75%, about 2.80%, about 2. .85%, about 2. .90%, about 2.95%, about 3.00%, about 3.05%, about 3. .10%, about 3.15%, about 3. .20%, about 3. .25%, about 3.30%, about 3.35%), about 3.40%, about 3. .45%, about 3.50%, about 3. .55%, about 3. .60%, about 3.65%), about 3.70%, about 3.75%, about 3. .80%, about 3.85%, about 3. .90%, about 3. .95%, about 4.00%, about 4.05%, about 4.10%, about 4. .15%, about 4.20%, about 4. .25%, about 4. .30%, about 4.35%. about 4.40%, about 4.45%, about 4.50%, about 4.55%, about 4.60%, about 4.65%, about 4.70%, about 4.75%, about 4.80%, about 4.85%, about 4.90%, about 4.95% or about 5.00% by weight of a polyanionic polymer.

In one embodiment, the polyanionic polymer may be a polystyrene sulfonate (such as sodium polystyrene sulfonate), a polyacrylate (such as sodium polyacrylate), a polymethacrylate (such as sodium polymethacrylate), a polyvinyl sulphate (such as sodium polyvinyl sulphate), a polyphosphate (such as sodium polyphosphate), Iota carrageenan, Kappa carrageenan, gellan gum, carboxyl methyl cellulose, carboxyl methyl agarose, carboxyl methyl dextran, carboxyl methyl chitin, carboxyl methyl chitosan, a polymer modified with a carboxyl methyl group, an alginate (such as sodium alginate), a polymer containing a plurality of carboxylate groups, a xanthan gum, and combinations thereof. In certain embodiments, the polyanionic polymer is an alginate. In certain embodiments, the polyanionic polymer is sodium alginate. In one embodiment, the polymeric composition comprises about 2.25% alginate by weight; in one embodiment the polymeric composition comprises about 2.50% alginate by weight. In one embodiment, the polymeric composition comprises about 2.10% to about 2.20% alginate by weight; in one embodiment the polymeric composition comprises about 2.12% alginate by weight. In one embodiment, the polymeric composition comprises about 3.5% to about 4% alginate by weight. In one embodiment, the polymeric composition comprises about 3.8% alginate by weight. In one embodiment, the polyanionic polymer has a chain length of between about 1,000 nm and about 3,000 nm. The increased chain length of a particular polyanionic polymer aids in the increased ability of the biocompatible polymeric composition - when applied to a wound - to adhere to tissue. Short-chain polyanionic polymers may yield a biocompatible polymeric gel composition having difficult or poor adhesion to a wound. The polyanionic polymer may have a chain length of about 1,000, about 1, 100, about 1,200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1,800, about 1,900, about 2,000, about 2, 100, about 2,200, about 2,300, about 2,400, about 2,500, about 2,600, about 2,700, about 2,800, about 2,900 or about 3,000 nm.

In one embodiment, the polyanionic polymer comprises particles having an average particle size of between 10 mesh and 300 mesh. As the particle size of the polyanionic polymer increases, the amount of cell adhesion to the polymer increases. However as the particle size of the

polyanionic polymer increases this may decrease surface area of wound coverage. In certain embodiments, the polyanionic polymer comprises particles having an average particle size of between 100 mesh and 270 mesh. In certain embodiments, the polyanionic polymer comprises particles having an average particle size of between 120 mesh and 250 mesh. In certain embodiments, the polyanionic polymer comprises particles having an average particle size of between 150 mesh and 200 mesh. In certain embodiments, the polyanionic polymer comprises particles having an average particle size of about 180 mesh. The polyanionic polymer may have an average particle size of about 80, about 100, about 120, about 150, about 180, about 200, about 250 or about 270 mesh.

In one embodiment, the polyanionic polymer has an average molecular weight (Mn) of greater than about 100 kDa. In certain embodiments, the polyanionic polymer has a molecular weight of between about 100 kDa to about 1,000 kDa. In certain embodiments, the polyanionic polymer has a molecular weight of between about 500 kDa to about 900 kDa. In certain embodiments, the polyanionic polymer has a molecular weight of between about 650 kDa to about 800 kDa. In certain embodiments, the polyanionic polymer has a molecular weight of about 800 kDa. Higher molecular weight polyanionic polymers will increase the viscosity of the polymeric gel composition and will maintain its flowability to resist fracture and prevent or reduce blood passage through it. The polyanionic polymer may have a molecular weight of about 100 kDa, about 150 kDa, about 200 kDa, about 250 kDa, about 300 kDa, about 350 kDa, about 400 kDa, about 450 kDa, about 500 kDa, about 550 kDa, about 600 kDa, about 650 kDa, about 700 kDa, about 750 kDa, about 800 kDa, about 850 kDa, about 900 kDa, about 950 kDa or about 1,000 kDa. In one embodiment, the polyanionic polymer has a viscosity of between about 100 centipoise (cP) to about 2,000 cP in a 1% weight per volume (w/v) solution of water at about 25°C. In certain embodiments, the polyanionic polymer has a viscosity of between about 100 cP to about 1,000 cP in a 1% w/v solution of water at about 25°C. The polyanionic polymer may have a viscosity of about 100 cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, about 600 cP, about 700 cP, about 800 cP, about 900 cP, about 1,000 cP, about 1, 100 cP, about 1,200 cP, about 1,300 cP, about 1,400 cP, about 1,500 cP, about 1,600 cP, about 1,700 cP, about 1,800 cP, about 1,900 cP or about 2,000 cP in a 1% w/v solution of water at about 25°C. In certain

embodiments, the polyanionic polymer has a viscosity of about 1,000 cP in a 1% w/v solution of water at about 25 °C. In certain embodiments, the polyanionic polymer present in the polymeric gel composition comprises the scaffold onto which fibrin adheres. The morphology of polyanionic polymer particles may be a mesh or combination of fibrous particles onto which fibrin can easily bind and form a patch at the wound bed. The polyanionic polymer particles may have a morphology that is fibrous, crystalline, amorphous, spherical, cuboidal or a combination thereof. Polyanionic polymers may be obtained from various commercial suppliers. However, the source of polyanionic polymer can impact the potential for foreign contaminants, such as prions, to be present in raw materials. In one embodiment the polyanionic polymer is obtained from an organic source. In certain embodiments, the polyanionic polymer is sodium alginate. In certain embodiments, the sodium alginate is obtained from marine algae such as Macrocystis pyrifera (kelp).

Polycationic Polymer

In certain embodiments, the polymeric gel composition comprises about 5% to about 40% by weight of a polycationic polymer (or more than one polycationic polymer). In certain embodiments, the polymeric gel composition comprises about 8% by weight of a polycationic polymer; or about 20% by weight of a polycationic polymer; or about 22% by weight of a polycationic polymer. The polymeric gel composition may comprise about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%) or about 40% by weight of a polycationic polymer.

In one embodiment, the polycationic polymer may be a chitosan (such as chitosan chloride), chitin, diethylaminoethyl-dextran, diethylaminoethyl- cellulose, diethylaminoethyl-agarose, diethylaminoethyl-alginate, a polymer modified with a diethylaminoethyl group, a polymer containing a plurality of protonated amino groups, and a polypeptide having an average residue isoelectric point above 7, and combinations thereof. In certain embodiments, the polycationic polymer is a chitosan. In certain embodiments, the polycationic polymer is chitosan chloride. In certain embodiments, the polycationic polymer is diethylaminoethyl-dextran (DEAE- Dextran).

In one embodiment, the polymeric composition comprises about 5% to about 40% chitosan by weight. In one embodiment the polymeric composition comprises about 18% to about 20% chitosan by weight. In one embodiment, the polymeric composition comprises about 19.8% chitosan by weight. In one embodiment, the polycationic polymer has a chain length of between about 2,000 nm and about 4,000 nm. In certain embodiments, the polycationic polymer has a chain length of between about 2,800 nm and about 2,900 nm. In certain embodiments, the polycationic polymer has a chain length of between about 2,850 nm. In certain embodiments, the polycationic polymer has a chain length of between about 2,849 nm. The polyanionic polymer may have a chain length of about 2,000, about 2, 100, about 2,200, about 2,300, about 2,400, about 2,500, about 2,600, about 2,700, about 2,800, about 2,900, about 3,000, about 3,100, about 3,200, about 3,300, about 3,400, about 3,500, about 3,600, about 3,700, about 3,800, about 3,900 or about 4,000 nm.

In one embodiment, the polycationic polymer comprises particles having an average particle size of between 50 mesh and 500 mesh. As the particle size of the polycationic polymer increases, the amount of cell adhesion to the polymer increases. However as the particle size of the polycationic polymer increases this may decrease surface area of wound coverage. In certain embodiments, the polycationic polymer comprises particles having an average particle size of between 60 mesh and 400 mesh. In certain embodiments, the polycationic polymer comprises particles having an average particle size of between 80 mesh and 325 mesh. In certain embodiments, the polycationic polymer comprises particles having an average particle size of between 80 mesh and 120 mesh. In certain embodiments, the polycationic polymer comprises particles having an average particle size of about 100 mesh. The polycationic polymer may have an average particle size of about 50, about 60, about 80, about 100, about 120, about 150, about 180, about 200, about 250, about 270, about 325, about 400 or about 500 mesh.

In one embodiment, the polycationic polymer has a number average molecular weight (Mn) of between about 1 kDa to about 2,000 kDa. In certain embodiments, the polycationic polymer has a molecular weight of between about 1 kDa to about 1,000 kDa. In certain embodiments, the polycationic polymer has a molecular weight of between about 800 kDa to about 1,200 kDa. In certain embodiments, the polycationic polymer has a molecular weight of between about 900 kDa to about 1,100 kDa. In certain embodiments, the polycationic polymer has a molecular weight of about 1,000 kDa. In certain embodiments, the polycationic polymer has a molecular weight of between about 100 kDa to about 500 kDa. In certain embodiments, the polycationic polymer has a molecular weight of between about 200 kDa to about 400 kDa. In certain embodiments, the polycationic polymer has a molecular weight of between about 250 kDa to about 300 kDa. Molecular weight of the polycationic polymer influences its ability to carry charge, and with greater molecular weight comes greater charge density, which in turn positively impacts hemostasis. The polycationic polymer may have a molecular weight of about 100 kDa, about 200 kDa, about 300 kDa, about 400 kDa, about 500 kDa, about 600 kDa, about 700 kDa, about 800 kDa, about 900 kDa, about 1,000 kDa, about 1, 100 kDa, about 1,200 kDa, about 1,300 kDa, about 1,400 kDa, about 1,500 kDa, about 1,600 kDa, about 1,700 kDa, about 1,800 kDa, about 1,900 kDa or about 2,000 kDa.

In one embodiment the polycationic polymer has a viscosity of between about 10 cP to about 1,000 cP in a 1% weight per volume (w/v) solution of 5% acetic acid at about 25°C. In certain embodiments, the polycationic polymer has a viscosity of between about 50 cP to about 1,000 cP in a 1% w/v solution of 5% acetic acid at about 25°C. The polycationic polymer may have a viscosity of about 10 cP, about 20 cP, about 30 cP, about 40 cP, about 50 cP, about 60 cP, about 70 cP, about 80 cP, about 90 cP, about 100 cP, about 110 cP, about 120 cP, about 130 cP, about 140 cP, about 150 cP, about 160 cP, about 170 cP, about 180 cP, about 190 cP, about 200 cP, about 210 cP, about 220 cP, about 230 cP, about 240 cP, about 250 cP, about 260 cP, about 270 cP, about 280 cP, about 290 cP, about 300 cP, about 310 cP, about 320 cP, about 330 cP, about 340 cP, about 350 cP, about 360 cP, about 370 cP, about 380 cP, about 390 cP, about 400 cP, about 410 cP, about 420 cP, about 430 cP, about 440 cP, about 450 cP, about 460 cP, about 470 cP, about 480 cP, about 490 cP, about 500 cP, about 510 cP, about 520 cP, about 530 cP, about 540 cP, about 550 cP, about 560 cP, about 570 cP, about 580 cP, about 590 cP, about 600 cP, about 610 cP, about 620 cP, about 630 cP, about 640 cP, about 650 cP, about 660 cP, about 670 cP, about 680 cP, about 690 cP, about 700 cP, about 710 cP, about 720 cP, about 730 cP, about 740 cP, about 750 cP, about 760 cP, about 770 cP, about 780 cP, about 790 cP, about 800 cP, about 810 cP, about 820 cP, about 830 cP, about 840 cP, about 850 cP, about 860 cP, about 870 cP, about 880 cP, about 890 cP, about 900 cP, about 910 cP, about 920 cP, about 930 cP, about 940 cP, about 950 cP, about 960 cP, about 970 cP, about 980 cP, about 990 cP or about 1,000 cP in a 1% w/v solution of 5% acetic acid at about 25°C. In certain embodiments, the polycationic polymer has a viscosity of about 80 cP in a 1% w/v 5% acetic acid solution at about 25°C. The polycationic polymer particles present in the polymeric gel composition comprise a surface onto which cells may adhere to permit platelet aggregation. A greater surface area of polycationic polymer particles may accelerate hemostasis. The morphology of polycationic polymer particles may by substantially spherical with pores and allows for aggregation both inside the particle as well as outside. The polycationic polymer particles may have a

morphology that is fibrous, crystalline, amorphous, spherical, cuboidal or a combination thereof.

The polycationic polymer may also be bound or functionalized to a core of a different material such as a polymeric substance. In one embodiment, the core is an inert core. In one

embodiment, the core is poly-L-lactic acid. Binding the polycationic polymer to a core may, for example, reduce the amount of polycationic polymer needed to achieve a given surface area compared with a solid particle of a given polycationic polymer. Binding the polycationic polymer to a core may also allow for a geometries that would otherwise be impossible or impractical absent the core. In one embodiment, a cuboidal core is coated in chitosan to yield a cuboidal geometry for chitosan - where chitosan on its own will not form cuboidal geometries under ordinary conditions. Binding the polycationic polymer to a core may also permit a polycationic polymer to exist in a crystalline form within the biocompatible polymer gel composition when such polymer would not otherwise be able to exist as a crystal based on the conditions in the biocompatible polymeric composition. In one embodiment a core of poly-L- lactic acid is bound to diethylaminoethyl-dextran (DEAE-Dextran) and used in a stable biocompatible polymer gel composition comprising alginate - where DEAE-Dextran cannot form a crystal on its own under ordinary conditions and may not form a stable gel when used with alginate alone. In certain embodiments, the one or more than one polycationic polymer comprises diethylaminoethyl-dextran bound as a coating to a core of poly-L-lactic acid; the one or more than one polycationic polymer comprises diethylaminoethyl-dextran covalently linked to a core of poly-L-lactic acid. Polycationic polymers may be obtained from various commercial suppliers. However, the source of polycationic polymer can impact the potential for foreign contaminants, such as prions, to be present in raw materials. In one embodiment the polycationic polymer is obtained from an organic source. When the polycationic polymer is chitosan, it may be obtained from crustaceans, fungi, insects, and other organisms. Chitosan may also be obtained from plant sources. In one embodiment the chitosan is obtained from algae. In certain embodiments, the polycationic polymer is chitosan and it is obtained from fungi such as the genus Pleurotus. In certain embodiments, the polycationic polymer is chitosan and it is obtained from marine invertebrates. In certain embodiments, the polycationic polymer is chitosan and it is obtained from Aspergillus niger. When the polycationic polymer is chitosan, the degree of deacetylation is a factor that impacts the properties of the polymeric gel composition. Chitosan is an analog to the commonly known chitin, and the degree of deacetylation of chitin coincides with hemostatic efficacy. In one embodiment, the chitosan has an average degree of deacetylation of between about 75.0% to about 99.5%. In certain embodiments, the chitosan has an average degree of deacetylation of between about 75.0% to about 85.0%. In certain embodiments, the chitosan has an average degree of deacetylation of between about 78.0% to about 83.0%. In certain embodiments, the chitosan has an average degree of deacetylation of between about 80.0% to about 81.0%. In certain embodiments, the chitosan has an average degree of deacetylation of 80.5%. The chitosan may have an average degree of deacetylation of about 75.0%, about 75.5%, about 76.0%, about 76.5%, about 77.0%, about 77.5%, about 78.0%, about 78.5%, about 79.0%, about 79.5%, about 80.0%, about 80.5%, about 81.0%, about 81.5%, about 82.0%, about 82.5%, about 83.0%, about 83.5%, about 84.0%, about 84.5%, about 85.0%, about 85.5%, about 86.0%, about 86.5%, about 87.0%, about 87.5%, about 88.0%, about 88.5%, about 89.0%, about 89.5%, about 90.0%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0% or about 99.5%.

Antifibnnolytic agent

In certain embodiments, the biocompatible polymeric compositions described herein are administered in combination with a viscous composition comprising an antifibrinolytic agent, or in certain embodiments, the biocompatible polymeric compositions described herein contain at least one antifibrinolytic agent.

Antifibrinolytic agents promote blood clotting by slowing, preventing or inhibiting the breakdown of blood clots. The amount of antifibrinolytic agent in the biocompatible polymeric composition may vary based on the required dose of the specific antifibrinolytic agent. In certain embodiments, provided is a composition comprising an antifibrinolytic agent for topical administration. The viscosity of the composition is typically high such that once administered, the composition stays in place. Exemplary thickening agents include, but are not limited to, alginate, carboxymethylcellulose, polyvinyl alcohol, or xantham gum.

In certain embodiments, when the biocompatible polymeric compositions described herein contain at least one antifibrinolytic agent, the biocompatible polymeric composition comprises at least about 1% antifibrinolytic agent. In certain embodiments, the antifibrinolytic agent may be present in the biocompatible polymeric composition in an amount of at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40% or less than about 40% by weight.

In certain embodiments, the antifibrinolytic agent may be present in the biocompatible polymeric composition in an amount of about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%), about 4%), about 4.5%, about 5% , about 5.5%, about 6%, or about 6.5%, or about 7%, or about 7.5%), or about 8%, or about 8.5%, or about 9%, or about 9.5% or about 10% by weight. In certain embodiments, biocompatible polymeric composition comprises between about 1% to about 25% by weight antifibrinolytic agent. In certain embodiments, the biocompatible polymeric composition comprises between about 1% to about 20% by weight antifibrinolytic agent; or between about 1% and about 10% by weight antifibrinolytic agent; or between about 1%) and 5% by weight antifibrinolytic agent; or between about 5% and about 20% by weight antifibrinolytic agent; or between about 10% and about 15% by weight antifibrinolytic agent; or at least about 15% by weight antifibrinolytic agent. In certain embodiments, the biocompatible polymeric composition comprises between about 4% to about 10% by weight antifibrinolytic agent. Non-limiting examples of antifibrinolytic agents which can be used in the biocompatible polymeric compositions described herein include aprotinin, aprotinin derivative, desmopressin, pirfenidone, alpha2-macroglobulin, an inhibitor or inactivator of protein C or activated protein C, a substrate mimic binding to plasmin that acts competitively with natural substrates, an antibody inhibiting fibrinolytic activity, human fibrinogen concentrate (FC), tranexamic acid (TXA), epsilon-aminocaproic acid and aminomethylbenzoic acid, or a combination thereof. In certain embodiments, the antifibrinolytic agent is tranexamic acid. Accordingly, in certain

embodiments, also provided is a viscous composition comprising tranexamic acid for topical administration, optionally comprising at least one thickening agent. Such compositions may have a viscosity of about 750 cP at 25°C, or greater than about 600, or about 650, or about 700, or about 750, or about 800 or about 850 cP at 25°C.

Solvent

In certain embodiments, the biocompatible polymeric compositions described herein comprise between about 50% to about 90% weight of a solvent. In certain embodiments, the

biocompatible polymeric compositions comprise between about 60% and about 90% solvent; or between about 75% and about 90% solvent. The solvent may be present in the biocompatible polymeric composition in an amount of about 50%, about 50.5%, about 51%, about 51.5%, about 52%, about 52.5%, about 53%, about 53.5%, about 54%, about 54.5%, about 55%, about 55.5%, about 56%, about 56.5%, about 57%, about 57.5%, about 58%, about 58.5%, about 59%, about 59.5%, about 60%, about 60.5%, about 61%, about 61.5%, about 62%, about 62.5%, about 63%, about 63.5%, about 64%, about 64.5%, about 65%, about 65.5%, about 66%, about 66.5%, about 67%, about 67.5%, about 68%, about 68.5%, about 69%, about 69.5%, about 70%, about 70.5%, about 71%, about 71.5%, about 72%, about 72.5%, about 73%, about 73.5%, about 74%, about 74.5%, about 75%, about 75.5%, about 76%, about 76.5%, about 77%, about 77.5%, about 78%, about 78.5%, about 79%, about 79.5%, about 80%, about 80.5%, about 81%, about 81.5%, about 82%, about 82.5%, about 83%, about 83.5%, about 84%, about 84.5%, about 85%, about 85.5%, about 86%, about 86.5%, about 87%, about 87.5%, about 88%, about 88.5%, about 89%, about 89.5%, about 90%, about 90.5%, about 91%, about 91.5%, about 92%, about 92.5%, about 93%, about 93.5%, about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99% or about 99.5%.

Non-limiting examples of solvents include water, ethanol, amyl acetate, acetone, methyl ethyl ketone, isopropanol, tetrahydrofuran, and combinations thereof. In certain embodiments, the solvent is polar. In certain embodiments, the solvent is substantially pH neutral (about 7). In certain embodiments, the solvent is water. In certain embodiments, the solvent is present in the biocompatible polymeric composition in an amount of about 89.5%. In certain embodiments, when the solvent is water, the water is present in the biocompatible polymeric composition in an amount of between about 77% and about 78%.

In certain embodiments, the biocompatible polymeric gel composition comprises (a) between about 0.020 g/mL and about 0.023 g/mL of one or more than one polyanionic polymer and (b) between about 0.185 g/mL and about 0.210 g/mL of one of more than one polycationic polymer. In certain embodiments, the biocompatible polymeric gel composition comprises (a) between about 0.020 g/mL and about 0.023 g/mL of sodium alginate and (b) between about 0.185 g/mL and about 0.200 g/mL of chitosan. In certain embodiments, the biocompatible polymeric gel composition further comprises(c) between about 0.04 g/mL and about 0.1 g/mL tranexamic acid. In certain embodiments, the biocompatible polymeric gel composition comprises about 0.02247 g/mL of one or more than one polyanionic polymer and about 0.200 g/mL of one of more than one polycationic polymer. In certain embodiments, the biocompatible polymeric gel

composition comprises about 0.02247 g/mL of sodium alginate and about 0.200 g/mL of chitosan measured as anhydrous powders. In certain embodiments, the biocompatible polymeric gel composition comprises about 0.0225 g/mL of sodium alginate and about 0.200 g/mL of chitosan measured as anhydrous powders. In certain embodiments, the biocompatible polymeric gel composition comprises about 0.0212 g/mL of one or more than one polyanionic polymer and about 0.1887 g/mL of one of more than one polycationic polymer. In certain embodiments, the biocompatible polymeric gel composition comprises about 0.0212 g/mL of sodium alginate and about 0.1887 g/mL of chitosan measured as anhydrous powders. In certain embodiments, the biocompatible polymeric gel composition comprises about 0.021 g/mL of sodium alginate and about 0.190 g/mL of chitosan measured as anhydrous powders. In certain embodiments, the solvent is water.

In certain embodiments, the biocompatible polymeric gel composition comprises (a) between about 0.020 g/mL and about 0.023 g/mL of sodium alginate and (b) between about 0.185 g/mL and about 0.200 g/mL of chitosan and (c) between about 0.04 g/mL and about 0.1 g/mL tranexamic acid.

In certain embodiments, the polyanionic polymer is sodium alginate having a chain length of between about 1,000 nm and about 3,000 nm, a molecular weight of about 800 kDa, a viscosity of about 1,000 cP in a 1% w/v solution of water at about 25°C, is comprised of particles having an average particle size of about 180 mesh with an amorphous morphology, and is sourced from marine algae.

In certain embodiments, the polycationic polymer is chitosan having an average degree of deacetylation of about 80 or greater, up to or more than about 90%, a chain length of between about 2,850 nm, a molecular weight of about 1,000 kDa, a viscosity of between about 80 cP in a 1%) w/v solution of 5% acetic acid at about 25°C, is comprised of particles having an average particle size of about 100 mesh with a porous and substantially spherical morphology, and is sourced from marine invertebrates.

In certain embodiments, provided herein is a biocompatible polymeric composition comprising about 3% to 4% w/w alginate, about 18% to 20% w/w chitosan, and about 1% to 20% w/w of a solution of tranexamic acid in water. In certain embodiments, provided herein is a biocompatible polymeric composition comprising about 3.8% by weight alginate, about 19.8% by weight chitosan, and about 12.5% by weight of a solution of tranexamic acid in water. In certain embodiments, provided herein is a biocompatible polymeric composition comprising about 3.5% to 4% w/w sodium alginate, about 19% to 20% w/w chitosan and about 4% to 10%> w/w tranexamic acid. In certain embodiments, provided herein is a biocompatible polymeric composition comprising about 3.7% to 4% w/w sodium alginate, about 19.5% to 20% w/w chitosan and about 2% to 5% w/w of tranexamic acid. In certain embodiments, provided herein is a biocompatible polymeric composition comprising about 3.8% by weight sodium alginate, about 19.8%) by weight chitosan and about 4% by weight of tranexamic acid. In certain embodiments, provided herein is a biocompatible polymeric composition comprising about 3.8% by weight sodium alginate, about 19.8% by weight chitosan, and about 4% by weight of tranexamic acid and water. In certain embodiments, the biocompatible polymeric composition does not comprise hyaluronic acid.

In certain embodiments, provided herein is a biocompatible polymeric composition comprising about 3%) to 4% by weight sodium alginate, about 18% to 20% by weight chitosan, about 1% to 20% by weight of tranexamic acid and water. In some embodiments, the biocompatible polymeric composition comprises from about 56% to 78% water. In certain embodiments, provided herein is a biocompatible polymeric composition comprising about 3.8%) by weight sodium alginate, about 19.8% by weight chitosan, about 4% by weight of tranexamic acid and water.

In certain embodiments, provided herein is a biocompatible polymeric composition consisting essentially of about 3% to 4% w/w sodium alginate, about 18% to 20% w/w chitosan, and about 1%) to 20%) w/w of a solution of tranexamic acid in water. In certain embodiments, provided herein is a biocompatible polymeric composition consisting essentially of about 3.5% to 4% w/w sodium alginate, about 19% to 20% w/w chitosan, and about 4% to 10% w/w tranexamic acid. In certain embodiments, provided herein is a biocompatible polymeric composition consisting essentially of about 3.7% to 4% w/w sodium alginate, about 19.5% to 20% w/w chitosan and about 2%) to 8% w/w of tranexamic acid. In certain embodiments, provided herein is a biocompatible polymeric composition consisting essentially of about 3.8% by weight sodium alginate, about 19.8% by weight chitosan, and about 4% by weight of tranexamic acid (as a solution of tranexamic acid in water).

In some embodiments, provided herein is a biocompatible polymeric composition consisting of about 3.8% by weight sodium alginate, about 19.8% by weight chitosan, about 4% by weight of tranexamic acid and water.

In certain embodiments, the disclosure provides the biocompatible polymeric gel composition comprising a unit dose of about 25 mL to about 60 mL. In certain embodiments, the disclosure provides the biocompatible polymeric gel composition comprising a unit dose of about 25 mL to about 35 mL, about 30 mL to about 40 mL, about 35 mL to about 45 mL, about 40 mL to about 50 mL, about 45 mL to about 55 mL or about 50 mL to about 60 mL. In certain embodiments, the disclosure provides the biocompatible polymeric gel composition comprising a unit dose of about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL or about 60 mL. In certain embodiments, the unit dose is for topical application.

In certain embodiments, the disclosure provides a syringe comprising the biocompatible polymeric composition as described herein. In certain embodiments, the disclosure provides a syringe comprising sodium alginate, chitosan, tranexamic acid and water. In certain

embodiments, the disclosure provides a syringe comprising 3.5% to 4% w/w sodium alginate, about 19%) to 20% w/w chitosan, about 1% to 6% w/w tranexamic acid and water. In certain embodiments, the disclosure provides a syringe consisting essentially of sodium alginate, chitosan, tranexamic acid and water. In some embodiments, the disclosure provides a syringe consisting essentially of about 3.8% by weight sodium alginate, about 19.8% by weight chitosan, about 4% by weight of tranexamic acid and water. Method of Manufacture

Production of the biocompatible polymeric composition generally proceeds as follows. First, a solution comprising the antifibrinolytic agent is prepared. In certain embodiments, the solution is an aqueous solution. The polyanionic polymer can then be mixed with the solution comprising the antifibrinolytic agent for a period of time such that the polyanionic polymer is substantially dissolved. In certain embodiments, the temperature is about 25°C. The polyanionic mixing may occur between approximately 20 revolutions per minute (RPM) to about 80 RPM, or about 48 RPM. Following this first mixing step, the polycationic polymer is added to the mixture and the components are mixed for a period of time at about 25°C. This mixing may occur between approximately 40 RPM to about 100 RPM, or about 62 RPM. In certain embodiments, the mixing in the first mixing period is performed at a lower speed than the mixing in the second mixing period.

In certain embodiments, the sodium alginate is mixed into a vessel with the solution comprising the antifibrinolytic agent to reach a desired viscosity at about 25 °C. This mixing may be performed for about six hours under low-shear mixing, at about 48 RPM. After the sodium alginate and solution comprising the antifibrinolytic agent are mixed, chitosan is added. In certain embodiments, the chitosan is added portion-wise over time (e.g., 2-5 hours) as a solid. The mixture including chitosan can be mixed under faster mixing than the sodium alginate / antifibrinolytic agent mixing for about one hour at about 25 °C. In certain embodiments, upon incorporation of chitosan, the mixing is performed at about 62 RPM.

In certain embodiments, the chitosan is not incorporated simultaneously with the sodium alginate and water as the chitosan particles are porous and tend to pull water out of solution.

Simultaneous mixing of all three components (as opposed to first mixing the water and sodium alginate) results in a less efficacious gel that is thicker than desired and may include undissolved sodium alginate. Such gel may comprise a compressible colloid of sodium alginate and wetted chitosan which may exhibit crosslinking issues and poor tissue adherence.

In certain embodiments, the antifibrinolytic agent is added to the composition after the chitosan. The antifibrinolytic agent can be added as a solid or a liquid (e.g., as an aqueous solution).

In certain embodiments, the disclosure provides a method of making a biocompatible polymeric composition comprising:

(a) dissolving tranexamic acid in water to provide a solution;

(b) adding alginate to the solution to provide a mixture; and

(c) adding chitosan to the mixture to provide the biocompatible polymeric

composition. In certain embodiments, the chitosan has an average particle size of about 100 mesh. In certain embodiments, the chitosan has a substantially spherical morphology. In certain embodiments, the disclosure provides a biocompatible polymeric composition made by the above method.

In certain embodiments, the disclosure provides a method of making a biocompatible polymeric composition comprising: (a) mixing sodium alginate with water at a first speed to provide a solution having a first viscosity;

(b) adding chitosan to solution and mixing at a second speed to make a mixture having a second viscosity; and

(c) adding tranexamic acid to the mixture to provide the biocompatible

polymeric composition.

In certain embodiments, the first viscosity is greater than about 1,000 cP at about 25°C. In certain embodiments, the chitosan has an average particle size of about 100 mesh. In certain embodiments, the chitosan has a substantially spherical morphology.

In certain embodiments, the disclosure provides a biocompatible polymeric composition made by the above method.

In certain embodiments, the biocompatible polymeric composition is a colloidal gel with solid particles dispersed in a solution. It is believed that the fluidity of the gel allows for aided wound surface area coverage as it conforms to the site of injury better than solids (such as gauzes or sponges) while the solid particles allow for weight to mechanically prevent bleeding through the fluid, as well as aiding in better cell adhesion/aggregation.

Kit

The packaging of the biocompatible polymeric composition into, for example, a kit or article of manufacture, and application device for any embodiment of the disclosure is chosen and manufactured by persons skilled in the art on the basis of their general knowledge, and adapted according to the nature of the biocompatible polymeric composition to be packaged. Moreover, the type of device to be used may be in particular linked to the consistency of the biocompatible polymeric composition, in particular to its viscosity; it may also depend on the nature of the constituents present in the biocompatible polymeric composition. The kit or article of manufacture may include, but is not limited to, the biocompatible polymeric composition, a device for the application of the biocompatible polymeric composition, instructions for the use and application of the biocompatible polymeric composition, one or more than one additional solution, a listing of ingredients and/or warnings, and the like. In one embodiment the kit includes a 5 mL syringe filled with the biocompatible polymeric composition described herein. In one embodiment the kit includes a 5 mL syringe filled with a

biocompatible polymeric composition along with a separate container containing 10% w/v calcium chloride solution in water.

Method of Use In certain embodiments, the biocompatible polymeric composition is applied to a wound including, for example, an external laceration, an abrasion, a burn, an ocular laceration, damage to a parenchymal organ, an internal laceration, a laceration in the gastrointestinal tract, superficial cuts and scrapes, internal bleeding, an arterial bleed, a venous bleed, dental or oral bleeds and incisions. The biocompatible polymeric composition is further useful for treating various wounds including those caused unintentionally (such as accidents or unforeseen injuries) as well as those caused intentionally (such as in surgery).

In certain methods of using the biocompatible polymeric composition, the biocompatible polymeric composition is applied topically directly onto a bleeding wound surface. When applied to a volume of blood, the biocompatible polymeric composition will aid in the clotting of blood at the gel-blood interface. When applying the product, efficacy may decrease if gel is not directly in contact with a bleeding wound surface, though is relatively close to the wound site. The administrator may employ a large-bore syringe in order to rapidly apply a substantial amount of biocompatible polymeric composition, due to its viscous nature. The biocompatible polymeric composition may be dispensed via catheter (such as a 16 gauge or larger) during laparoscopic procedures. In another embodiment, the biocompatible polymeric composition may be dispensed across a gauze pad to increase the surface area of exposed biocompatible polymeric composition for treatment of large surface bleeds.

Patients that can benefit from wound treatment using the polymeric compositions include a variety of animals including humans, mammals such as horses, sheep, cattle, hogs, dogs, cats, and marine animals such as whales, dolphins, seals, otters, fish and reptiles such as turtles. In one embodiment, the patient is a human.

After application to a wound, the biocompatible polymeric composition may be cross-linked by addition of a di- or higher valent cation to facilitate removal. Addition of the di- or higher valent cation may assist with removal of the product from the wound site. The di- or higher valent cation may be one or more of Ca²⁺, Fe²⁺, Fe³⁺, Ag²⁺, Ag³⁺, Au²⁺, Au³⁺, Mg²⁺, Cu²⁺, Cu³⁺ and Zn²⁺. In one embodiment, the cation is Ca²⁺. In certain embodiments, the di- or higher valent cation is delivered in a solution. The di- or higher valent cation may be present in solution from about 0.1% to about 30% w/v. In certain embodiments, the solvent is water. In certain embodiments, a 10% w/v calcium chloride solution in water may be used.

In some embodiments, the disclosure provides a method of treating an external laceration, an abrasion, a burn, an ocular laceration, damage to a parenchymal organ, an internal laceration, a laceration in the gastrointestinal tract, superficial cuts and scrapes, internal bleeding, an arterial bleed, a venous bleed, dental or oral bleeds and incisions, wherein the method comprises applying a biocompatible polymeric composition comprising about 3.5% to 4% w/w sodium alginate, about 19% to 20% w/w chitosan and about 4% to 10% w/w tranexamic acid. In a further embodiment, the composition comprises water. In certain embodiments, the

biocompatible polymeric composition does not comprise hyaluronic acid.

In some embodiments, the disclosure provides a method of treating a bleed, wherein the method comprises applying to a bleed-site a biocompatible polymeric composition comprising about 3.5% to 4%) w/w sodium alginate, about 19% to 20% w/w chitosan and about 4% to 10% w/w tranexamic acid. In a further embodiment, the composition comprises water. In some embodiments, the bleed is an arterial bleed, a venous bleed, a dental bleed or an oral bleed. In certain embodiments, the biocompatible polymeric composition does not comprise hyaluronic acid.

In some embodiments, the disclosure provides a method of treating a bleed, wherein the method comprises applying to a bleed-site a biocompatible polymeric composition comprising about 3.8%) by weight sodium alginate, about 19.8% by weight chitosan and about 4% by weight of tranexamic acid. In a further embodiment, the composition comprises water. In some embodiments, the bleed is an arterial bleed, a venous bleed, a dental bleed or an oral bleed. In certain embodiments, the biocompatible polymeric composition does not comprise hyaluronic acid.

In certain embodiments, the disclosure provides a method of treating a bleed, wherein the wherein the method comprises applying to a bleed-site a biocompatible polymeric composition consisting essentially of alginate, chitosan, tranexamic acid and water. In certain embodiments, this disclosure provides a method of treating a bleed, wherein the wherein the method comprises applying to a bleed-site a biocompatible polymeric composition consisting essentially of about 3% to 4% by weight sodium alginate, about 18% to 20% by weight chitosan, about 1% to 20% by weight of tranexamic acid and water. In certain embodiments a method of treating a bleed, wherein the wherein the method comprises applying to a bleed-site a biocompatible polymeric composition consisting essentially of about 3.8% by weight sodium alginate, about 19.8% by weight chitosan, about 4% by weight of tranexamic acid and water.

In certain embodiments, the disclosure provides a method of treating a wound, wherein the wherein the method comprises applying to a wound-site a biocompatible polymeric composition consisting essentially of alginate, chitosan, tranexamic acid and water. In certain embodiments, this disclosure provides a method of treating a wound, wherein the wherein the method comprises applying to a wound-site a biocompatible polymeric composition consisting essentially of about 3% to 4% by weight sodium alginate, about 18% to 20% by weight chitosan, about 1%) to 20% by weight of tranexamic acid and water. In certain embodiments, the disclosure provides a method of treating a wound, wherein the method comprises applying to a wound-site a biocompatible polymeric composition consisting essentially of about 3.8% by weight sodium alginate, about 19.8% by weight chitosan, about 4% by weight of tranexamic acid and water. In some embodiments, the disclosure provides a biocompatible polymeric composition for use in treating an external laceration, an abrasion, a burn, an ocular laceration, damage to a

parenchymal organ, an internal laceration, a laceration in the gastrointestinal tract, superficial cuts and scrapes, internal bleeding, an arterial bleed, a venous bleed, dental or oral bleeds and incisions, wherein the composition comprises about 3.5% to 4% w/w sodium alginate, about 19% to 20%) w/w chitosan and about 4% to 10%> w/w tranexamic acid. In a further embodiment, the composition comprises water. In certain embodiments, the biocompatible polymeric composition does not comprise hyaluronic acid.

In some embodiments, the disclosure provides a biocompatible polymeric composition for use in treating a wound, wherein the composition comprises about 3.5% to 4% w/w sodium alginate, about 19%) to 20%) w/w chitosan and about 4% to 10% w/w tranexamic acid. In a further embodiment, the composition comprises water. In certain embodiments, the biocompatible polymeric composition does not comprise hyaluronic acid.

In some embodiments, the disclosure provides a biocompatible polymeric composition for use in treating a bleed, wherein the composition comprises about 3.5% to 4% w/w sodium alginate, about 19%) to 20%) w/w chitosan and about 4% to 10% w/w tranexamic acid. In a further embodiment, the composition comprises water. In some embodiments, the bleed is an arterial bleed, a venous bleed, a dental bleed or an oral bleed. In certain embodiments, the

biocompatible polymeric composition does not comprise hyaluronic acid. In some embodiments, the disclosure provides a biocompatible polymeric composition for use in treating a bleed, wherein the composition comprises about 3.7% to 4% w/w sodium alginate, about 19.5%) to 20% w/w chitosan and about 4% to 8% w/w tranexamic acid. In a further embodiment, the composition comprises water. In some embodiments, the bleed is an arterial bleed, a venous bleed, a dental bleed or an oral bleed. In certain embodiments, the

biocompatible polymeric composition does not comprise hyaluronic acid.

In some embodiments, the disclosure provides a biocompatible polymeric composition for use in treating a bleed, wherein the composition comprises about 3.8% by weight sodium alginate, about 19.8%) by weight chitosan and about 4% by weight of tranexamic acid. In a further embodiment, the composition comprises water. In some embodiments, the bleed is an arterial bleed, a venous bleed, a dental bleed or an oral bleed. In certain embodiments, the

biocompatible polymeric composition does not comprise hyaluronic acid.

In certain embodiments, the disclosure provides a biocompatible polymeric composition for use in treating a bleed, wherein the composition comprises about 3% to 4% by weight alginate, about 18% to 20%) by weight chitosan, about 1%> to 20% by weight of tranexamic acid and water. In some embodiments, the biocompatible polymeric composition comprises from about 56%> to 78% water.

In certain embodiments, the disclosure provides a biocompatible polymeric composition for use in treating a wound, wherein the composition comprises about 3.8%> by weight sodium alginate, about 19.8%) by weight chitosan, about 4% by weight of tranexamic acid and water.

In certain embodiments, the disclosure provides a biocompatible polymeric composition for use in treating a bleed, wherein the composition comprises about 3.8%> by weight sodium alginate, about 19.8%) by weight chitosan, about 4% by weight of tranexamic acid and water. In certain embodiments, the disclosure provides a biocompatible polymeric composition for use in treating a wound, wherein the composition consists essentially of alginate, chitosan, tranexamic acid and water. In certain embodiments, this disclosure provides a biocompatible polymeric composition for use in treating a wound, wherein the composition consists essentially of about 3%o to 4%> by weight sodium alginate, about 18%> to 20% by weight chitosan, about 1% to 20% by weight of tranexamic acid and water. In certain embodiments, this disclosure provides a biocompatible polymeric composition for use in treating a wound, wherein the composition consists essentially of about 3.8% by weight sodium alginate, about 19.8% by weight chitosan, about 4% by weight of tranexamic acid and water.

In certain embodiments, the disclosure provides a biocompatible polymeric composition for use in treating a bleed, wherein the composition consists essentially of alginate, chitosan, tranexamic acid and water. In certain embodiments, this disclosure provides a biocompatible polymeric composition for use in treating a bleed, wherein the composition consists essentially of about 3% to 4%) by weight sodium alginate, about 18% to 20% by weight chitosan, about 1% to 20% by weight of tranexamic acid and water. In certain embodiments, this disclosure provides a biocompatible polymeric composition for use in treating a bleed, wherein the composition consists essentially of about 3.8% by weight sodium alginate, about 19.8% by weight chitosan, about 4%) by weight of tranexamic acid and water. EXAMPLES

Example 1: Preparation of TXA containing biocompatible polymeric composition

An exemplary biocompatible polymeric composition can be prepared by dissolving 4% (w/w) of TXA in water and then gradually adding 3.8% (w/w) high molecular weight alginate into the TXA solution, and then stirring in 19.77% (w/w) of chitosan (added portion-wise). In certain embodiments, the alginate and aqueous TXA solution is left to sit for up to about 6 hours to ensure full dissolution. After the alginate is dissolved, chitosan is added and the composition is mixed until fully incorporated.

Alternatively, alginate 3.8% (w/w) is dissolved in water first and then chitosan 19.77%) (w/w) is added followed by 4% (w/w) tranexamic acid as a solution in water.

The components of the biocompatible polymer composition can be sterilized by standard methods such as electron beam irradiation, steam sterilization, or sterile filtration. The resulting composition can then be loaded into a syringe aseptically and subsequently packaged for use.

Example 2: Application of TXA containing biocompatible polymeric composition The biocompatible polymeric composition of the disclosure is applied directly to a wound-site such as an external laceration, an abrasion, a burn, an ocular laceration, damage to a

parenchymal organ, an internal laceration, a laceration in the gastrointestinal tract, superficial cuts and scrapes, internal bleeding, an arterial bleed, a venous bleed, dental or oral bleeds or an incision. The composition is dispensed directly from a syringe or a suitable delivery device to the wound-site or bleed-site and it stops the flow of blood by creating a strong, natural clot without the need to apply pressure. The material conforms to the injury being treated, with the ability to deliver the antifibrinolytic agent uniformly throughout the area despite potentially complex wound geometries. Over the course of wound treatment, the antifibrinolytic agent is gradually being absorbed into local coagulated blood, allowing for a delayed clot breakdown time and thus a higher likelihood to maintain clot strength during patient transport or while awaiting follow-on treatment.

Claims

What is claimed is:

1. A biocompatible polymeric composition comprising:

(a) at least one polyanionic polymer;

(b) at least one polycationic polymer; and

(c) at least one antifibrinolytic agent.

2. The biocompatible polymeric composition of claim 1, comprising:

(a) about 0.1% to about 5% by weight polyanionic polymer;

(b) about 5% to about 40% by weight polycationic polymer;

(c) at least about 1% by weight antifibrinolytic agent; and

(d) about 50% to about 94% by weight solvent.

3. The biocompatible polymeric composition of claim 1 or 2, wherein the composition does not comprise hyaluronic acid.

4. The biocompatible polymeric composition of any preceding claim, wherein the polyanionic polymer comprises alginate.

5. The biocompatible polymeric composition of any preceding claim, wherein the polycationic polymer comprises chitosan.

6. The biocompatible polymeric composition of any preceding claim, wherein the antifibrinolytic agent is tranexamic acid.

7. The biocompatible polymeric composition of any preceding claim, wherein the solvent is water.

8. The biocompatible polymeric composition of any preceding claim, wherein the polyanionic polymer is sodium alginate having a molecular weight of greater than about 650 kDa.

9. The biocompatible polymeric composition of any preceding claim, wherein the polyanionic polymer is sodium alginate having a molecular weight of about 650 to about 800 kDa.

10. The biocompatible polymeric composition of any preceding claim, wherein the polyanionic polymer is sodium alginate having a viscosity of greater than about 1000 cP when tested in a 1% solution at 20-25 °C.

11. The biocompatible polymeric composition of any preceding claim, wherein the polycationic polymer is chitosan having a molecular weight of greater than about 250 kDa.

12. The biocompatible polymeric composition of any preceding claim, wherein the polycationic polymer is chitosan having a molecular weight of from about 250 to about 300 kDa.

13. The biocompatible polymeric composition of any preceding claim, wherein polycationic polymer is chitosan having an average degree of deacetylation of at least about 80%.

14. The biocompatible polymeric composition of any preceding claim, wherein polycationic polymer is chitosan having an average degree of deacetylation of greater than about 90%.

15. The biocompatible polymeric composition of any preceding claim, wherein the biocompatible polymeric composition exhibits hemostatic efficacy in vitro in less than about 30 seconds upon introduction to blood.

16. The biocompatible polymeric composition of any preceding claim, wherein the biocompatible polymeric composition provides maximum clot strength from about 90 to about 200 clot strength units.

17. The biocompatible polymeric composition of any preceding claim, wherein the composition withstands a vertical strain of up to about 0.5 Newtons per square millimeter without fracture.

18. The biocompatible polymeric composition of any preceding claim, wherein the polycationic polymer is dispersed as solid phase particles in a solution of polyanionic polymer.

19. The biocompatible polymeric composition of any preceding claim, wherein the storage modulus is between about 8 kPa and about 15 kPa.

20. The biocompatible polymeric composition of any preceding claim, wherein the storage modulus is greater than about 12 kPa.

21. A biocompatible polymeric composition comprising:

(a) about 3% to 4% by weight alginate;

(b) about 18% to 20% by weight chitosan;

(c) about 1%) to 20%) by weight tranexamic acid; and

(d) the remainder by weight water.

22. The biocompatible polymeric composition of claim 21, wherein the composition does not comprise hyaluronic acid.

23. A viscous composition comprising at least one antifibrinolytic agent for topical administration, and optionally comprising at least one thickening agent.

24. The viscous composition of claim 23, wherein the antifibrinolytic agent is tranexamic acid.

25. A method of making a biocompatible polymeric composition comprising:

(a) dissolving tranexamic acid in water to provide a solution;

(b) adding alginate to the solution to provide a mixture; and

(c) adding chitosan to the mixture to provide the biocompatible polymeric composition.

26. The method of claim 25, wherein the chitosan has an average particle size of about 100 mesh.

27. The method of claim 25, wherein the chitosan has a substantially spherical morphology.

28. A biocompatible polymeric composition made by the method of claim 25.

29. A biocompatible polymeric composition prepared by the method of claim 25, having (a) between about 0.0200 g/mL and about 0.0230 g/mL sodium alginate; and (b) between about 0.185 g/mL and about 0.200 g/mL chitosan.

30. The biocompatible polymeric composition of claim 29, further comprising (c) between about 0.02 g/mL and about 0.1 g/mL tranexamic acid.

31. A kit comprising the biocompatible polymeric composition of any one of claims 1-22 or 28-30.

32. The kit of claim 31, wherein the biocompatible polymeric composition is in a syringe.

33. The kit of claim 31, further comprising a container comprising a calcium chloride solution.

34. The kit of claim 33, wherein the calcium chloride solution is a 10% w/v calcium chloride solution in water.

35. A method of treating a wound in a patient in need thereof, comprising

administering the biocompatible polymeric composition of any one of claims 1-22 or 28-30 to a patient in need thereof.

36. The method of claim 35, wherein the wound is a traumatic wound.

37. The method of claim 35, wherein the wound is the result of surgery.