Film compositions for hemostasis

Abstract

In aspects, the present application provides dried hemostatic films, and methods of making and using such films. The present application contemplates dried hemostatic film compositions comprising hydrophobically-modified chitosan (hm-chitosan) and polyvinyl alcohol (PVA) and / or Pluronic acid. The present application further contemplates methods for hemostasis during vascular access procedures in patients in need thereof.

Description

[0001] FILM COMPOSITIONS FOR HEMOSTASIS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 622,328, filed January 18, 2024, the entire contents of which are hereby incorporated by reference in their entirety.

[0004] BACKGROUND

[0005] Vascular access procedures that require cannulation of large arteries or veins can present hemostasis challenges. The procedures are often conducted in the context of an outpatient setting, where patients are required to secure hemostasis at the access site before regaining mobility. For some procedures relying solely on manual compression methods, this can mean extended wait times, greater discomfort, and prolonged immobility. Achieving hemostasis can be particularly difficult for patients having coagulation disorders and / or undergoing therapy with anticoagulant or anti-platelet medications, such as, warfarin, heparin, and dabigatran.

[0006] Accordingly, there remains a need for hemostatic devices that rapidly achieve hemostasis following vascular access procedures. The subject matter of the present application addresses these and other objectives.

[0007] BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 depicts a photograph of a dried film composition suitable for use as a hemostatic device for vascular access bleeds and exhibiting favorable properties, such as being free of wrinkles, having a consistent thickness, being flat and flexible, and being semitransparent.

[0009] FIG. 2 depicts a photograph of a dried film composition that is not suitable for use as a hemostatic device for vascular access bleeds because it does not exhibit favorable properties. FIG. 3 depicts photographs of dried fdm compositions having various formulations, for example, including polyvinyl alcohol (PVA) or other excipients or polymers, and showing that the film containing PVA exhibits beneficial properties as compared to films containing other ingredients.

[0010] DETAILED DESCRIPTION OF THE INVENTION

[0011] In various aspects and embodiments, the present application contemplates dried hemostatic film compositions, as well as uses and methods of making the same. In embodiments, the dried hemostatic film comprises hydrophobically-modified chitosan (hm- chitosan) and a polyvinyl alcohol (PVA) and / or a Pluronic acid. The hm-chitosan comprises linear hydrocarbon groups independently selected from the range of C8 to C18 attached to the chitosan backbone on about 0.5% to about 5% of chitosan monomers. In embodiments, about 30% to about 80% of chitosan monomers comprise a free amine.

[0012] The present subject matter contemplates dried hemostatic films prepared from hm- chitosan and which have good physical properties for ease of handling and use, including, but not limited to, lack of wrinkles, consistent thickness, flatness, flexibility, and at least semi-transparency. Without wishing to be bound by theory, the present application contemplates that the hemostatic films of the present subject matter provide efficient means for achieving hemostasis in patients undergoing vascular access procedures, including arterial and venous access procedures.

[0013] In various embodiments, the dried hemostatic film of the present application has a thickness of about 0.05 mm to about 0.20 mm, or about 0.08 mm to about 0.15 mm, or about 0.10 mm to about 0.12 mm. In embodiments, the dried hemostatic film of the present application has an average mass of about 0.05 g to about 0.20 g. In embodiments, the dried hemostatic film has an average mass of about 0.05 g, about 0.10 g, or about 0.15 g, or about 0.20 g.

[0014] In various embodiments of the present application, the dried hemostatic film has a width and / or length of at least about 1 inch, at least about 1.25 inches, at least about 1.5 inches, or at least about 2 inches. In embodiments, the dried hemostatic film has a width and / or length ranging from about 1 inch to about 3 inches, about 1 inch to about 2.5 inches, about 1 inch to about 2 inches, about 1 inch to about 1.5 inches, about 1 inch to about 1 .25 inches, about 1.25 inches to about 3 inches, about 1.25 inches to about 2.5 inches, about 1.25 inches to about 2 inches, about 1.25 inches to about 1.5 inches, or about 1.5 inches to about 2 inches.

[0015] The hemostatic film compositions provided in the present application comprise a hydrophobically-modified chitosan (hm-chitosan) and PVA and / or Pluronic acid. In embodiments, the hm-chitosan comprises hydrocarbon groups attached to the chitosan backbone. In embodiments, the hydrocarbon groups comprise hydrocarbon groups independently selected from linear C8 to Cl 8 hydrocarbon chains, which provide effective hemostatic properties. In embodiments, about 30% to about 80% of chitosan monomers comprise a free amine.

[0016] Chitosan is the common name of the linear, random copolymer that consists of P-(l- 4)-linked D-glucosamine and N-acetyl-D-glucosamine. The molecular structure of chitosan consists of a linear backbone linked with glycosidic bonds. Chitosan is the major component of crustacean shells such as crab, shrimp, krill and crawfish shells. Additionally, chitosan is the second most abundant natural biopolymer after cellulose. Commercial chitosan samples are typically prepared by chemical de-N-acetylation of chitin under alkaline conditions. Depending on the source of the natural chitin (extracted from shells) and its production process, chitosan can differ in size (average molecular weight, Mw) and degree of N- acetylation (%DA). While the poor solubility of chitosan in water and in common organic solvents restricts its applications, reactive amino groups in the chitosan backbone make it possible to chemically conjugate chitosan with various molecules and to modulate its properties.

[0017] The hm-chitosan included in the hemostatic film of the present application in some embodiments is prepared using fatty acid anhydride chemistry, resulting in amide bonds with the chitosan polymer and the hydrocarbon chains. See U.S. Patent No. 11,274,194, which is hereby incorporated by reference in its entirety. Amide bonds can generally be susceptible to hydrolysis in solution. Hydrolysis of amide bonds is generally known to occur in the presence of acids, which act as catalysts for the reaction between the amide and water. Amides are also susceptible to alkaline hydrolysis. However, the amide bonds formed between chitosan and fatty acid anhydrides are shelf stable, even in the presence of dilute acids that are required to maintain solubility of the hm-chitosan. Accordingly, the modified chitosans may be prepared using a one-pot synthesis, without the need for harsh reagents, including reducing agents.

[0018] In embodiments, the hm-chitosan is derived from a deacteylated chitin, which may be derived from one or more of crab, shrimp, krill, and crawfish. The charge density of chitosan is an important parameter for its tissue adherent properties, and can impact the properties of the dried film. The amount of acetylation can be tuned by adding C1-C4 hydrocarbon groups (e.g., acetyl groups) back to the chitosan, according to this disclosure. Thus, according to embodiments of this disclosure, the modified chitosan will have a free amine at about 40% of its monomers or more, or at about 50% of its monomers or more, or at about 60% of its monomers or more, or at about 70% of its monomers or more. In various embodiments, the modified chitosan according to this disclosure comprises a free amine on about 30% to about 80% of it monomers, or on about 40% to about 80% of its monomers, or on about 50% to about 80% of its monomers, or on about 55% to about 80% of its monomers. The structure of chitosan (shown deacetylated) is depicted in Formula 1 :

[0019] In embodiments, the molecular weight of the hm-chitosan ranges from about 400,000 to about 1,500,000 grams per mole. In embodiments, the chitosan is a high molecular weight chitosan, or a medium molecular weight chitosan, or a small molecular weight chitosan. Generally, the molecular weight of the hm-chitosan will range from about 25,000 to about 1,500,000 grams per mole. In embodiments, the molecular weight of the hm-chitosan ranges from about 200,000 to about 1,500,000 grams per mole, or from about 250,000 to about 1,500,000 grams per mole, or from about 300,000 to about 1,500,000 grams per mole, or from about 350,000 to about 1,500,000 grams per mole, or from about 400,000 to about 1,500,000 grams per mole, or from about 450,000 to about 1,500,000 grams per mole, or from about 500,000 to about 1,500,000 grams per mole. In embodiments, the chitosan has a low molecular weight of less than 150,000 Daltons (prior to modification). In other embodiments, the chitosan has a medium molecular weight of about 150,000 to about 350,000 Daltons (prior to modification). In yet other embodiments, the chitosan has a high molecular weight of about 400,000 Daltons or more (prior to modification).

[0020] As used herein, the term “molecular weight” means weight average molecular weight. In some embodiments, the chitosan is a high molecular weight chitosan. Methods for determining average molecular weight of bio-polymers include low angle laser light scattering (LLS) and Size Exclusion Chromatography (SEC). In performing low angle LLS, a dilute solution of a polysaccharide, typically 2% or less, is placed in the path of a monochromatic laser. Light scattered from the sample hits the detector, which is positioned at a low angle relative to the laser source. Fluctuation in scattered light over time is correlated with the average molecular weight of the polysaccharide in solution. In performing SEC measurements, again a dilute solution of biopolymer, typically 2% or less, is injected into a packed column. The polysaccharide is separated based on the size of the dissolved polymer molecules and compared with a series of standards to derive the molecular weight.

[0021] In various embodiments, the hydrophobically-modified chitosan contains hydrophobic grafts (i.e., hydrophobic substituents) that are hydrocarbons of from 8 to 18 carbon atoms. In various embodiments, the hydrocarbon chains are linear (i.e., not branched) hydrocarbon chains. In some embodiments, the hydrocarbon groups comprise an arylalkyl group. As used herein, the term “arylalkyl group” means a group containing both aromatic and aliphatic structures. In embodiments, the hydrophobic grafts can be a uniform size or a combination of sizes. In some embodiments, the hydrophobic grafts are attached to the chitosan backbone on about 0.01% to about 15% or about 0.01% to about 10% of the chitosan monomers. In some embodiments, the hm-chitosan has from about 0.5% to about 5%, or from about 0.5% to about 3% of chitosan monomers modified with a hydrocarbon chain independently selected from the range of C8 to C 18. In embodiments, the hydrocarbon group comprises one or more of linear C8, CIO, C12, C14, C16, and C18 hydrocarbon chains. In some embodiments the C8 to Cl 8 group is an alkyl group. In some embodiments, the hm-chitosan comprises hydrophobic grafts selected from one or a combination of C8, Cl 2, Cl 4, Cl 6, and Cl 8. In some embodiments, the hm-chitosan comprises C8 hydrocarbon chains present on about 0.5% to about 3% of chitosan monomers. In some embodiments, the hm-chitosan comprises C8 hydrocarbon chains present on about 1% of chitosan monomers.

[0022] In embodiments, from about 25% to about 85%, or from about 30% to about 80% of chitosan monomers of the hydrophobically-modified chitosan comprise a free amine. In embodiments, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of chitosan monomers of the hydrophobically- modified chitosan comprises a free amine.

[0023] In various embodiments, the hydrophobically-modified chitosan further comprises smaller hydrocarbon substituents (including C2, i.e., acetyl substituents as in chitin) to tune the density of positive charges. In some embodiments, the smaller hydrocarbon substituents are selected from the range of a Cl to C4 hydrocarbon. In various embodiments, the Cl to C4 hydrocarbon substituents (e.g., C2) along the chitosan backbone are present in the range of about 5% to about 50% of chitosan monomers, or in the range of about 15% to about 50% of chitosan monomers, or in the range of about 25% to about 45% of chitosan monomers. In embodiments, the hydrophobic groups comprise Cl to C4 hydrocarbon groups present on at least or about 35% of chitosan monomers. In embodiments, C2 hydrocarbon groups are present on at least or about 35% of chitosan monomers.

[0024] In embodiments, the hydrophobically-modified chitosan further comprises one or more dihydrocaffeic acid groups, and optionally oxidized forms thereof, to tune adhesive and cohesive properties of the composition. In embodiments, the one or more dihydrocaffeic acid groups comprise a catechol moiety, and optionally oxidized forms thereof. In embodiments, at least some of the dihydrocaffeic acid groups are oxidized to the corresponding quinone. In embodiments, the dihydrocaffeic acid groups, and optionally oxidized forms thereof, are grafted to the hm-chitosan at a density from about 0.1 mol% to about 15 mol% of chitosan monomers, or from about 5 mol% to about 15 mol% of chitosan monomers, or from about 0.1 mol% to about 12 mol% of chitosan monomers, or from about 0.1 mol% to about 2 mol% of chitosan monomers, or from about 0.1 mol% to about 1 mol% of chitosan monomers. In various embodiments, from about 1% to about 70% of the dihydrocaffeic acid groups are oxidized to the corresponding quinone, or from about 1% to about 10% of the dihydrocaffeic acid groups are oxidized to the corresponding quinone, or from about 5% to about 50% of the dihydrocaffeic acid groups are oxidized to the corresponding quinone, or from about 15% to about 50% of the dihydrocaffeic acid groups are oxidized to the corresponding quinone, or from about 20% to about 50% of the dihydrocaffeic acid groups are oxidized to the corresponding quinone, or from about 25% to about 50% of the dihydrocaffeic acid groups are oxidized to the corresponding quinone, or from about 30% to about 50% of the dihydrocaffeic acid groups are oxidized to the corresponding quinone, or from about 40% to about 50% of the dihydrocaffeic acid groups are oxidized to the corresponding quinone.

[0025] In embodiments, the contemplated hemostatic film comprises hm-chitosan and a polyvinyl alcohol (PVA) and / or a Pluronic acid. The vascular films of the present application are generally prepared by combining the hydrophobically modified chitosans (HMC) (as described) and other components into a homogenized solution that is then dried to form a film. In embodiments, formulation components of the present dried films include polyvinyl alcohol (PVA) of different molecular weights, glycerol, pluronic acid, polyethylene glycol (PEG), low molecular weight (LMW) chitosan, and high molecular weight (HMW) chitosan.

[0026] In embodiments, the dried hemostatic film of the present application is produced by a process comprising steps of: (a) preparing a solution of hm-chitosan in organic acid; (b) preparing a solution of PVA and / or Pluronic acid in deionized water; (c) combining the solution of (a) with the solution of (b); and (d) pouring the homogenized combined solutions into a container having a flat surface and allowing the solution to dry at room temperature to form a film.

[0027] In embodiments, a solution is provided that is dried to form the dried hemostatic film of the present application. In various embodiments, the solution that is dried to form the film comprises hm-chitosan at a concentration of from about 0.1 wt% to about 2 wt%, or from about 0.5 wt% to about 2 wt%, or from about 1 wt% to about 2 wt%. In some embodiments, the solution that is dried to form the film comprises hm-chitosan at a concentration of about 0.1 wt%, about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.5 wt%, or about 2 wt%.

[0028] In some embodiments, the solution that is dried to form the dried hemostatic fdm of the present application comprises hm-chitosan formulated in an organic acid. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group -COOH. For example, the organic acid may have a pKa of from about 2 to about 5, or from about 2.5 to about 4, or from about 3 to about 4, or from about 3.5 to about 4. Exemplary organic acids include acetic acid, succinic acid, citric acid, glycolic acid, fumaric acid, malic acid, glutaric acid, oxaloacetic acid, lactic acid, and pyruvic acid. In some embodiments, the organic acid is selected from acetic acid, succinic acid, citric acid, glycolic acid, fumaric acid, malic acid, glutaric acid, oxaloacetic acid, lactic acid, and pyruvic acid. In some embodiments, the solution that is dried to form the film comprises hm-chitosan formulated in from about 0.05 M to about 0.5 M organic acid, such as acetic acid. In some embodiments, the hm-chitosan is formulated in about 0.05 M to about 0.2 M acetic acid. In some embodiments, the hm-chitosan is formulated in about 0.1 M acetic acid. In some embodiments, the hm-chitosan solution will have a pH of less than about 5, or less than about 4, or less than about 3. In some embodiments, the pH of the hm-chitosan solution is from about 2 to about 4.

[0029] In embodiments, illustrative polyvinyl alcohol (PVA) included in the present dried hemostatic film comprises a molecular weight of from about 60 kDa to about 135 kDa. For example, the PVA may comprise a molecular weight of about 67 kDa, about 77 kDa, or about 125 kDa. In embodiments, the PVA comprises a molecular weight of from about 65 kDa to about 70 kDa, optionally about 67 kDa. In embodiments, the PVA comprises a molecular weight of from about 75 kDa to about 125 kDa. In embodiments, the solution that is dried to form the hemostatic film of the present application comprises PVA at a concentration of from about 0.1 wt% to about 2.0 wt%, or from about 0.5 wt% to about 2.0 wt%. In embodiments, the solution that is dried to form the hemostatic film of the present application comprises PVA at a concentration of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, about 1.5 wt%, or about 2.0 wt%. In various embodiments, the dried hemostatic fdm of the present application comprises Pluronic acid. In embodiments, the solution that is dried to form the film comprises Pluronic acid at a concentration of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, about 1.5 wt%, or about 2.0 wt%.

[0030] In embodiments, the solution that is dried to form the film comprises PVA and / or Pluronic acid formulated in deionized water.

[0031] The present application contemplates that the dried hemostatic film may further comprise other polymers or reagents. In embodiments, the reagent is selected from a polyethylene glycol (PEG), glycerin, propylene glycol, poly(7V-vinylpyrrolidone), a polyacrylamide, a polybetaine, a poly(2-oxazoline), a polyester and a polysarcosine. In embodiments, the solution that is dried to form the film comprises the reagent at a concentration of from about 0.01 wt% to about 2.0 wt%, or from about 0.1 wt% to about 2.0 wt%, or from about 0.5 wt% to about 2.0 wt%.

[0032] In various embodiments, the present application contemplates methods for using the dried hemostatic film for achieving hemostasis in patients in need thereof. For example, the present application contemplates that the dried hemostatic film can be used to achieve hemostasis in patients undergoing a vascular access procedure.

[0033] In embodiments, the present application provides methods for hemostasis during a vascular access procedure in a patient comprising: applying the dried hemostatic film described herein to a site comprising a vascular bleed with compression. In embodiments, the present application contemplates that the patient using the dried hemostatic film described herein can reach hemostasis in less than about 30 minutes, or less than about 20 minutes, or less than about 15 minutes, or less than about 10 minutes, or less than about 5 minutes.

[0034] In embodiments, it is contemplated that the patient is in particular need of efficient hemostasis following vascular access procedures due to the patient undergoing therapy with an anticoagulant or anti-platelet medication. In embodiments, illustrative anticoagulant therapies include, but are not limited to, heparin, warfarin, dabigatran, apixaban, betrixaban, edoxaban, rivaroxaban, dalteparin, and enoxaparin. In various embodiments, it is contemplated that the patient is in particular need of efficient hemostasis following vascular access procedures due to the patient having a coagulation disorder. For example, the present application provides that the patient may have hemophilia, clotting factor deficiency, or von Willebrand disease.

[0035] As used herein, the term “about” means ± 10% of a reference value, unless the context requires otherwise.

[0036] Other aspects and embodiments of this disclosure will be apparent from the following working examples and claims.

[0037] EXAMPLES

[0038] Example 1 : Preparation and analysis of vascular films

[0039] Various prototypes of vascular films were prepared and analyzed for their physical properties. Prototypes are described in Table 1.

[0040] The vascular films were generally prepared by combining chitosan or one of various candidate hydrophobically modified chitosans (HMC) and other components as shown in Table 1 into a homogenized solution that was then allowed to completely dry to form a film. Candidate formulation components included polyvinyl alcohol (PVA) of different molecular weights, glycerol, pluronic acid, polyethylene glycol (PEG), low molecular weight (LMW) chitosan, and high molecular weight (HMW) chitosan.

[0041] The prototype films were constructed with the following HMC materials:

[0042] HM-Chitosan (high molecular weight, with 1 mol% C8 grafts and 35 mol% C2 grafts) (designated in Table 1 as HMC-INT);

[0043] HM-Chitosan (high molecular weight, with 1 mol% C8 grafts and 35 mol% C2 grafts), with 10 mol% dihydrocaffeic acid grafts, with <5% of dihydrocaffeic groups oxidized into quinone groups (designated in Table 1 as HMC-X); HM-Chitosan (high molecular weight, with 1 mol% C8 grafts and 35 mol% C2 grafts), with 0.8 mol% dihydrocaffeic acid grafts, with about 5% to about 50% of dihydrocaffeic groups oxidized into quinone groups (designated in Table 1 as HMC-0);

[0044] HM-Chitosan (high molecular weight, with 9 mol% C16 grafts) (designated in Table 1 as HMC-OTC);

[0045] Prototypes were evaluated for a look and feel suitable for use as a hemostatic device for vascular access bleeds. Specifically, a suitable film formulation should be free of wrinkles, have a consistent thickness, be flat and flexible, and be at least semi-transparent.

[0046] Table 1 : Vascular Film Prototypes

[0047] These studies identified a prototype having a concentration of 1 wt% HMC-INT, 0.5 wt% polyvinyl alcohol (PVA) (about 67 kDa), in 0.1 M acetic acid (no. 40 of Table 1 above) as having particularly desirable properties. Batch sizes of 200 mL of solution per 22 cm x 22 cm tray resulted in a film thickness of around 0.10 to 0.12 mm and an average mass of approximately 0.10 g for a chosen dimension of 1.5” x 1.25”. The film can be dried in ambient conditions (25 °C, 40% RH), over the course of 72 h. Other films containing higher amounts of PVA (e.g., 1 wt%) as well as similar films constructed with Pluronic acid, also showed desirable properties. An illustrative example of a film of the present application having favorable properties (e.g., free of wrinkles, having a consistent thickness, flat and flexible, and semitransparent) suitable for use as a hemostatic device for vascular access bleeds is shown in FIG. 1. An example of a film lacking these favorable properties is shown in FIG. 2.

[0048] An exemplary process for preparing HMC-INT films with PVA involves preparing a solution of HMC-INT in acetic acid and combining the same with a solution of PVA in deionized water. Once homogenized, portions of the solution are poured into containers having an essentially flat surface and allowed to dry at room temperature until completely dried out to a film consistency.

[0049] Example 2: Vascular films containing PVA as compared to different polymers or excipients

[0050] This experiment shows that formulation of HMC with synthetic polymers, and particularly polyvinyl alcohol (PVA), including when formulating as a clear film, provides advantages in physical properties of the material for commercial applications, such as being significantly free of wrinkles, lacking brittle texture, having consistent thickness, being flat and flexible, and being at least semi-transparent.

[0051] To demonstrate that PVA exhibits superior properties when formulated with HMC in a dried film format, a comparative experiment was conducted. In this experiment, films were prepared by overnight drying of solution containing lwt% of an exemplary hydrophobically-modified chitosan (C2 groups incorporated at 35 mol% and C8 groups incorporated at 1 mol%) in acetic acid and an equal weight of either PVA or a different polymer or excipient. Specifically, the comparator films contained an equal amount (by weight) of: glycerin (Film B); polyethylene oxide (PEO) (Film C); polypropylene glycol (PPG) (Film D); Pluronic acid F-127 (Film E); glycerol (Film F); Tween 20 (Film G) or glycerin (Film H).

[0052] FIG. 3 provides visual evidence of the superior properties of the film containing PVA as compared to each of the other reagents. For example, Film A (containing PVA) demonstrated a flat, uniform film, without wrinkles, while Films B through H demonstrated numerous wrinkles, bubbles, and undesired structural curvature. These results demonstrate that hemostatic film products containing hydrophobically-modified chitosan and PVA exhibit unique beneficial properties that are not seen in films prepared with other traditional reagents.

[0053] Example 3 : Vascular films containing PVA and hydrophobically-modified chitosan (HMC) display beneficial properties despite varying amounts of PVA and / or HMC

[0054] This experiment shows that formulation of HMC with PVA as a clear film, including when the amounts of PVA and / or HMC are varied, provides beneficial material properties, such as being significantly free of wrinkles, lacking brittle texture, having consistent thickness, being flat and flexible, and being at least semi-transparent.

[0055] To demonstrate that PVA exhibits superior properties when formulated with HMC in a dried film format, despite varying amounts of the ingredients, a comparative experiment was conducted. In this experiment, films were prepared by overnight drying of solution containing hydrophobically-modified chitosan (C2 groups incorporated at 35 mol% and C8 groups incorporated at 1 mol%) in acetic acid and PVA (as shown in Examples 1 and 2). Specifically, the comparator films contained: 100% HMC / 0% PVA; 67% HMC / 33% PVA; 50% HMC / 50% PVA; and 33% HMC / 67% PVA.

[0056] The film containing 100% HMC / 0% PVA is clear but exhibits many kinks and contours, lacks consistency and smoothness, and is brittle (e.g., can snap when bent). However, the films containing varying amounts of HMC and PVA are each clear and smooth and exhibit flexibility upon bending.

[0057] These results demonstrate that, while hemostatic film products containing HMC (e.g., HMC having about 1 mol% C8 grafts and about 35 mol% C2 grafts) alone are brittle and show a significant degree of kinking, films containing the hydrophobically-modified chitosan and PVA exhibit unique beneficial properties such as being smooth and flexible, with no kinking at the comers or edges. This effect is seen even with relative low amounts of PVA (e.g. 33% PVA), up through relative high amounts of PVA (e.g. 67%).

Claims

CLAIMSWhat is claimed is:

1. A dried hemostatic film, comprising:(a) a hydrophobically-modified chitosan (hm-chitosan) comprising linear hydrocarbon groups independently selected from the range of C8 to C18 attached to the chitosan backbone on about 0.5% to about 5% of chitosan monomers, and where from about 30% to about 80% of chitosan monomers comprise a free amine; and(b) a polyvinyl alcohol (PVA) and / or a Pluronic acid.

2. The film of claim 1, wherein the hydrocarbon groups within the range of C8 to Cl 8 are present on about 0.5% to about 3% of chitosan monomers.

3. The film of claim 2, wherein the hydrocarbon groups comprise C8 hydrocarbon chains present on about 0.5% to about 3%, and optionally about 1%, of chitosan monomers.

4. The film of any one of claims 1 to 3, wherein the hydrophobic groups further comprise Cl to C4 hydrocarbon groups, and optionally C2 hydrophobic groups, present on about 15% to about 50%, and optionally about 25% to about 45% of chitosan monomers.

5. The film of claim 4, wherein the hydrophobic groups comprise Cl to C4 hydrocarbon groups present on about 35% of chitosan monomers, optionally C2 hydrophobic groups present on about 35% of chitosan monomers.

6. The film of any one of claims 1 to 5, wherein the chitosan is a high molecular weight chitosan.

7. The film of any one of claims 1 to 6, wherein the hm-chitosan further comprises one or more dihydrocaffeic acid groups, and optionally oxidized forms thereof.

8. The film of any one of claims 1 to 7, wherein the solution that is dried to form the film comprises hm-chitosan at a concentration of from about 0.1 wt% to about 2 wt%, and optionally at a concentration of about 1 wt%.

9. The film of any one of claims 1 to 8, wherein the solution that is dried to form the film comprises hm-chitosan formulated in an organic acid, optionally selected from aceticacid, succinic acid, citric acid, glycolic acid, fumaric acid, malic acid, glutaric acid, oxaloacetic acid, lactic acid, and pyruvic acid.

10. The film of claim 9, wherein the solution that is dried to form the film comprises hm- chitosan formulated in from about 0.05 M to about 0.5 M organic acid, and optionally acetic acid.

11. The film of claim 10, wherein the solution that is dried to form the film comprises hm-chitosan formulated in about 0.1 M acetic acid.

12. The film of any one of claims 1 to 11, wherein the PVA has a molecular weight of from about 60 kDa to about 135 kDa.

13. The film of claim 12, wherein the PVA has a molecular weight of from about 65 kDa to about 70 kDa, optionally about 67 kDa.

14. The film of any one of claims claim 1 or 13, wherein the solution that is dried to form the film comprises PVA at a concentration of about 0.5 wt%.

15. The film of any one of claims 1 to 14, wherein the solution that is dried to form the film comprises Pluronic acid at a concentration of about 0.2 wt%.

16. The film of any one of claims 12 to 15, wherein the solution that is dried to form the film comprises PVA and / or Pluronic acid formulated in deionized water.

17. The film of any one of claims 1 to 16, further comprising a polymer selected from a polyethylene glycol (PEG), glycerin, propylene glycol, poly(A-vinylpyrrolidone), a polyacrylamide, a polybetaine, a poly(2-oxazoline), a polyester and a polysarcosine.

18. The film of claim 17, wherein the solution that is dried to form the film comprises the polymer at a concentration of from about 0.01 wt% to about 2 wt%.

19. The film of any one of claims 1 to 18, wherein the film exhibits one or more properties selected from lack of wrinkles, consistent thickness, flatness, flexibility, and semitransparency.

20. The film of any one of claims 1 to 19, wherein the film has a thickness of about 0.05 mm to about 0.20 mm, optionally about 0.08 mm to about 0.15 mm, optionally about 0.10 mm to about 0.12 mm.

21. The film of any one of claims 1 to 20, wherein the film has an average mass of about 0.05 g to about 0.15 g, optionally about 0.10 g.

22. The film of any one of claims 1 to 21, wherein the film has a width and / or length of at least about 1 inch, at least about 1.25 inches, at least about 1.5 inches, or at least about 2 inches.

23. The film of any one of claims 1 to 22, wherein the film has a width and / or length ranging from about 1 inch to about 3 inches, about 1 inch to about 2.5 inches, about 1 inch to about 2 inches, about 1 inch to about 1.5 inches, about 1 inch to about 1.25 inches, about 1.25 inches to about 3 inches, about 1.25 inches to about 2.5 inches, about 1.25 inches to about 2 inches, about 1.25 inches to about 1.5 inches, or about 1.5 inches to about 2 inches.

24. The dried hemostatic film of any one of claim 1 to 23, produced by a process comprising:(a) preparing a solution of hm-chitosan in organic acid;(b) preparing a solution of PVA and / or Pluronic acid in deionized water;(c) combining the solution of (a) with the solution of (b); and(d) pouring the homogenized combined solutions into a container having a flat surface and allowing the solution to dry at room temperature to form a film.

25. A method of making the film of any one of claims claim 1 to 24, comprising:(a) preparing a solution of hm-chitosan in organic acid;(b) preparing a solution of PVA and / or Pluronic acid in deionized water;(c) combining the solution of (a) with the solution of (b); and(d) pouring the homogenized combined solutions into a container having a flat surface and allowing the solution to dry at room temperature to form a film.

26. A method for hemostasis during a vascular access procedure in a patient in need thereof, the method comprising: applying the film of any one of claims 1 to 24 to a site comprising a vascular bleed with compression.

27. The method of claim 26, wherein the patient is undergoing therapy with an anticoagulant.

28. The method of claim 27, wherein the anticoagulant is selected from heparin, warfarin, dabigatran, apixaban, betrixaban, edoxaban, rivaroxaban, dalteparin, and enoxaparin.

29. The method of claim 26, wherein the patient has a coagulation disorder.

30. The method of claim 29, wherein the patient has hemophilia, clotting factor deficiency, or von Willebrand disease.

31. The method of any one of claims 26 to 30, wherein the patient reaches hemostasis in less than about 30 minutes, or less than about 20 minutes, or less than about 15 minutes, or less than about 10 minutes, or less than about 5 minutes.

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