TWI769136B - Highly efficacious hemostatic adhesive polymer scaffold - Google Patents

Abstract

The invention relates to biocompatible polymer gel compositions useful in facilitating and maintaining hemostasis. The biocompatible polymeric gel composition is comprised of (a) one or more than one polyanionic polymer, (b) one or more than one polycationic polymer, and (c) a solvent. A preferred composition includes sodium alginate, chitosan, and water to produce an adhesive hemostatic device that is useful in facilitating and maintaining rapid hemostasis.

Description

Highly effective hemostatic adhesive polymer stent

Hemostasis is a complex, multi-stage mechanism involving a concerted effort in terms of numerous cell types and scaffold structures to initiate the production of an initial platelet plug at the wound site and then to grow a fully mature clot capable of blocking blood flow. Hemostasis is usually divided into three phases: initial hemostasis, coagulation cascade, and fibrinolysis. Initially, after platelets adhere to the collagen fibers surrounding the damaged surface, platelet plugs form in response to exposed endothelial cells at the surface. Exposure to collagen "activates" platelets, promoting their release of coagulation factors that allow the coagulation cascade to proceed. At the end of the process, thrombin cleaves fibrinogen, forming the building block of the clot (called fibrin).

A significant challenge in treating bleeding wound surfaces presents the adhesive properties of the physical barrier components of a given hemostatic device. If the continuous blood flow is particularly strong, hemostasis can be interrupted because immature platelet plugs and fibrin clots can rupture in the process. This difficulty can be exacerbated if the hemostatic device lacks sufficient adhesiveness and a partially formed plug or clot is prematurely detached from the wound site. Various hemostatic devices attempt to increase adhesive strength by dewatering the wound site with a drying device. These devices delay epithelialization and, in turn, significantly slow wound healing.

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

The present invention is a biocompatible polymer combination that can be used to promote and maintain hemostasis thing.

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

Various properties associated with each component of the biocompatible polymeric 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 solvents include pH and polarity. Final biocompatible polymer composition properties include viscosity, hemostatic efficiency, burst strength and pH.

Factors that affect the properties of the final product include the amount of each component and the method of manufacture.

Figure 1 schematically illustrates the Fourier Transform Infrared spectrum of sodium alginate.

Figure 2 schematically illustrates the Fourier transform infrared spectrum of chitosan.

Figure 3 schematically illustrates the Fourier transform infrared spectrum of the biocompatible polymeric composition of the present invention.

The invention disclosed herein is a class of biocompatible polymer gel compositions that can be used to promote and maintain hemostasis. Biocompatible polymeric gel compositions typically comprise (a) a polyanionic polymer, (b) a polycationic polymer, and (c) a solvent.

polyanionic polymer

Preferably, the polymeric gel composition comprises from about 0.10% to about 5.00% by weight of the polymer Anionic polymer (or more than one polyanionic polymer). Preferably, the polymeric gel composition comprises from about 1.00% to about 4.00% by weight of the polyanionic polymer; preferably, the polymeric gel composition comprises from about 2.00% to about 3.00% by weight of the polyanionic polymer thing. The polymeric gel composition may comprise by weight 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% polyanionic polymer.

卡拉膠(carrageenan)、κ卡拉膠、結蘭膠(gellan gum)、羧甲基纖維素、羧甲基瓊脂醣、羧甲基聚葡萄 糖、羧甲基幾丁質、羧甲基幾丁聚醣、經羧甲基修飾之聚合物、海藻酸鹽(例如海藻酸鈉)、含有複數個羧酸鹽基團之聚合物、黃原膠及其組合。較佳地，聚陰離子聚合物係海藻酸鹽、更佳海藻酸鈉。在一個實施例中，聚合組合物包含以重量計約2.25%海藻酸鹽；在一個實施例中，聚合組合物包含以重量計約2.50%海藻酸鹽。 In one embodiment of the present invention, the polyanionic polymer may be polystyrene sulfonate (eg sodium polystyrene sulfonate), polyacrylate (eg sodium polyacrylate), polymethacrylate (eg polymethyl methacrylate) polyacrylate), polyvinyl sulfate (such as sodium polyvinyl sulfate), polyphosphate (such as sodium polyphosphate),

Carrageenan, kappa carrageenan, gellan gum, carboxymethyl cellulose, carboxymethyl agarose, carboxymethyl polydextrose, carboxymethyl chitin, carboxymethyl chitosan , carboxymethyl-modified polymers, alginates (eg, sodium alginate), polymers containing multiple carboxylate groups, xanthan gum, and combinations thereof. Preferably, the polyanionic polymer is alginate, more preferably sodium alginate. In one embodiment, the polymeric composition comprises about 2.25% by weight alginate; in one embodiment, the polymeric composition comprises about 2.50% by weight alginate.

In one embodiment of the present invention, the chain length of the polyanionic polymer is between about 1,000 nm and about 3,000 nm. The increased chain length of certain polyanionic polymers helps to increase the ability of the composition to adhere to tissue when applied to a wound. Short chain polyanionic polymers can produce biocompatible polymeric gel compositions with difficult or poor adhesion to wounds. The chain length of the polyanionic polymer can be about 1,000 nm, about 1,100 nm, about 1,200 nm, about 1,300 nm, about 1,400 nm, about 1,500 nm, about 1,600 nm, about 1,700 nm, about 1,800 nm, about 1,900 nm, about 2,000 nm, about 2,100 nm, about 2,200 nm, about 2,300 nm, about 2,400 nm, about 2,500 nm, about 2,600 nm, about 2,700 nm, about 2,800 nm, about 2,900 nm, 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 cells adhering to the polymer increases. However, as the particle size of the polyanionic polymer increases, this can reduce the surface area covered by the wound. Preferably, the polyanionic polymer comprises particles with an average particle size between 100 mesh and 270 mesh. Preferably, the polyanionic polymer comprises particles with an average particle size between 120 mesh and 250 mesh. Preferably, the polyanionic polymer comprises particles with 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 average particle size of the polyanionic polymer can be about 80 mesh, about 100 mesh, about 120 mesh, about 150 mesh, about 180 mesh, about 200 mesh, about 250 mesh, or about 270 mesh.

In one embodiment, the number average molecular weight (Mn) of the polyanionic polymer is between 100 kDa and about 1,000 kDa. Preferably, the molecular weight of the polyanionic polymer is between about 500 kDa and about 900 kDa. In preferred embodiments, the polyanionic polymer The molecular weight is about 800kDa. Higher molecular weight polyanionic polymers will increase the viscosity of the polymeric gel composition and will maintain its flowability to resist rupture and prevent or reduce the passage of blood therethrough. The molecular weight of the polyanionic polymer can be 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 viscosity of the polyanionic polymer is between about 100 centipoise (cP) to about 2,000 cP in a 1% weight/volume (w/v) aqueous solution at about 25°C. Preferably, the viscosity of the polyanionic polymer is between about 100 cP to about 1,000 cP in a 1% w/v aqueous solution at about 25°C. The viscosity of the polyanionic polymer can be 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 1,000cP, about 1,100cP, about 1,200cP, about 1,300cP, about 1,400cP, about 1,500cP, about 1,600cP, about 1,700cP, about 1,800cP, about 1,900cP, or about 2,000cP. Preferably, the viscosity of the polyanionic polymer is about 1,000 cP in a 1% w/v aqueous solution at about 25°C.

The polyanionic polymer present in the polymeric gel composition comprises a scaffold to which fibrin adheres. The morphology of the polyanionic polymer particles is preferably a network or combination of fibrous particles to which fibrin can readily adhere and form a patch at the wound bed. The morphology of the polyanionic polymer particles can be fibrous, crystalline, amorphous, spherical, cubic, or combinations thereof.

Polyanionic polymers are available from various suppliers. However, the source of the polyanionic polymer can affect the likelihood of foreign contaminants (eg, prion) being 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 sea Sodium alginate is obtained from marine algae such as Macrocystis pyrifera (kelp).

polycationic polymer

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

In one embodiment of the present invention, the polycationic polymer may be chitosan (eg chlorinated chitosan), chitin, diethylaminoethyl-polydextrose, diethylaminoethyl Alginate-cellulose, diethylaminoethyl-agarose, diethylaminoethyl-alginate, diethylaminoethyl-modified polymers, polymers containing multiple protonated amine groups Polypeptides with an average residue isoelectric point higher than 7 and combinations thereof. Preferably, the polycationic polymer is chitosan; preferably, the polycationic polymer is chlorinated chitosan. Preferably, the polycationic polymer is diethylaminoethyl-polydextrose (DEAE-polydextrose).

In one embodiment of the present invention, the chain length of the polycationic polymer is between about 2,000 nm and about 4,000 nm. In a preferred embodiment, the chain length of the polycationic polymer is between about 2,800 nm and about 2,900 nm. In a preferred embodiment, the chain length of the polycationic polymer is about 2,850 nm. In a preferred embodiment, the chain length of the polycationic polymer is about 2,849 nm. The chain length of the polycationic polymer can be about 2,000 nm, about 2,100 nm, about 2,200 nm, about 2,300 nm, about 2,400 nm, about 2,500 nm, about 2,600 nm, about 2,700 nm, about 2,800 nm, about 2,900 nm, about 3,000nm, about 3,100nm, about 3,200nm, about 3,300nm, about 3,400nm, about 3,500nm, about 3,600 nm, about 3,700 nm, about 3,800 nm, about 3,900 nm, 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 cells adhering to the polymer increases. However, as the particle size of the polycationic polymer increases, this reduces the surface area covered by the wound. Preferably, the polycationic polymer comprises particles with an average particle size between 60 mesh and 400 mesh. Preferably, the polycationic polymer comprises particles with an average particle size between 80 mesh and 325 mesh. Preferably, the polycationic polymer comprises particles with 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 average particle size of the polycationic polymer can be about 50 mesh, about 60 mesh, about 80 mesh, about 100 mesh, about 120 mesh, about 150 mesh, about 180 mesh, about 200 mesh, about 250 mesh, about 270 mesh, About 325 mesh, about 400 mesh 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 molecular weight of the polycationic polymer is between about 1 kDa and about 1,000 kDa. Preferably, the molecular weight of the polycationic polymer is between about 800 kDa and about 1,200 kDa. Preferably, the molecular weight of the polycationic polymer is between about 900 kDa and about 1,100 kDa. In a preferred embodiment, the molecular weight of the polycationic polymer is about 1,000 kDa. The molecular weight of the polycationic polymer affects its ability to carry charges, and the larger the molecular weight, the greater the charge density, which in turn positively affects hemostasis. The molecular weight of the polycationic polymer can be 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 viscosity of the polycationic polymer in a 1% weight/volume (w/v) solution of 5% acetic acid at about 25°C is between about 10 cP to about 1,000 cP. better Typically, the viscosity of the polycationic polymer in a 1% w/v solution of 5% acetic acid at about 25°C is between about 50 cP to about 1,000 cP. The viscosity of the polycationic polymer in a 1% w/v solution of 5% acetic acid at about 25°C can be 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 90cP, about 100cP, about 110cP, about 120cP, about 130cP, about 140cP, about 150cP, about 160cP, about 170cP, about 180cP, about 190cP, about 200cP, about 210cP, about 220cP, about 230cP, about 240cP, about 250cP, about 260cP, about 270cP, about 280cP, about 290cP, about 300cP, about 310cP, about 320cP, about 330cP, about 340cP, about 350cP, about 360cP, about 370cP, about 380cP, about 390cP, about 400cP, about 410cP, about 420cP , about 430cP, about 440cP, about 450cP, about 460cP, about 470cP, about 480cP, about 490cP, about 500cP, about 510cP, about 520cP, about 530cP, about 540cP, about 550cP, about 560cP, about 570cP, about 580cP, about 590cP, about 600cP, about 610cP, about 620cP, about 630cP, about 640cP, about 650cP, about 660cP, about 670cP, about 680cP, about 690cP, about 700cP, about 710cP, about 720cP, about 730cP, about 740cP, about 750cP, about 760cP, about 770cP, about 780cP, about 790cP, about 800cP, about 810cP, about 820cP, about 830cP, about 840cP, about 850cP, about 860cP, about 870cP, about 880cP, about 890cP, about 900cP, about 910cP, about 920cP , 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 viscosity of the polycationic polymer in a 1% w/v solution of 5% acetic acid at about 25°C is about 80 cP.

The polycationic polymer particles present in the polymeric gel composition comprise a surface to which cells can adhere to allow platelet aggregation. The larger surface area of the polycationic polymer particles can accelerate hemostasis. The morphology of the polycationic polymer particles is preferably spherical with pores and allows aggregation inside and outside the particles. The morphology of the polycationic polymer particles can be fibrous, crystalline, amorphous, spherical, cubic, or combinations thereof.

Polycationic polymers can also be bound or functionalized to the core of different materials such as polymeric substances. In one embodiment, the core is an inert core. In one embodiment, the core is poly-L-lactic acid. Binding the polycationic polymer to the core can, for example, reduce the amount of polycationic polymer required to achieve a given surface area compared to solid particles of a given polycationic polymer. Binding the polycationic polymer to the core may also allow for geometries that would otherwise be impossible or impractical in the absence of the core. In one embodiment, the cubic core is encapsulated in chitosan to obtain a cubic geometry of chitosan, wherein the chitosan itself would not form a cubic geometry under ordinary conditions. Binding this polymer to the core may also allow the polycationic polymer to exist in crystalline form within the biocompatible polymer gel composition when conditions in the polycationic polymer-based composition would not otherwise exist as crystals. In one embodiment, a core of poly-L-lactic acid is bonded to diethylaminoethyl-polydextrose (DEAE-polydextrose) and used in a stable biocompatible polymer gel composition comprising alginate Among them, DEAE-polydextrose by itself cannot form crystals under ordinary conditions and cannot form stable gels when used only with alginate. In a preferred embodiment, one or more polycationic polymers comprise diethylaminoethyl-polydextrose as a coating bonded to the core of poly-L-lactic acid; one or more polycationic polymers comprise covalent Diethylaminoethyl-polydextrose attached to the core of poly-L-lactic acid.

Polycationic polymers are available from various suppliers. However, the source of the polycationic polymer can affect the likelihood of foreign contaminants such as prion proteins being present in the raw material. In one embodiment, the polycationic polymer is obtained from an organic source. When the polycationic polymer is chitosan, it can be obtained from crustaceans, fungi, insects and other organisms. Chitosan can also be obtained from plant sources. In one embodiment, chitosan is obtained from algae. In a preferred embodiment, the polycationic polymer is chitosan and is obtained from a fungus (eg, Pleurotus). In a preferred embodiment, the polycationic polymer is chitosan and is obtained from marine invertebrates. 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 polymeric gel composition. Chitosan is a well-known analog of chitin, and the degree of deacetylation of chitin is consistent with the hemostatic effect. In one embodiment, the average degree of deacetylation of chitosan is between about 75.0% and about 99.5%. Preferably, the average degree of deacetylation of chitosan is between about 75.0% and about 85.0%. Preferably, the average degree of deacetylation of chitosan is between about 78.0% and about 83.0%. Preferably, the average degree of deacetylation of chitosan is between about 80.0% and about 81.0%. Preferably, the average deacetylation level of chitosan is 80.5%. The average degree of deacetylation of chitosan can be 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%.

solvent

The biocompatible polymeric compositions of the present invention contain between about 50.0% to about 90.0% solvent by weight. Preferably, the composition comprises between about 50.0% and about 90.0% solvent; preferably, the composition comprises between about 60.0% and about 90.0% solvent; preferably, the composition comprises a medium Between about 75.0% and about 90.0% solvent. The solvent can be present in the biocompatible polymeric composition in the following amounts: 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 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%, 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 polymeric composition in an amount of about 89.5%. Preferably, when the solvent is water, the solvent is present in the biocompatible polymeric composition in an amount between about 77.0% and about 78.0%.

Biocompatible polymer composition

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

In preferred embodiments, the biocompatible polymeric gel composition comprises (a) between about One or more polyanionic polymers between 0.0200 g/mL and about 0.0230 g/mL and (b) one or more polycationic polymers between about 0.185 g/mL and about 0.210 g/mL. In a preferred embodiment, the biocompatible polymeric gel composition comprises (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 0.210 g/mL of chitosan. In a preferred embodiment, the biocompatible polymeric 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 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 a preferred embodiment, 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 a preferred embodiment, the biocompatible polymeric gel composition comprises about 0.0212 g/mL of one or more polyanionic polymers and about 0.1887 g/mL of one or more polycationic polymers. In a preferred embodiment, 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 a preferred embodiment, 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. The preferred solvent is water.

The biocompatible polymeric gel composition of the present invention is capable of rapidly clotting blood while maintaining a firm clot. Clot strength is the primary measure of the efficacy of a biocompatible polymeric composition. The Sonoclot Coagulation Analyzer (sold by Sienco as the Sonoclot Analyzer) is recognized as a suitable method for testing the effectiveness of hemostatic devices. The clot strength of the formed clot increases with time, depending on the activator to which it is exposed. The clot strength of the clot on a wound exposed to the biocompatible polymeric composition of the present invention can be 50% higher than that of the clot formed without exposure to the composition of the present invention. In a preferred embodiment, the clot strength of the clot on a wound exposed to the biocompatible polymeric composition of the present invention is from about 90 to about 200 clot strength units (CSU) at t=15 minutes.

Setting time is another primary measure of the efficacy of a biocompatible polymeric composition. Clot strength (and clot strength units) increased over time. Hemostasis of the wound should be achieved quickly to minimize blood loss. When applied to a wound, the biocompatible polymeric composition promotes hemostasis, and the clotting time is preferably in 120 seconds or less, preferably in 90 seconds or less, preferably in 60 seconds or less Achieved in 60 seconds, preferably 30 seconds or less, preferably 15 seconds or less. The clotting time of wounds exposed to the biocompatible polymeric compositions of the present invention was approximately 190% faster than that of wounds not exposed to the compositions of the present invention. In vitro, the biocompatible polymeric composition may preferably be in 120 seconds or less, preferably in 90 seconds or less, preferably in 60 seconds or less, preferably in 30 seconds or less The blood is allowed to clot in seconds or less, preferably 15 seconds or less. Blood exposed to the biocompatible polymeric composition of the present invention clotted time (in vitro) about 190% faster than clotting time (in vitro) not exposed to the composition of the present invention. In one embodiment, about 13 mg or more of a composition of the present invention clots about 0.34 mL of blood in vitro.

Adhesive strength is another measure of the utility of a biocompatible polymeric gel composition. The compositions of the present invention should exhibit sufficient adhesion to the wound to retain the composition at the wound site without the persistence of adhesives such as cyanoacrylate glue. The biocompatible polymeric composition preferably withstands vertical strains of up to 0.5 Newtons per square millimeter without rupture between two samples of tissue. In one embodiment, 1 mL of the biocompatible polymeric gel is placed between two pieces of chicken liver (20mm x 20mm x 5mm) and compressed, and the gel is then subjected to about 0.5 N/L when the tissue sample is pulled vertically apart Square millimeter of vertical strain without rupture.

Biocompatible polymeric gel compositions can be characterized by various methods, including viscosity, pH, Fourier transform infrared (FTIR) spectroscopy, and chemical analysis.

The biocompatible polymeric compositions of the present invention preferably have a viscosity between about 145,000 (centipoise) cP and about 250,000 cP at about 25°C. In a preferred embodiment, the biocompatible polymeric composition has a viscosity between about 165,000 cP and about 174,000 cP at about 25°C. In a preferred embodiment, the biocompatible polymeric composition has a temperature of about 25°C. There is a viscosity between about 169,000 cP and about 170,000 cP. In a preferred embodiment, the biocompatible polymeric composition has a viscosity of about 169,500 cP at about 25°C. The preferred viscosity allows for maximum tack, which in turn affects performance. Small changes in viscosity can have dramatic effects on product utility. The viscosity of the biocompatible polymeric composition at about 25°C can be 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 149,500cP, 150,000cP, 150,500cP, 151,000cP, 151,500cP, 152,000cP, 152,500cP, 153,000cP 155,500cP, approx. 156,000cP, approx. 156,500cP, approx. 157,000cP, approx. 157,500cP, approx. 158,000cP, approx. 158,500cP, approx. 159,000cP, approx. 159,500cP, approx. 160,000cP, approx. 160,500cP, approx. 162,000cP 168,500cP, 169,000cP, 169,500cP, 170,000cP, 170,500cP, 171,000cP, 171,500cP, 172,000cP 174,500cP, 175,000cP, 175,500cP, 176,000cP, 176,500cP, 177,000cP, 177,500cP, 178,000cP, 178,500cP, 178,500cP, 179,500cP, 180,000cP 181,000cP cP, about 187,500cP, about 188,000cP, about 188,500cP, about 189,000cP, about 189 ,500cP, about 190,000cP, about 190,500cP, about 191,000cP, about 191,500cP, about 192,000cP, about 192,500cP, about 193,000cP, about 193,500cP, about 194,000cP 194,500cP, 195,000cP, about 195,500cP, about 196,000cP, about 196,500cP, about 197,000cP, about 197,500cP, about 198,000cP, about 198,500cP, about 199,000cP, about 199,500cP, about P20, about 200,000 201,000cP, 201,500cP, 202,000cP, 202,500cP, 203,000cP, 203,500cP, 204,000cP, 204,500cP, 205,000cP, 2005,500cP, 206,000cP, 200cP, 206,500cP , approx. 207,500cP, approx. 208,000cP, approx. 208,500cP, approx. 209,000cP, approx. 209,500cP, approx. 213,500cP, approx. 214,000cP, approx. 214,500cP, 215,000cP, approx. 215,500cP, approx. 216,000cP, approx. 216,500cP, approx. 217,000cP, approx. 217,500cP, approx. 218,000cP, approx. 218,500cP, approx. 220,000cP, 220,500cP, 221,000cP, 221,500cP, 222,000cP, 222,500cP, 223,000cP, 223,500cP, 224,000cP, 224,500cP, 225,000cP, 225,000cP, 225,000cP, 225,000cP 226,500cP 232,500cP, approx. 233,000cP, approx. 233,500cP, approx. 234,000cP, approx. 234,500cP, 235,000cP, approx. 235,500cP, approx. 236,000cP, approx. 236,500cP, approx. 237,000cP, approx. 237,500cP, approx. About 239,000cP, about 239,500cP, about 240 ,000cP, approximately 240,500cP, approximately 241,000cP, approximately 241,500cP, approximately 242,000cP, approximately 242,500cP, approximately 243,000cP, approximately 243,500cP, approximately 244,000cP, approximately 244,500cP, 245,000cP, approximately 245,500cP 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 with a chain length between about Between 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, including particles having an amorphous morphology with an average particle size of about 180 mesh , and is derived from marine algae.

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, and a concentration of 5% acetic acid at about 25°C. The viscosity in a 1% w/v solution is about 80 cP, which includes particles with a porous spherical morphology with an average particle size of about 100 mesh, and is derived from marine invertebrates.

In a preferred embodiment, the solvent is water.

The biocompatible polymeric compositions of the present invention preferably have 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 pH.

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 polymeric gel composition is shown in FIG. 3 .

Figure 1 schematically illustrates the Fourier transform infrared spectrum of the preferred sodium alginate. The main absorption peaks appear as follows: about 3,600cm ^-1 to about 3,000cm ^-1 -OH stretching vibration, about 2,900cm ^-1 CH stretching vibration, about 1,600cm ^-1 C=O stretching vibration of carboxyl group, about 1,400cm A broad peak at ^-1 overlapping the stretching vibration of the carboxyl group and the CH deformation, and a multi-peak at about 1,000 cm ^-1 corresponding to the CO vibration of the polysaccharide structure.

Figure 2 schematically illustrates the Fourier transform infrared spectrum of a preferred chitosan. The absorption peaks appear as follows: OH stretching vibrations overlapped with NH stretching vibrations at about 3,600 cm- ¹ to about 3,000 cm ^{- 1} , CH stretching vibrations at about 2,910 cm- ¹ and about 2,870 cm ^-1 , acyl hydride at about 1,650 cm-1 C=O stretching vibrations of amines, broad peaks for NH deformation at about 1,580 cm- ¹ , multiple peaks for CH deformation at about 1,400 cm ^-1 , and multiple peaks for CO vibrations corresponding to polysaccharide structures at about 1,000 cm ^-1 .

Figure 3 schematically illustrates the Fourier transform infrared spectrum of a preferred biocompatible polymeric composition. The absorption peaks appear as follows: OH stretching vibrations overlapped with NH stretching vibrations at about 3,600 cm- ¹ to about 3,000 cm ^{- 1} , CH stretching vibrations at about 2,900 cm ^-1 , C=O stretching vibrations at about 1,640 cm-1, and C=O stretching vibrations at about 1,590 Broad peaks for NH deformation at cm ⁻¹ , multiple peaks for CH deformation at about 1,400 cm ⁻¹ and multiple peaks for CO vibrations corresponding to polysaccharide structures at about 1,000 cm ⁻¹ .

The biocompatible polymeric compositions of the present invention are intended to be stored at about 25°C. In one embodiment, the biocompatible polymeric composition has a density between about 1.00 g/mL and 1.40 g/mL at about 25°C. In one embodiment, the biocompatible polymeric composition has a density between about 1.10 g/mL and 1.30 g/mL at about 25°C. In one embodiment, the biocompatible polymeric composition has a density between about 1.20 g/mL and 1.22 g/mL at about 25°C. A preferred biocompatible polymeric composition gel has a density of about 1.21 g/mL at about 25°C. The density of the biocompatible polymeric composition at about 25°C may be 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 mL, about 1.06g/mL, about 1.07g/mL, about 1.08g/mL, about 1.09g/mL, about 1.10g/mL, about 1.11g/mL, about 1.12g/mL, about 1.13g/mL, About 1.14g/mL, about 1.15g/mL, about 1.16g/mL, about 1.17g/mL, about 1.18g/mL, about 1.19g/mL, about 1.20g/mL, about 1.21g/mL, about 1.22 g/mL, about 1.23g/mL, about 1.24g/mL, about 1.25g/mL, about 1.26g/mL, about 1.27g/mL, about 1.28g/mL, about 1.29g/mL, about 1.30g/ mL, about 1.31g/mL, about 1.32g/mL, about 1.33g/mL, about 1.34g/mL, about 1.35g/mL, about 1.36g/mL, about 1.37g/mL, about 1.38g/mL, About 1.39 g/mL or about 1.40 g/mL.

The biocompatible polymeric compositions of the present invention have an elastic modulus between about 6 kPa and about 23 kPa. In one embodiment, the biocompatible polymeric composition has an elastic modulus of about 16 kPa. The elastic modulus of the biocompatible polymeric composition can be 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 media containers for biocompatible polymeric compositions include syringes, bags, sachets, tubes, buckets, pumps, bottles and bags. Preferably, the polymeric composition is sterile and suitable for use in humans and animals. A preferred storage medium is a 5 mL syringe (sterile); a preferred storage medium is a 10 mL syringe (sterile).

The biocompatible polymeric composition may further include optional ingredients such as antimicrobial agents, preservatives or therapeutic agents. Compositions may include silver salts, metal or carbon nanoparticles, antibiotics, hormones, proteins (eg, calreticulin, thrombin, prothrombin, factor VIII), methylparaben, chlorocresol, bromide Cetyltrimethylammonium and iodine and combinations thereof. In one embodiment, the composition further includes iodine. In one embodiment, the composition further comprises silver nitrate. In one embodiment, the composition further comprises methylparaben.

Manufacturing method

The production of biocompatible polymeric compositions is generally carried out as follows. One or more polyanionic polymers are first mixed with a solvent for a period of time to achieve the desired viscosity at about 25°C. Polyanionic mixing can occur at between about 20 revolutions per minute (RPM) to 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 period of time to achieve a final desired viscosity at about 25°C; this mixing may be between about 40 RPM to about 100 RPM time, preferably at about 62 RPM. In a preferred embodiment, the mixing in the first mixing period is performed at a lower speed than the mixing in the second mixing period.

In a preferred embodiment, sodium alginate is mixed with water in a vessel to achieve the desired viscosity at about 25°C. This mixing was carried out with low shear mixing at about 48 RPM for about 6 hours. Chitosan was added after the sodium alginate was mixed with the water. The mixture including the chitosan was mixed for about 1 hour at about 25°C with faster mixing than the sodium alginate/water mixing. Preferably, mixing is carried out at about 62 RPM when incorporating the chitosan.

Preferably, chitosan should not be incorporated simultaneously with sodium alginate and water, as the chitosan particles are porous and tend to pull water out of solution. Mix all three components at the same time (with the first Mixing the water and sodium alginate first (in contrast) produces a less effective gel that is thicker than desired and may include undissolved sodium alginate. This gel may contain a compressible colloid of sodium alginate and wetted chitosan, which may exhibit cross-linking problems and poor tissue adhesion.

In a preferred embodiment, the biocompatible polymeric composition is a colloidal gel having solid particles dispersed in solution. It is believed that the fluidity of the gel allows it to assist in covering the wound surface area as it conforms better to the injured site than solids such as gauze or sponge, while the weight of the solid particles allows mechanical resistance to pass through Fluid bleeding, and contributes to better cell adhesion/aggregation.

set

Packaging of the biocompatible polymeric compositions of the present invention into, for example, kits or articles of manufacture and application devices for use in any embodiment of the present disclosure are selected and manufactured by those skilled in the art based on their general knowledge , and adjusted according to the nature of the composition to be packaged. Furthermore, the type of device to be used can be correlated, inter alia, with the consistency of the composition, especially its viscosity; it can also depend on the nature of the ingredients present in the composition.

A kit or article of manufacture may include, but is not limited to, the composition of the present invention, a device for applying the composition of the present invention, instructions for using and applying the composition of the present invention, one or more other solutions, a list of ingredients, and/or warnings and the like. In one embodiment, the kit includes a 5 mL syringe filled with the biocompatible polymeric gel of the present invention and a separate syringe containing a 10% w/v calcium chloride solution in water.

While the invention has been illustrated and described in various embodiments of varying scope, it will be immediately apparent to those skilled in the art that changes can be made within the spirit and scope of the invention. Therefore, unless expressly provided, the scope of the invention as described in the appended claims is not intended to be limited by any specific wording in the foregoing description.

Instructions

In the primary method of using the polymeric gel of the present invention, the gel is applied to wounds including, for example, external lacerations, abrasions, burns, ocular lacerations, damage to parenchymal organs wounds, internal lacerations, lacerations in the gastrointestinal tract, superficial cuts and abrasions, internal bleeding, arterial bleeding, venous bleeding, dental or oral bleeding, and incisions. The polymeric gels of the present invention can be used to treat a variety of wounds, including those caused unintentionally (eg, accidents or accidental injuries) and those caused intentionally (eg, during surgery).

In the primary method of using the polymeric gel of the present invention, the gel can be applied directly to the surface of a bleeding wound. When applied to large volumes of blood, the gel will help coagulate the blood at the gel-blood interface. When the product is applied, if the gel is not in direct contact with the bleeding wound surface, then even relatively close to the wound site, the effectiveness is reduced. Due to the viscous nature of the gel, the operator may prefer to use a large-bore syringe to quickly apply large quantities of gel. During laparoscopic surgery, the gel can be dispensed via a catheter (eg, 16 gauge or larger). In another embodiment, the polymeric gel of the present invention can be dispensed across a gauze pad to increase the surface area of the exposed gel for the treatment of large surface bleeding.

Individuals who may benefit from wound treatment using the polymeric compositions of the present invention include numerous animals, including humans, mammals (eg, horses, sheep, cattle, pigs, dogs, cats) and marine animals such as (whales, dolphins, seals, otters) , fish) and reptiles (eg turtles).

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

example

In one form of producing a biocompatible gel, the operator received a beaker, stir bar, 106 mL of water, 2.247 g of sodium alginate, and 20 g of chitosan. Add 106mL to the beaker water. The operator slowly added up to 50 mg of sodium alginate at a time, followed by vigorous manual stirring for 2 minutes. Do this until all the sodium alginate is incorporated and dissolved in the water. The aqueous solution of sodium alginate was allowed to stand for less than 6 hours to ensure complete dissolution. After confirming complete dissolution, the operator slowly added up to 50 mg of chitosan at a time, followed by vigorous manual stirring for 2 minutes. This step is performed until all of the chitosan is incorporated and the solution is homogeneously mixed.

Claims (10)

A polymeric composition comprising: a. about 1% to about 5% by weight sodium alginate; b. about 5% to about 40% by weight chitosan, wherein the chitosan has an average degree of deacetylation between about 75.0% to about 99.5%; and c. about 50% to about 90% by weight solvent, wherein the solvent is water, wherein the sodium alginate is dissolved in the water to form a solution; and wherein the polymeric composition is a colloidal gel having chitosan solid particles dispersed in the solution. The polymeric composition of claim 1, wherein the composition exhibits hemostatic efficacy in vitro in less than about 30 seconds after introduction into the blood. The polymeric composition of claim 1 having a density between about 1.10 g/mL and about 1.30 g/mL at about 25°C. The polymeric composition of claim 1, wherein about 13 mg or more of the composition coagulates about 0.34 mL of blood in vitro. The polymeric composition of claim 1, wherein the elastic modulus is about 16 kPa. A method of making the polymeric composition of claim 1, comprising: a. mixing sodium alginate with water to make a first mixture, wherein in the first mixture, the sodium alginate is dissolved in water; and b. Chitosan is added to the first mixture to provide the polymeric composition. The polymeric composition of claim 1 for promoting and maintaining hemostasis. A polymeric composition for promoting and maintaining hemostasis, comprising: a. about 2% to about 5% by weight sodium alginate; b. about 10% to about 30% by weight chitosan, wherein the chitosan has an average degree of deacetylation between about 75.0% and about 99.5%; and c. from about 60% to about 88% by weight of solvent, wherein the solvent is water, wherein the sodium alginate is dissolved in the water to form a solution, wherein the polymeric composition has chitin dispersed in the solution A colloidal gel of polysaccharide solid particles, wherein the fluidity of the gel is such that it assists in covering the wound surface area, and the chitosan solid particles impart weight to avoid bleeding. The polymeric composition of claim 7 or 8, wherein the hemostasis comprises stopping arterial or venous bleeding. The polymeric composition of claim 7 or 8, wherein the hemostasis comprises stopping oral bleeding.

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