JP7493961B2 - Highly useful adhesive polymer scaffolds for hemostasis - Google Patents

Description

2. Background of the Invention Hemostasis is a complex, multi-step mechanism that requires concerted efforts among many cell types and scaffold formations to initiate the formation of an initial platelet plug at the wound site and then generate a fully mature clot capable of stopping blood flow. Hemostasis is usually divided into three phases: primary hemostasis, the coagulation cascade, and fibrinolysis. Platelets first adhere to collagen fibers surrounding the injured surface, followed by the formation of a platelet plug in response to the exposed endothelial cells of said surface. Exposure to collagen "activates" the platelets, prompting them to release clotting factors that advance the coagulation cascade. The process culminates with the cleavage of fibrinogen by thrombin, forming the building block of the clot known as fibrin.

A notable challenge in the treatment of bleeding wound surfaces is presented by the adhesive nature of the physical barrier components of a given hemostatic device. If sustained blood flow is particularly strong, hemostasis may be impeded as immature platelet and fibrin clots may rupture in the process. This difficulty may be exacerbated if the hemostatic device is not sufficiently adhesive, causing a partially formed thrombus or clot to prematurely detach from the wound site. Various hemostatic devices attempt to increase adhesive strength by utilizing desiccation devices that dehydrate the wound site. Such devices retard epithelialization and therefore substantially slow wound healing.

It would be advantageous to develop an adhesive hemostatic device that does not limit wound hydration during and after hemostasis.

SUMMARY OF THEINVENTION The present invention is in the field of biocompatible polymeric compositions useful for facilitating and maintaining hemostasis.

In one embodiment of the invention, the biocompatible polymer composition comprises (a) one or more polyanionic polymers, (b) one or more polycationic polymers, and (c) a solvent. In one embodiment of the invention, one polyanionic polymer comprises sodium alginate; in one embodiment of the invention, one polycationic polymer comprises chitosan; in one embodiment of the invention, the solvent comprises water. In a preferred embodiment of the invention, the biocompatible polymer composition comprises sodium alginate, chitosan, and water.

Various properties associated with each component of the biocompatible polymer composition can affect 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. Properties associated with the solvent include pH and polarity. Properties of the final biocompatible polymer composition include viscosity, hemostatic efficiency, breaking strength, and pH.

Factors that affect the properties of the final product include the amounts of each component as well as the method of preparation.
In an embodiment of the present invention, for example, the following items are provided:
(Item 1)
a. about 0.1% to about 5% by weight of one or more polyanionic polymers;
b. about 5% to about 40% by weight of one or more polycationic polymers, and c. about 50% to about 99.9% by weight of a solvent.
(Item 2)
2. The polymer composition of claim 1, wherein the one or more polyanionic polymers comprise sodium alginate, the one or more polycationic polymers comprise chitosan, and the solvent is water.
(Item 3)
3. The polymer composition of claim 2, wherein the sodium alginate has a chain length of between about 1,000 nm and about 3,000 nm.
(Item 4)
3. The polymer composition of claim 2, wherein the sodium alginate has an average molecular weight of about 100 kDa to about 1,000 kDa.
(Item 5)
3. The polymer composition of claim 2, wherein the sodium alginate has an average molecular weight of about 500 kDa to about 900 kDa.
(Item 6)
3. The polymer composition of claim 2, wherein the sodium alginate has an average molecular weight of about 800 kDa.
(Item 7)
3. The polymer composition of claim 2, wherein the chitosan has a chain length of between about 2,000 nm and about 4,000 nm.
(Item 8)
3. The polymer composition of claim 2, wherein the chitosan has a chain length of between about 2,800 nm and about 2,900 nm.
(Item 9)
10. The polymer composition of claim 2, wherein the chitosan has a chain length of about 2,850 nm.
3. The polymer composition of claim 2, wherein the chitosan has an average molecular weight between about 1 kDa and about 2,000 kDa.
(Item 11)
3. The polymer composition of claim 2, wherein the chitosan has an average molecular weight of between about 1 kDa and about 1,000 kDa.
(Item 12)
3. The polymer composition according to claim 2, wherein the chitosan has an average molecular weight of about 1,000 kDa.
(Item 13)
3. The polymer composition of claim 2, wherein the chitosan has an average degree of deacetylation between about 75.0% and about 99.5%.
(Item 14)
3. The polymer composition according to claim 2, wherein said chitosan is derived from an organic source.
(Item 15)
3. The polymer composition of claim 2, wherein the chitosan is derived from at least one of a marine invertebrate and a fungus.
(Item 16)
3. The polymer composition of claim 2, wherein the sodium alginate is derived from an organic source.
(Item 17)
3. The polymer composition according to claim 2, wherein the sodium alginate is derived from seaweed.
(Item 18)
3. The polymer composition of claim 2, which exhibits hemostatic efficacy in vitro in less than about 30 seconds when introduced into blood.
(Item 19)
3. The polymer composition of claim 2, wherein the in vitro hemostatic efficiency comprises an increase in clot strength units over a given time interval.
(Item 20)
20. The polymer composition according to claim 19, wherein said hemostatic efficiency is measured by a coagulation analyzer.
(Item 21)
20. The polymer composition according to claim 19, wherein the clot strength unit corresponds to the resistance of the clot to vibration of a probe perpendicular to the fibers of the clot.
(Item 22)
3. The polymer composition of claim 2 having a maximum clot strength of about 90 to about 200 clot strength units.
(Item 23)
3. The polymer composition of claim 2, which withstands a normal strain of up to about 0.5 Newtons per square millimeter without fracture.
(Item 24)
2. The polymer composition of claim 1, wherein one or more of said polycationic polymers are dispersed as solid phase particles in one or more solutions of said polyanionic polymers.
(Item 25)
3. The polymer composition of claim 2, wherein the viscosity is from about 145,000 cP to about 250,000 cP at about 25° C.
(Item 26)
3. The polymer composition of claim 2, wherein the viscosity is about 169,500 cP at about 25° C.
(Item 27)
3. The polymer composition of claim 2 having a pH of about 7.0.
(Item 28)
Item 3. The polymer composition according to item 2, having a Fourier transform infrared spectrum as shown in FIG.
(Item 29)
3. The polymer composition of claim 2, having a Fourier transform infrared spectrum comprising absorption peaks at about 3,600 cm ⁻¹ to about 3,000 cm ⁻¹ , about 2,900 cm ⁻¹ , about 1,640 cm ⁻¹ , and about 1,590 cm ⁻¹ .
(Item 30)
3. The polymer composition of claim 2, wherein the chitosan has an average degree of deacetylation between about 75.0% and about 85.0%.
(Item 31)
3. The polymer composition of claim 2, wherein the chitosan has an average degree of deacetylation between about 78.0% and about 83.0%.
(Item 32)
3. The polymer composition of claim 2, wherein the chitosan has an average degree of deacetylation between about 80.0% and about 81.0%.
(Item 33)
3. The polymer composition according to claim 2, wherein said chitosan has an average degree of deacetylation of about 80.5%.
(Item 34)
3. The polymer composition of claim 2, having a density of between about 1.10 g/mL and about 1.30 g/mL at about 25° C.
(Item 35)
3. The polymer composition of claim 2, having a density of about 1.21 g/mL at about 25° C.
(Item 36)
3. The polymer composition of claim 2, wherein about 13 mg or more of the composition clots about 0.34 mL of blood in vitro.
(Item 37)
3. The polymer composition of claim 2, having an elastic modulus of between about 6 kPa and about 23 kPa.
(Item 38)
38. The polymer composition according to claim 37, wherein the elastic modulus is about 16 kPa.
(Item 39)
a. about 2.5% by weight of sodium alginate;
b. about 8% by weight of chitosan, and c. about 89.5% by weight of water.
(Item 40)
A method of making a polymer composition comprising: a. mixing sodium alginate with water at a first speed to create a first mixture having a first viscosity, and then b. adding chitosan to the first mixture and mixing at a second speed to create a second mixture having a second viscosity.
(Item 41)
41. The method of claim 40, wherein the first viscosity is between about 500 cP and about 2,000 cP at about 25°C.
(Item 42)
41. The method of claim 40, wherein the sodium alginate comprises particles having an average particle size between 10 mesh and 300 mesh.
(Item 43)
41. The method of claim 40, wherein the chitosan has a viscosity of between about 100 cP and about 1,000 cP in a 1% w/v solution in 5% acetic acid at about 25°C.
(Item 44)
45. The method of claim 40, wherein the second viscosity is about 169,500 cP at about 25° C.
41. The method of claim 40, wherein the chitosan comprises particles having an average particle size between 50 mesh and 500 mesh.
(Item 46)
41. The method of claim 40, wherein mixing the sodium alginate with water at a first speed is performed for about 6 hours.
(Item 47)
41. The method of claim 40, wherein said mixing at the second speed is carried out for about 1 hour.
(Item 48)
Item 41. The method of item 40, wherein the second speed is greater than the first speed.
(Item 49)
41. The method of claim 40, wherein the sodium alginate has at least one of the following morphologies: fibrous, crystalline, amorphous, spherical, and cubic.
(Item 50)
41. The method of claim 40, wherein the chitosan has at least one of the following morphologies: fibrous, crystalline, amorphous, spherical, and cubic.
(Item 51)
41. The method of claim 40, wherein the chitosan has a spherical morphology.
(Item 52)
41. A polymer composition made by the method of claim 40.
(Item 53)
41. A polymer composition made by the method of claim 40 having (a) between about 0.0200 g/mL and about 0.0230 g/mL of sodium alginate, and (b) between about 0.185 g/mL and about 0.210 g/mL of chitosan.
(Item 54)
41. A polymer composition made by the method of claim 40 having a Fourier transform infrared spectrum as shown in FIG.
(Item 55)
41. A polymer composition made by the method of claim 40, wherein said sodium alginate has a Fourier transform infrared spectrum comprising absorption peaks at about 3,600 cm ⁻¹ to about 3,000 cm ⁻¹ , about 2,900 cm ⁻¹ , about 1,600 cm ⁻¹ , and about 1,400 ^cm −1 .
(Item 56)
41. A polymer composition made by the method of claim 40, wherein the sodium alginate has a Fourier transform infrared spectrum as shown in FIG.
(Item 57)
41. A polymer composition made by the method of claim 40, wherein said chitosan has a Fourier transform infrared spectrum comprising absorption peaks at about 3,600 cm ⁻¹ to about 3,000 cm ⁻¹ , about 2,910 cm ⁻¹ , about 2,870 cm ⁻¹ , about 1,650 cm ⁻¹ , and about 1,580 cm ⁻¹ .
(Item 58)
41. A polymer composition made by the method of claim 40, wherein the chitosan has a Fourier transform infrared spectrum as shown in FIG.
(Item 59)
41. A polymer composition made by the method of claim 40 having a pH of about 7.0.
(Item 60)
41. The method of claim 40, wherein the chitosan has an average degree of deacetylation between about 75.0% and about 99.5%.
(Item 61)
41. The method of claim 40, wherein the chitosan has an average degree of deacetylation between about 75.0% and about 85.0%.
(Item 62)
41. The method of claim 40, wherein the chitosan has an average degree of deacetylation between about 78.0% and about 83.0%.
(Item 63)
41. The method of claim 40, wherein the chitosan has an average degree of deacetylation between about 80.0% and about 81.0%.
(Item 64)
41. The method of claim 40, wherein the chitosan has an average degree of deacetylation of about 80.5%.
(Item 65)
41. A polymer composition made by the method of claim 40 having a density of between about 1.10 g/mL and 1.30 g/mL at about 25° C.
(Item 66)
41. A polymer composition made by the method of claim 40 having a density of about 1.21 g/mL at about 25° C.
(Item 67)
41. The method of claim 40, wherein the sodium alginate comprises particles having an average particle size of about 180 mesh.
(Item 68)
41. The method of claim 40, wherein the chitosan comprises particles having an average particle size of about 100 mesh.
(Item 69)
A sterile polymeric composition having a viscosity of between about 165,000 cP and about 174,000 cP at about 25° C. comprising: (a) an alginate; and (b) a chitosan having an average degree of deacetylation of between about 75.0% and about 99.5%.
(Item 70)
70. The sterile polymer composition of claim 69, having a viscosity of about 169,500 cP at about 25° C.
(Item 71)
70. The sterile polymer composition of claim 69, wherein the chitosan has an average degree of deacetylation between about 75.0% and about 99.5%.
(Item 72)
70. The sterile polymer composition of claim 69, wherein the chitosan has an average degree of deacetylation of between about 75.0% and about 85.0%.
(Item 73)
70. The sterile polymer composition of claim 69, wherein the chitosan has an average degree of deacetylation of between about 78.0% and about 83.0%.
(Item 74)
70. The sterile polymer composition of claim 69, wherein the chitosan has an average degree of deacetylation of between about 80.0% and about 81.0%.
(Item 75)
70. The sterile polymer composition of claim 69, wherein the chitosan has an average degree of deacetylation of about 80.5%.
(Item 76)
71. The sterile polymer composition of claim 70, wherein the chitosan has an average degree of deacetylation of about 80.5%.
(Item 77)
70. The sterile polymer composition of claim 69, having a density of between about 1.10 g/mL and 1.30 g/mL at about 25° C.
(Item 78)
70. The sterile polymer composition of claim 69, having a density of about 1.21 g/mL at about 25° C.
(Item 79)
70. The sterile polymer composition of claim 69, having a pH of about 7.0.
(Item 80)
A polymer composition having a Fourier transform infrared spectrum shown in FIG.
(Item 81)
A polymeric composition comprising sodium alginate and chitosan, having a Fourier transform infrared spectrum comprising absorption peaks at about 3,600 cm ⁻¹ to about 3,000 cm ⁻¹ , about 2,900 cm ⁻¹ , about 1,640 cm ⁻¹ , and about 1,590 cm ⁻¹ .
(Item 82)
3. A kit comprising a first container having the polymer composition of claim 2.
(Item 83)
83. The kit of claim 82, further comprising a second container having a calcium chloride solution.
(Item 84)
84. The kit according to item 83, wherein the calcium chloride solution is a 10% w/v aqueous calcium chloride solution.
(Item 85)
A polymer composition comprising: a. an alginate having a chain length between about 1,000 nm and about 3,000 nm and an average molecular weight of about 800 kDa; and b. a chitosan having a chain length between about 2,800 nm and about 2,900 nm and an average molecular weight of about 1,000 kDa.
(Item 86)
3. The polymer composition according to claim 2, wherein the chitosan is derived from a plant.
(Item 87)
3. The polymer composition according to claim 2, wherein the chitosan is derived from algae.
(Item 88)
41. A polymer composition made by the method of claim 40 having (a) about 0.0225 g/mL sodium alginate and (b) about 0.200 g/mL chitosan.
(Item 89)
41. A polymer composition made by the method of claim 40 having (a) about 0.021 g/mL sodium alginate and (b) about 0.190 g/mL chitosan.
(Item 90)
41. A polymer composition made by the method of claim 40 having (a) about 0.02247 g/mL sodium alginate and (b) about 0.200 g/mL chitosan.
(Item 91)
41. A polymer composition made by the method of claim 40 having (a) about 0.0212 g/mL sodium alginate and (b) about 0.1887 g/mL chitosan.
(Item 92)
3. The polymer composition of claim 2, wherein the chitosan is bound to a core comprising a polymeric material.
(Item 93)
3. The polymer composition of claim 2, wherein the polymer composition is attached to a core comprising poly-L-lactic acid.
(Item 94)
2. The polymer composition of claim 1, wherein the one or more polyanionic polymers comprise sodium alginate, the one or more polycationic polymers comprise diethylaminoethyl-dextran attached to a core of poly-L-lactic acid, and the solvent is water.
(Item 95)
3. The polymer composition of claim 2, further comprising methylparaben.

FIG. 1 is a schematic diagram showing the Fourier transform infrared spectrum of sodium alginate.

FIG. 2 is a schematic diagram showing the Fourier transform infrared spectrum of chitosan.

FIG. 3 is a schematic diagram showing the Fourier transform infrared spectrum of the biocompatible polymer composition of the present invention.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS The inventions disclosed herein are in the field of biocompatible polymer gel compositions useful for facilitating and maintaining hemostasis. Biocompatible polymer gel compositions generally include (a) a polyanionic polymer, (b) a polycationic polymer, and (c) a solvent.

Polyanionic polymers

Preferably, the polymer gel composition comprises from about 0.10% to about 5.00% by weight of a polyanionic polymer (or more than one polyanionic polymer). Preferably, the polymer gel composition comprises from about 1.00% to about 4.00% by weight of a polyanionic polymer; preferably, the polymer gel composition comprises from about 2.00% to about 3.00% by weight of a polyanionic polymer. The polymer gel composition may comprise a polyanionic polymer in an amount of about 0.10 wt%, about 0.15 wt%, about 0.20 wt%, about 0.25 wt%, about 0.30 wt%, about 0.35 wt%, about 0.40 wt%, about 0.45 wt%, about 0.50 wt%, about 0.55 wt%, about 0.60 wt%, about 0.65 wt%, about 0.70 wt%, about 0.75 wt%, about 0.80 wt%, about 0.85 wt%, about 0.90 wt%, about 0.95 wt%, about 1.00 wt%, about 1.05 wt%, about 1.10 wt%, about 1.15 wt%, about 1.20 wt%, About 1.25% by weight, about 1.30% by weight, about 1.35% by weight, about 1.40% by weight, about 1.45% by weight, about 1.50% by weight, about 1.55% by weight, about 1.60% by weight, about 1.65% by weight, about 1.70% by weight, about 1.75% by weight, about 1.80% by weight, about 1.85% by weight, about 1.90% by weight, about 1.95% by weight, about 2.00% by weight, about 2.05% by weight, about 2.10% by weight, about 2.15% by weight, about 2.20% by weight, about 2.25% by weight, about 2.30% by weight, about 2.35% by weight, about 2.40% by weight, about 2.45% by weight, about 2.50% by weight %, about 2.55 wt%, about 2.60 wt%, about 2.65 wt%, about 2.70 wt%, about 2.75 wt%, about 2.80 wt%, about 2.85 wt%, about 2.90 wt%, about 2.95 wt%, about 3.00 wt%, about 3.05 wt%, about 3.10 wt%, about 3.15 wt%, about 3.20 wt%, about 3.25 wt%, about 3.30 wt%, about 3.35 wt%, about 3.40 wt%, about 3.45 wt%, about 3.50 wt%, about 3.55 wt%, about 3.60 wt%, about 3.65 wt%, about 3.70 wt%, about 3.75 wt%, about 3.80 %, about 3.85 wt%, about 3.90 wt%, about 3.95 wt%, about 4.00 wt%, about 4.05 wt%, about 4.10 wt%, about 4.15 wt%, about 4.20 wt%, about 4.25 wt%, about 4.30 wt%, about 4.35 wt%, about 4.40 wt%, about 4.45 wt%, about 4.50 wt%, about 4.55 wt%, about 4.60 wt%, about 4.65 wt%, about 4.70 wt%, about 4.75 wt%, about 4.80 wt%, about 4.85 wt%, about 4.90 wt%, about 4.95 wt%, or about 5.00 wt%.

In one embodiment of the present invention, the polyanionic polymer may be polystyrene sulfonate (such as sodium polystyrene sulfonate), polyacrylate (such as sodium polyacrylate), polymethacrylate (such as sodium polymethacrylate), polyvinyl sulfate (such as sodium polyvinyl sulfate), polyphosphate (such as sodium polyphosphate), iota carrageenan, kappa carrageenan, gellan gum, carboxymethyl cellulose, carboxymethyl agarose, carboxymethyl dextran, carboxymethyl chitin, carboxymethyl chitosan, polymers modified with carboxymethyl groups, alginates (such as sodium alginate), polymers containing multiple carboxylate groups, xanthan gum, and combinations thereof. Preferably, the polyanionic polymer is an alginate, more preferably sodium alginate. In one embodiment, the polymer composition comprises about 2.25% by weight of alginate; in one embodiment, the polymer composition comprises about 2.50% by weight of alginate.

In one embodiment of the present invention, the polyanionic polymer has a chain length between about 1,000 nm and about 3,000 nm. The longer chain length of a particular polyanionic polymer aids in enhancing the ability of the composition to adhere to tissue when applied to a wound. Short chain polyanionic polymers may result in a biocompatible polymer gel composition that has difficulty or poor adhesion to wounds. 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 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, the surface area of the wound covering may decrease. Preferably, the polyanionic polymer comprises particles having an average particle size between 100 mesh and 270 mesh. Preferably, the polyanionic polymer comprises particles having an average particle size between 120 mesh and 250 mesh. Preferably, the polyanionic polymer comprises particles having an average particle size between 150 mesh and 200 mesh. Preferably, 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 a number average molecular weight (Mn) between 100 kDa and about 1,000 kDa. Preferably, the polyanionic polymer has a molecular weight between about 500 kDa and about 900 kDa. In a preferred embodiment, the polyanionic polymer has a molecular weight of about 800 kDa. Higher molecular weight polyanionic polymers increase the viscosity of the polymer gel composition and maintain its fluidity to resist collapse and prevent or reduce blood flow therethrough. 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) and about 2,000 cP in a 1% weight/volume (w/v) aqueous solution at about 25° C. Preferably, the polyanionic polymer has a viscosity of between about 100 cP and about 1,000 cP in a 1% w/v aqueous solution 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 aqueous solution at about 25° C. Preferably, the polyanionic polymer has a viscosity of about 1,000 cP in a 1% w/v aqueous solution at about 25° C.

The polyanionic polymer present in the polymer gel composition comprises a scaffold to which fibrin adheres. The morphology of the polyanionic polymer particles is preferably a mesh or a combination of fibrous particles to which fibrin can readily 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.

The polyanionic polymer may be obtained from a variety of commercial suppliers. However, the source of the polyanionic polymer may affect the likelihood that adventitious contaminants, such as prions, are present in the raw material. In one embodiment, the polyanionic polymer is obtained from an organic source. In a preferred embodiment, the polyanionic polymer is sodium alginate. In a preferred embodiment, the sodium alginate is obtained from a marine alga, such as Macrocystis pyrifera (kelp).

Polycationic polymers

Preferably, the polymer gel composition comprises about 5% to about 40% by weight of polycationic polymer (or more than one polycationic polymer). Preferably, the polymer gel composition comprises about 8% by weight of polycationic polymer; preferably, the polymer gel composition comprises about 22% by weight of polycationic polymer. The polymer 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 the polycationic polymer.

In one embodiment of the present invention, the polycationic polymer may be chitosan (such as chitosan chloride), chitin, diethylaminoethyl-dextran, diethylaminoethyl-cellulose, diethylaminoethyl-agarose, diethylaminoethyl-alginate, polymers modified with diethylaminoethyl groups, polymers containing multiple protonated amino groups, and polypeptides having an average residue isoelectric point greater than 7, and combinations thereof. Preferably, the polycationic polymer is chitosan; preferably, the polycationic polymer is chitosan chloride. Preferably, the polycationic polymer is diethylaminoethyl-dextran (DEAE-dextran).

In one embodiment of the invention, the polycationic polymer has a chain length between about 2,000 nm and about 4,000 nm. In a preferred embodiment, the polycationic polymer has a chain length between about 2,800 nm and about 2,900 nm. In a preferred embodiment, the polycationic polymer has a chain length between about 2,850 nm. In a preferred embodiment, the polycationic polymer has a chain length 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 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, the surface area of the wound covering may decrease. Preferably, the polycationic polymer comprises particles having an average particle size between 60 mesh and 400 mesh. Preferably, the polycationic polymer comprises particles having an average particle size between 80 mesh and 325 mesh. Preferably, the polycationic polymer comprises particles having an average particle size between 80 mesh and 120 mesh. Preferably, 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) between about 1 kDa and about 2,000 kDa. Preferably, the polycationic polymer has a molecular weight between about 1 kDa and about 1,000 kDa. Preferably, the polycationic polymer has a molecular weight between about 800 kDa and about 1,200 kDa. Preferably, the polycationic polymer has a molecular weight between about 900 kDa and about 1,100 kDa. In a preferred embodiment, the polycationic polymer has a molecular weight of about 1,000 kDa. The molecular weight of the polycationic polymer affects its ability to retain a charge, with the higher the molecular weight the greater the charge density, thus positively affecting 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 and about 1,000 cP in a 1% weight/volume (w/v) solution of 5% acetic acid at about 25° C. Preferably, the polycationic polymer has a viscosity of between about 50 cP and about 1,000 cP in a 1% w/v solution of 5% acetic acid at about 25° C. The polycationic polymer has 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 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 P, 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 5 00 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. Preferably, the polycationic polymer has a viscosity of about 80 cP in a 5% acetic acid solution at about 25° C., 1% w/v.

The polycationic polymer particles present in the polymer gel composition include a surface to which cells may adhere to allow platelet aggregation. The greater the surface area of the polycationic polymer particles, the faster hemostasis may occur. The morphology of the polycationic polymer particles is preferably spherical with pores, allowing aggregation both inside as well as outside the particle. The polycationic polymer particles may have a morphology that is fibrous, crystalline, amorphous, spherical, cuboidal, or a combination thereof.

The polycationic polymer may be attached or functionalized to a core of a different material, such as a polymeric material. In one embodiment, the core is an inert core. In one embodiment, the core is poly-L-lactic acid. Attaching the polycationic polymer to the core reduces the amount of polycationic polymer required to achieve a given surface area, for example, compared to a solid particle of a given polycationic polymer. Attaching the polycationic polymer to the core may also enable geometries that would not normally be possible or practical without the core. In one embodiment, a cube-like core is coated with chitosan to provide a cube-like geometry of chitosan - where chitosan does not form a cube-like geometry by itself under normal conditions. Attaching the polycationic polymer to the core may also allow the polycationic polymer to exist in a crystalline form in a biocompatible polymer gel composition when such a polymer would not normally be able to exist as a crystal based on the conditions in the composition. In one embodiment, the poly-L-lactic acid core is conjugated to diethylaminoethyl-dextran (DEAE-dextran) and used in a stable biocompatible polymer gel composition with alginate - where DEAE-dextran is unable to form crystals by itself under normal conditions and is unable to form a stable gel when used with alginate alone. In a preferred embodiment, the one or more polycationic polymers comprise diethylaminoethyl-dextran conjugated as a coating to the poly-L-lactic acid core; the one or more polycationic polymers comprise diethylaminoethyl-dextran covalently conjugated to the poly-L-lactic acid core.

The polycationic polymer may be obtained from a variety of commercial suppliers. However, the source of the polycationic polymer may affect the likelihood that adventitious contaminants such as prions are present in the raw material. 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. The chitosan may be obtained from a plant source. In one embodiment, the chitosan is obtained from algae. In a preferred embodiment, the polycationic polymer is chitosan and is obtained from fungi such as the genus Pleurotus. In a preferred embodiment, the polycationic polymer is chitosan and is obtained from a marine invertebrate. In one embodiment, the polycationic polymer is chitosan and is obtained from Aspergillus niger.

When the polycationic polymer is chitosan, the degree of deacetylation is a factor that affects the properties of the polymer gel composition. Chitosan is a commonly known analogue of chitin, and the degree of deacetylation of chitin corresponds to hemostatic efficacy. In one embodiment, the chitosan has an average degree of deacetylation between about 75.0% and about 99.5%. Preferably, the chitosan has an average degree of deacetylation between about 75.0% and about 85.0%. Preferably, the chitosan has an average degree of deacetylation between about 78.0% and about 83.0%. Preferably, the chitosan has an average degree of deacetylation between about 80.0% and about 81.0%. Preferably, the chitosan has an average degree of deacetylation of 80.5%. Chitosan is 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 It may have an average degree of deacetylation of 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%.

Solvent

The biocompatible polymer compositions of the present invention contain between about 50.0% and about 90.0% by weight of a solvent. Preferably, the composition contains between about 50.0% and about 90.0% of a solvent; preferably, the composition contains between about 60.0% and about 90.0% of a solvent; preferably, the composition contains between about 75.0% and about 90.0% of a solvent. The solvent may be present in the biocompatible polymer composition at about 50.0%, about 50.5%, about 51.0%, about 51.5%, about 52.0%, about 52.5%, about 53.0%, about 53.5%, about 54.0%, about 54.5%, about 55.0%, about 55.5%, about 56.0%, about 56.5%, about 57.0%, about 57.5%, about 58.0%, about 58.5%, about 59.0%, about 59.5%, about 60.0%, about 60.5%, about 61.0%, about 61.5%, about 62.0%, about 62.5%, about 63.0%, about 63.5%, about 64.0%, about 64.5%, about 65.0%, about 65.5%, about 66.0%, about 66.5%, about 67.0%, about 67.5%, about 68.0%, about 68.5%, about 69.0%, about 70.0%, about 71.0%, about 72.5%, about 73.0%, about 74.0%, about 75.0%, about 76.0%, about 77.0%, about 78.0%, about 79.0%, about 80.0%, about 81.0%, about 82.5%, about 83.0%, about 84.0%, about 85.0%, about 86.0%, about 87.0%, about 88.0%, about 89.0%, about 90.0%, about 91.0%, about 92.0%, about 93.0%, about 94.0%, about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.0%, about 91.0%, about .5%, about 62.0%, about 62.5%, about 63.0%, about 63.5%, about 64.0%, about 64.5%, about 65.0%, about 65.5%, about 66.0%, about 66.5%, about 67.0%, about 67.5%, about 68.0%, about 68.5%, about 69.0%, about 69.5%, about 70.0%, about 70.5%, about 71.0%, about 71.5%, about 72.0%, about 72.5%, about 73.0%, about 73.5%, about 74.0%, about 74.5% %, 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%, It may be present in an amount of 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%.

Non-limiting examples of solvents include water, ethanol, amyl acetate, acetone, methyl ethyl ketone, isopropanol, tetrahydrofuran, and combinations thereof. Preferably, the solvent is polar. Preferably, the solvent is pH neutral (about 7.0). Preferably, the solvent is water. Preferably, when the solvent is water, the solvent is present in the biocompatible polymer composition in an amount of about 89.5%. Preferably, when the solvent is water, the solvent is present in the biocompatible polymer composition in an amount between about 77.0% and about 78.0%.

Biocompatible polymer composition

The biocompatible polymer composition may be a gel comprising between about 0.1% and about 5% by weight of one or more polyanionic polymers, between about 10% and about 40% by weight of one or more polycationic polymers; and between about 50% and 99.9% by weight of a solvent.

In a preferred embodiment, the biocompatible polymer gel composition comprises (a) between about 0.0200 g/mL and about 0.0230 g/mL of one or more polyanionic polymers, and (b) between about 0.185 g/mL and about 0.210 g/mL of one or more polycationic polymers. In a preferred embodiment, the biocompatible polymer gel composition comprises (a) between about 0.0200 g/mL and about 0.0230 g/mL of sodium alginate, and (b) between about 0.185 g/mL and about 0.210 g/mL of chitosan. In a preferred embodiment, the biocompatible polymer gel composition comprises about 0.02247 g/mL of one or more polyanionic polymers, and about 0.200 g/mL of one or more polycationic polymers. In a preferred embodiment, the biocompatible polymer gel composition comprises about 0.02247 g/mL sodium alginate and about 0.200 g/mL chitosan, measured as anhydrous powders. In a preferred embodiment, the biocompatible polymer gel composition comprises about 0.0225 g/mL sodium alginate and about 0.200 g/mL chitosan, measured as anhydrous powders. In a preferred embodiment, the biocompatible polymer gel composition comprises about 0.0212 g/mL one or more polyanionic polymers and about 0.1887 g/mL one or more polycationic polymers, measured as anhydrous powders. In a preferred embodiment, the biocompatible polymer gel composition comprises about 0.0212 g/mL sodium alginate and about 0.1887 g/mL chitosan, measured as anhydrous powders. In a preferred embodiment, the biocompatible polymer gel composition contains about 0.021 g/mL sodium alginate and about 0.190 g/mL chitosan, measured as anhydrous powders. The preferred solvent is water.

The biocompatible polymer gel composition of the present invention can clot blood quickly while maintaining a strong clot. Clot strength is the primary metric for biocompatible polymer compositions. The Sonoclot coagulation analyzer (sold by Sienco as the Sonoclot Analyzer) is recognized as a suitable method for testing the efficacy of hemostatic devices. The clot strength of the clot formed increases over time depending on the activating factor to which the clot is exposed. The clot strength of a clot on a wound exposed to the biocompatible polymer composition of the present invention can be 50% higher than the strength of a clot formed without exposure to the composition of the present invention. In a preferred embodiment, the clot strength of a clot on a wound exposed to the biocompatible polymer composition of the present invention is about 90 to about 200 clot strength units (CSU) at t=15 minutes.

Time to clot is another key metric for the usefulness of biocompatible polymer compositions. Clot strength (and clot strength units) increases over time. Hemostasis in a wound should be achieved quickly so that blood loss is minimized. The biocompatible polymer composition facilitates hemostasis when applied to a wound, and preferably the clotting time is achieved in 120 seconds or less, preferably 90 seconds or less, preferably 60 seconds or less, preferably 30 seconds or less, preferably 15 seconds or less. The clotting time of a wound exposed to the biocompatible polymer composition of the present invention is about 190% faster than the clotting time of a wound not exposed to the composition of the present invention. The biocompatible polymer composition preferably allows blood to clot in vitro in 120 seconds or less, preferably 90 seconds or less, preferably 60 seconds or less, preferably 30 seconds or less, preferably 15 seconds or less. The clotting time of blood exposed to the biocompatible polymer composition of the present invention (in vitro) is about 190% faster than the clotting time of blood not exposed to the composition of the present invention (in vitro). In one embodiment, about 13 mg or more of the composition of the present invention clots about 0.34 mL of blood in vitro.

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

Biocompatible polymer gel compositions can be characterized by a variety of methods, including viscosity, pH, Fourier transform infrared (FTIR) spectroscopy, and chemical analysis.

The biocompatible polymer composition of the present invention preferably has a viscosity of between about 145,000 (centipoise) cP and about 250,000 cP at about 25° C. In a preferred embodiment, the biocompatible polymer composition has a viscosity of between about 165,000 cP and about 174,000 cP at about 25° C. In a preferred embodiment, the biocompatible polymer composition has a viscosity of between about 169,000 cP and about 170,000 cP at about 25° C. In a preferred embodiment, the biocompatible polymer composition has a viscosity of about 169,500 cP at about 25° C. The preferred viscosity allows for maximum adhesive ability, which affects performance. Small changes in viscosity can have a substantial effect on the efficacy of the product. The biocompatible polymer composition has 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 1 64,000 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 170,50 0 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 P, 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 19 7,500 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 204,0 00 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 P, 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 2 31,000 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 237,50 0 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, It may have a viscosity of 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.

In a preferred embodiment, the polyanionic polymer is sodium alginate having a chain length 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 aqueous solution at about 25° C., comprises particles having an average particle size of about 180 mesh with an amorphous morphology, and is sourced from seaweed.

In a preferred embodiment, the polycationic polymer is chitosan having an average degree of deacetylation of about 80.5%, a chain length of about 2,850 nm, a molecular weight of about 1,000 kDa, a viscosity of about 80 cP in a 1% w/v solution in 5% acetic acid at about 25° C., comprises particles having an average particle size of about 100 mesh with porous and spherical morphology, and is sourced from a marine invertebrate.

In a preferred embodiment, the solvent is water.

The biocompatible polymer composition of the present invention preferably has a pH between about 6.0 and about 8.0, preferably between about 6.5 and about 7.5, preferably between about 6.8 and about 7.2, preferably about 7.0.

The FTIR spectra of the preferred components alginate and chitosan are shown in Figures 1 and 2, respectively. The FTIR spectrum of the preferred biocompatible polymer gel composition is shown in Figure 3.

1 is a schematic diagram showing the Fourier transform infrared spectrum of a preferred sodium alginate. The main absorption peaks appear as follows: a broad peak at about 3,600 cm ⁻¹ to about 3,000 cm ⁻¹ for —OH stretching vibration, at about 2,900 cm ⁻¹ for C—H stretching vibration, at about 1,600 cm ⁻¹ for C═O stretching vibration of the carboxyl group, at about 1,400 cm ⁻¹ for carboxyl group stretching vibration overlapping with C—H bending, and a number of peaks around 1,000 cm ⁻¹ for C—O vibration corresponding to the polysaccharide structure.

2 shows a schematic Fourier transform infrared spectrum of a preferred chitosan. The absorption peaks appear as follows: a broad peak at about 3,600 cm ⁻¹ to about 3,000 cm ⁻¹ for the O—H stretching vibration overlapping with the N—H stretching vibration, at about 2,910 cm ⁻¹ and about 2,870 cm ⁻¹ for the C—H stretching vibration, at about 1,650 cm ⁻¹ for the C═O stretching vibration of amide, at about 1,580 cm ⁻¹ for the N—H bending, multiple peaks at about 1,400 cm ⁻¹ for the C—H bending, and multiple peaks at about 1,000 cm ⁻¹ for the C—O vibration corresponding to the polysaccharide structure.

3 is a schematic diagram showing the Fourier transform infrared spectrum of a preferred biocompatible polymer composition, with the absorption peaks appearing as follows: a broad peak at about 3,600 cm ⁻¹ to about 3,000 cm ⁻¹ for O—H stretching vibrations overlapping with N—H stretching vibrations, at about 2,900 cm ⁻¹ for C—H stretching vibrations, at about 1,640 cm ⁻¹ for C═O stretching vibrations, at about 1,590 cm ⁻¹ for N—H bending, multiple peaks around 1,400 cm ⁻¹ for C—H bending, and multiple peaks around 1,000 cm ⁻¹ for C—O vibrations corresponding to the polysaccharide structure.

The biocompatible polymer composition of the present invention is intended to be stored at about 25° C. In one embodiment, the biocompatible polymer composition has a density of between about 1.00 and 1.40 g/mL at about 25° C. In one embodiment, the biocompatible polymer composition has a density of between about 1.10 and 1.30 g/mL at about 25° C. In one embodiment, the biocompatible polymer composition has a density of between about 1.20 and 1.22 g/mL at about 25° C. A preferred biocompatible polymer composition gel has a density of about 1.21 g/mL at about 25° C. The biocompatible polymer composition has a viscosity 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 2.2 ... It may have a density of about 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.

The biocompatible polymer composition of the present invention has a modulus of elasticity between about 6 kPa and about 23 kPa. In one embodiment, the biocompatible polymer composition has a modulus of elasticity of about 16 kPa. The biocompatible polymer composition may have a modulus of elasticity 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, or about 23 kPa.

Preferred storage medium containers for the biocompatible polymeric composition include syringes, packets, sachets, tubes, tubs, pumps, bottles, and bags. Preferably, the polymeric composition is sterile and suitable for human and animal application. One preferred storage medium is a 5 mL syringe (sterile); one preferred storage medium is a 10 mL syringe (sterile).

The biocompatible polymer composition may further comprise optional ingredients such as antimicrobial agents, preservatives, or therapeutic agents. The composition may comprise silver salts, metal or carbon nanoparticles, antibiotics, hormones, proteins (such as calreticulin, thrombin, prothrombin, factor VIII, etc.), methylparaben, chlorocresol, cetrimide, and iodine, and combinations thereof. In one embodiment, the composition further comprises iodine. In one embodiment, the composition further comprises silver nitrate. In one embodiment, the composition further comprises methylparaben.

Production method

The production of the biocompatible polymer composition generally proceeds as follows: First, one or more polyanionic polymers are mixed with a solvent for a time until the desired viscosity is reached at about 25° C. The polyanionic mixing may be performed at between about 20 revolutions per minute (RPM) and about 80 RPM, preferably about 48 RPM. After this first mixing step, one or more polycationic polymers are added to the mixture and the components are mixed for a time until the final desired viscosity is reached at about 25° C.; this mixing may be performed at between about 40 RPM and about 100 RPM, preferably about 62 RPM. In a preferred embodiment, the mixing during the first mixing period is performed at a slower speed than the mixing during the second mixing period.

In one preferred embodiment, sodium alginate is mixed in a tank with water to reach a desired viscosity at about 25°C. This mixing occurs at about 48 RPM for about 6 hours under low shear mixing. After the sodium alginate and water are mixed, chitosan is added. The mixture containing chitosan is mixed at about 25°C for about 1 hour under faster mixing than the sodium alginate/water mixing. Preferably, after chitosan is incorporated, mixing occurs at about 62 RPM.

Preferably, chitosan should not be incorporated simultaneously with the sodium alginate and water, as chitosan particles are porous and tend to pull water out of solution. Simultaneous mixing of all three components (as opposed to mixing water and sodium alginate first) results in less potent gels that are thicker than desired and may contain undissolved sodium alginate. Such gels may contain compressible colloids of sodium alginate and wet chitosan that may exhibit cross-linking problems and poor tissue adhesion.

In a preferred embodiment, the biocompatible polymer composition is a colloidal gel with solid particles dispersed in a solution. It is believed that the flowability of the gel allows it to aid in covering the wound surface area because it conforms to the injury site better than a solid (such as gauze or sponge) while allowing the solid particles to act as a weight to mechanically impede bleeding through the fluid, thus aiding in better adhesion/cohesion.

Kit

The packaging of the biocompatible polymer composition of the present invention, for example in a kit or article of manufacture, and the application device for any embodiment of the present disclosure, can be selected and manufactured by the skilled artisan based on his general knowledge and adapted according to the nature of the composition to be packaged. Furthermore, the type of device used may be particularly related to the consistency of the composition, in particular its viscosity; it may also depend on the nature of the components present in the composition.

The kit or article of manufacture may include, but is not limited to, the composition of the invention, a device for applying the composition of the invention, instructions for use and application of the composition of the invention, one or more additional solutions, a list of ingredients and/or warnings, etc. In one embodiment, the kit includes a 5 mL syringe filled with the biocompatible polymer gel of the invention along with another syringe containing a 10% w/v calcium chloride solution in water.

While the present invention has been illustrated and described in many embodiments varying in scope, it will be readily apparent to those skilled in the art that modifications may be made within the spirit and scope of the invention. Accordingly, the scope of the invention as set forth in the appended claims is not intended to be limited by any specific wording in the foregoing description, except as expressly set forth.

how to use

In the primary method of using the polymer gels of the present invention, the gels are applied to wounds including, for example, external lacerations, abrasions, burns, eye lacerations, parenchymal organ injuries, internal lacerations, lacerations of the gastrointestinal tract, superficial cuts and abrasions, internal bleeding, arterial bleeding, venous bleeding, dental or oral bleeding, and incisions. The polymer gels of the present invention are useful in treating a variety of wounds, including those caused unintentionally (accidents or unintentional injuries) and those caused intentionally (such as surgery).

In the primary method of using the polymer gel of the present invention, the gel is applied directly to the bleeding wound surface. When applied to a volume of blood, the gel will aid in blood clotting at the gel-blood interface. Efficacy may be reduced if the gel is relatively close to the wound site when the product is applied but is not in direct contact with the bleeding wound surface. Due to the gel's viscosity, practitioners may preferentially use a syringe with a large bore to quickly apply a significant amount of gel. The gel may be dispensed through a catheter (such as 16 gauge or larger) during a laparoscopic procedure. In another embodiment, the polymer gel of the present invention may be dispensed across a gauze pad to increase the surface area of exposed gel to treat large surface bleeding.

Subjects that may benefit from wound treatment using the polymer compositions of the present invention include a variety of animals, including humans, mammals such as horses, sheep, cows, pigs, dogs, and cats, marine animals such as whales, dolphins, sea lions, otters, and fish, and reptiles such as turtles.

After application of the composition to the wound, the composition may be crosslinked by adding divalent or higher cations. Addition of divalent or higher cations may aid in removal of the product from the wound site. The divalent or higher cations may be one or more of Ca2+, Fe2+, Fe3+, Ag2+, Ag3+, Au2+, Au3+, Mg2+, Cu2+, Cu3+, and Zn2+. In one embodiment of the present invention, the cation is Ca2+. In a preferred embodiment, the divalent or higher cations are delivered in solution. The divalent or higher cations may be present in the solution at about 0.1% to about 30% w/v. Preferably, the solvent is water. In a preferred embodiment, a 10% w/v aqueous solution of calcium chloride may be used.

In one form of generating a biocompatible gel, an operator received a beaker, a stir bar, 106 mL of water, 2.247 g of sodium alginate, and 20 g of chitosan. 106 mL of water was added to the beaker. The operator slowly added 50 mg of sodium alginate at a time, followed by vigorous hand stirring for 2 minutes. This stirring was continued until all of the sodium alginate was incorporated and dissolved in the water. The sodium alginate and aqueous solution was allowed to sit for less than 6 hours to ensure complete dissolution. Once complete dissolution was confirmed, the operator slowly added 50 mg of chitosan at a time, followed by vigorous hand stirring for 2 minutes. This stirring was continued until all of the chitosan was incorporated and the solution was evenly mixed.

Claims (9)

A polymer composition comprising:
a. 1% to 5% by weight of sodium alginate;
b. 10% to 30% by weight of chitosan, the chitosan having an average degree of deacetylation between 75.0% and 99.5%; and c. 50% to 89% by weight of a solvent, the solvent in the polymer composition consisting of water;
The sodium alginate is dissolved in the water to form a solution, and the polymer composition is a colloidal gel with solid chitosan particles dispersed in the solution. The polymer composition of claim 1, wherein the composition exhibits an in vitro hemostatic effect in less than 30 seconds when introduced into blood. The polymer composition of claim 1, having a density between 1.10 g/mL and 1.30 g/mL at 25°C. The polymer composition of claim 1, wherein 13 mg or more of the composition clots 0.34 mL of blood in vitro. The polymer composition of claim 1, having an elastic modulus of 16 kPa. 13. A method of making the polymer composition of claim 1, comprising:
A method comprising the steps of: a. mixing sodium alginate with water to create a first mixture, wherein the sodium alginate is dissolved in the water in the first mixture; and b. adding chitosan to the first mixture to provide the polymer composition. The polymer composition of claim 1 for use in facilitating and maintaining hemostasis. 1. A polymeric composition for use in facilitating and maintaining hemostasis, the polymeric composition comprising:
a. Sodium alginate;
b. chitosan; and c. a polymeric composition comprising water as a solvent, the solvent in said polymeric composition consisting of water, said polymeric composition being a colloidal gel with solid particles of chitosan dispersed in a solution of said sodium alginate dissolved in said water, the flowability of said gel allowing it to assist in covering the wound surface area and allowing said solid particles of chitosan to act as a weight to prevent bleeding. 9. The polymer composition for use according to claim 7 or claim 8 , wherein said hemostasis comprises stopping arterial bleeding, venous bleeding, dental bleeding or oral bleeding.