NZ723969B2 - In-situ cross-linkable polymeric compositions and methods thereof - Google Patents

Abstract

Provided is a biocompatible polymeric composition comprising 1) one or more polyanionic polymers, such as alginates or hyaluronates, and 2) one or more polycationic polymers, such as chitosan or DEAE-Dextran. The composition may be useful in the treatment of wounds as the polymers cross link in situ in a wound forming a gel. In a preferred embodiment the composition consists of 0.1 to 5% by weight of sodium alginate, 2 to 25% by weight of chitosan, and water as a solvent. in a wound forming a gel. In a preferred embodiment the composition consists of 0.1 to 5% by weight of sodium alginate, 2 to 25% by weight of chitosan, and water as a solvent.

Description

PATENTS FORM NO. 5 Our ref: CLM 237497NZPR DIVISIONAL APPLICATION FILED OUT OF NZ 624233 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION In-situ cross-linkable polymeric compositions and methods thereof We, Suneris Inc. of 180 Hardenburgh Road, Pine Bush, 12566, New York, United States of America hereby e the invention, for which we pray that a patent may be granted to us and the method by which it is to be med, to be particularly described in and by the following statement: (Followed by page 1a) 103923515_1.docx:JX:ewa IN-SITU CROSS-LINKABLE POLYMERIC COMPOSITIONS AND S THEREOF This application claims the benefit of provisional patent application Ser. No. 61/559,110, filed 13 November 2011, the entire disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION The present invention s generally to a composition using a biocompatible polymeric formulation and, in particular, to a hemophilic polymeric matrix for use in wound healing, blood ation, and cosmetic use.

BACKGROUND OF THE INVENTION Wound healing is an intricate, orchestrated s involving the interactions of various cells and matrix components to first establish a provisional tissue and then remodel this while forming the mature replacement. lly, the hemostatic platelet plug reestablishes the infection-limiting and desiccation-limiting barrier, and elicits the first wave of ar infiltrates. This ts mainly of leukocytes that provide both innate and ed immunity. These cells produce enzymes and biocidal molecules to eliminate microbial contamination; however, these same e isms are detrimental to the keratinocytes, fibroblasts and endothelial cells required to rate the lost tissue. Thus, as healing proceeds, the events and processes of the inflammatory phase need to regress.

A particular challenge is d in the case of skin wound repair, which occurs at a contaminated surface. If a wound becomes infected, the normal healing is disrupted as the inflammatory phase becomes chronic, suppressing the regenerative phase. Further, the enzymes liberated by both the microbes and leukocytes break down the wound tissue as well as surrounding skin. Thus, it is critical to ensure proper healing to prevent ions being established by normal skin wound contaminants.

Wound healing is usually divided into three : the inflammatory phase, the proliferative phase, and the remodeling phase. Fibronectin has been reported to be involved in each stage of the wound healing process, particularly by creating a scaffold to which the invading cells will adhere. Initially, there is a release of many mediators to the wound site, such as fibronectin and fibrinogen. Fibronectin promotes inflammatory cell migration into the wound and debris phagocytosis by monocytes. Thereafter, angiogenesis and (Followed by page 2) helialization take place. At this stage, fibronectin exerts chemotactic activity on elial cells, and promotes epithelial cell and fibroblast migration onto the basal membrane. Fibronectin also appears to be essential in the remodeling phase where it plays a major role in the organization of collagen fibrils. The fibrillar en tely forms fibrous bundles that enhance the tissue tensile strength, leading to would closure.

Hydrogels have typically been utilized as topical formulations for promoting the wound healing process. The gel compositions have been selected for their properties of swelling degree, biocompatibility, permeability, and swelling cs. Examples of such compounds have included vinyl polymers (e.g. polyacrylic acid), cellulose, and cellulose derivatives. Polyacrylic acid polymer, also referred to as carbomer, has been used because of its superiority in delivering fibronectin to skin wounds.

Naturally occurring biopolymers have applications in tissue engineering, regenerative medicine, drug delivery, medical implant, plastic surgery, and . Such products have components including hyaluronic acid (HA), an, heparin, chondroitin sulfate, alginate and other glucosamine and glycosaminoglycans, other polysaccharides, and derivatives thereof.

In combination, concentrations of fibronectin (and r proteins) have been utilized with alginate salt to treat chronic ulcers. The dressing system has been solidified, converting the gel into fibers, by a s of freeze-drying. This procedure creates a sponge-like structure with hilic properties. In the presence of fluids, the dressings can return to a gel-like state, ing up to 20 times their weight in wound exudate. The dressing is easily d after the wound treatment because of its sponge-like structure and moisture retention. However, once hydrated with saline on, the fibronectin-cellulose dressing does not provide the desired fibrous protective film on the surface of the deepithelialized human skin. Debridement is then performed upon removal of the dressing to remove any necrotic material.

Thus, problems exist in the treatment of acute and c wounds, including delayed healing, reduced granulation and epithelialization, and persistent wound inflammation.

Compromised wound healing can result in other cations and problems, such as infection, pain, and development of chronic (non-healing) wounds. t needs exist in the treatment of chronic wounds which would assist g, decrease inflammation, reduce pain, and prevent scar formation with both acute and chronic wounds. Such acute wounds that could be treated include burns, abrasions, dry skin, post-op surgical incisions, cuts, puncture wounds, blisters, insect bites, and other severe tissue injury. c wound treatment might encompass slow to heal wounds ing pressure , venous ulcers, diabetic foot ulcers, decubitus ulcers, and non-healing tissue injuries.

Overall, a composition is desired that will be easily applied, forming a matrix conducive to the healing of a tissue, and having anti-microbial properties. The composition may be biocompatible or quickly reacted to avoid possibilities of cytotoxicity. Further, the composition will stimulate and ze wound healing while providing a controlled method for providing thin and thick layers of a solidified wound ng, as desired.

Indirect effects may include reduced need for medical procedures such as debridement, decreased hospitalization time, reduced postoperative recovery times, shortened return interval to daily functions and work, and reduced overall treatment costs. Desirably, these improvements to wound g, including application and method of use, will be valuable in treating and repairing various tissue(s).

Y OF THE INVENTION The following invention is a biocompatible polymeric composition that is a gelatinous wound healing and hemostatic matrix able to be formed and solidified both internally and ally.

In one embodiment of the invention, the biocompatible polymeric composition comprises 1) one or more than one polyanionic r and 2) one or more than one polycationic polymer. In one embodiment of the invention, the one or more than one polyanionic polymer includes at least one cross-linkable polyanionic polymer. In another embodiment of the invention, the one or more than one ionic polymer includes at least one cross-linkable polyanionic r and at least one non-cross-linkable polyanionic polymer.

In one embodiment of the invention, the patible polymeric composition comprises a mixture of 1) one or more than one polyanionic polymer able to be formed on the surface of a wound and 2) one or more than one polycationic polymer that assists in the solidification process as well as speeds up blood clotting. In another embodiment of the invention, the biocompatible polymeric composition ses a mixture of 1) one or more than one polyanionic r able to be formed on the surface of a wound; 2) one or more than one polycationic polymer that assists in the solidification process as well as speeds up blood clotting; and 3) a cross-linking mist that cross-links the gel in the wound while disinfecting the surrounding area.

In one embodiment of the invention, the one or more than one polyanionic polymer comprises alginates or hyaluronates. In one embodiment of the invention, the one or more than one polycationic polymer ses chitosan. In one embodiment of the invention, the cross-linking mist may be aqueous calcium chloride.

One or more methods of using the medical gel of the invention are also disclosed, including rapidly achieving hemostasis without the need to apply pressure, and providing a biocompatible wound g .

Various embodiments of the invention allow the formulation to be adjusted and implemented for varying the desired viscosity and pre-determined characteristic functions. In one aspect, the ratio of the tionic r to the ionic polymer may be improved, having g degrees of efficiency in wound healing. In another aspect, therapeutics can be added to integrate drug formulations for drug delivery options. Further, other features may encompass controlling temperature(s) and/or pressure(s) during the ation of the medical gel, during application of the gel, and implementing a control for the elasticity or rigidity of the solidified . The matrix formulation, both liquid and solidified structures, may also be dependent on anatomical and physiological measurements and conditions.

Various embodiments of the invention allow the ition to be adjusted and implemented at a first tissue site or a second tissue site, and such modification deemed obvious may be integrated and combined in varying quantities to provide for a structural matrix of any size, shape, and configuration.

DESCRIPTION OF THE DRAWINGS is a side view of an embodiment of the present invention. is a microscopic depiction of how the present ion interacts with blood and itself.

FIGS. 3A to 3I show various polymeric subunits that can be used to make up the polycationic or polyanionic rs. shows the benefits of the present invention as compared to existing technology.

DETAILED DESCRIPTION OF THE INVENTION In the following detailed description, for purposes of explanation and not limitation, exemplary embodiments disclosing specific details are set forth in order to provide a thorough understanding of the present ion. However, it will be nt to one having ordinary skill in the art that the present invention may be practiced in other ments that depart from the specific details disclosed herein. In other instances, detailed descriptions of well-known compositions and methods may be omitted so as not to obscure the description of the present invention. patible polymeric compositions of the present invention may be used to treat external wounds as well as internal wounds. In one ment of the invention, the biocompatible polymeric composition may be applied to a variety of wounds. Non-limiting examples of wounds include, but are not limited to: an external laceration, an abrasion, a burn, an ocular laceration, damage to a parenchymal organ, an internal laceration, a laceration in the gastrointestinal tract, superficial cuts and scrapes, internal bleeding, an arterial bleed, a venous bleed, dental or oral bleeds and incisions. Subjects who can benefit from such wound treatment include a variety of animals including humans, mammals such as horses, sheep, cattle, hogs, dogs, cats, and marine animals such as whales, dolphins, seals, otters, fish, and reptiles such as turtles.

An illustration of a structural matrix in accordance with one embodiment of the invention is shown in As ed, a damaged section of , wound (112) , has vasculature (116) protruding hout. A patible polymeric ition (114) has been applied to the wound (112), which has been coated with protective coat (110) . shows a magnified view of one embodiment of biocompatible ric composition (114), which comprises structural r (226 ) and hemophilic polymer (224) .

Structural polymer (226 ) comprises about 0.1% to 95% by total composition weight of a cross-linkable polyanionic polymer and 0% to 95% by total composition weight of a ss-linkable polyanionic polymer. Hemophilic polymer (224 ) comprises about 1% to 90% by total composition weight of a polycationic polymer. Red blood cell (210 ) is shown in relation to the cationic function groups (212 ) via a red blood cell-cationic group e (216 ).

FIGS. 3A to 3I show various polymers that can be chosen as structural polymer (226) or hemophilic polymer (224) . Polymers can be modified through the addition of carboxymethyl (CM) groups to gain anionic functional groups (218 ). shows carboxymethyl cellulose. Alginate (3A ), sodium hyaluronate (3F ), κ-carrageenan (3G ), geenan (3H ), and sodium polyacrylate (3I ) are es of polymers that would function as structural polymer (226 ). Likewise, chitin (3B ) and chitosan (3C ) are examples of polymers that would function as hemophilic r ( 224 ). shows how any polymer (340) can be modified with a diethylaminoethyl (DEAE) group to gain cationic functional groups (212 ).

Biocompatible polymeric ition (114 ) contains about 0.1% to 99.8% by total composition weight of a solvent. In one embodiment of the invention, the solvent is ethanol.

Preferably the solvent is a 5% aqueous solution of ethanol in water. Non-limiting examples of solvents e water, ethanol, amyl acetate, acetone, methyl ethyl ketone, isopropanol, and tetrahydrofuran. In solution, structural polymer (226 ) and hemophilic polymer (224 ) experience intermolecular interactions which bind them er. Cationic function groups (212 ) on hemophilic polymer (224 ) attract anionic functional groups (218 ) on structural polymer (226 ) and result in ionic cross-linking (214 ). Additionally, hemophilic polymer (224 ) and ural polymer (226 ) can be covalently cross-linked (228 ), similar to a Schiff base or azomethine linkage.

Protective coat (110 ) comprises 0.1% to 30% by weight of a di- or higher valent cation (220 ), 0% to 90% by weight of a hydrophobic polymer, and 5% to 99.9% by weight of a solvent. Protective coat (110 ) cross-links composition (114) by diffusing divalent cation (220 ) s, which s in divalent cation cross-linking (222 ) of structural polymer (226 ). This increases the rigidity of composition (114 ) and allows for better stability.

Protective coat (110 ) can also contain hydrophobic polymers, which limit the water loss from composition (114 ) and improve durability. The hydrophobic polymer may be a polyurethane, nitrocellulose, a cyanoacrylate, a styrene, a polytetrafluoroethane, and a silicone, and combinations thereof. The solvent may be water, amyl acetate, acetone, methyl ethyl ketone, isopropanol, and tetrahydrofuran, and combinations thereof. The di- or higher valent cation may be Ca2+, Fe2+, Fe3+, Ag2+, Ag3+, Au2+, Au3+, Mg2+, Cu2+, Cu3+, and Zn2+. In one embodiment of the invention, the cation is Ca2+.

In one embodiment of the invention, structural polymer (226 ) comprises 0.1% to 5% by weight of sodium alginate and 1% to 5% by weight of sodium hyaluronate, hemophilic polymer (224 ) comprises 2% to 25% by weight of chitosan chloride, and the solvent comprises 65% to 96.9% by weight of a 5% s solution of ethanol in water. In this embodiment, the composition functions as a wound g matrix to facilitate faster tissue regeneration.

In another ment, structural polymer (226 ) comprises 2% to 5% by weight of sodium te and 0% to 2% by weight of sodium hyaluronate, hemophilic r (224 ) comprises 5% to 20% by weight of chitosan chloride, and the solvent comprises 73% to 93% by weight of a 5% aqueous solution of ethanol in water. In this embodiment, the composition functions as a thick gel for rapidly achieving hemostasis without the need to apply pressure.

The composition can be delivered topically to the mised blood vessel.

In another embodiment of the invention, structural r (226 ) comprises 0.1% to 4% by weight of sodium alginate and 1% to 5% by weight of a -rich polypeptide, hemophilic polymer (224 ) comprises 5% to 25% by weight of diethylaminoethyl-dextran (DEAE-Dextran), and the solvent ses 65% to 93% by weight of a 5% aqueous solution of ethanol in water. The biocompatible polymeric composite (114 ) is then linked in situ by applying an aerosol mist comprising 0.1% to 1% by weight of calcium chloride, 1% to 5% by weight of nitrocellulose, and 94% to 98.9% by weight of amyl acetate. In this embodiment, the composition functions as a protective covering for cuts and scrapes that is durable and limits water loss from the wound.

In one embodiment of the invention, the biocompatible ric composition comprises about 3.6% by weight of sodium alginate, about 7% by weight of chitosan chloride, and about 89.4% by weight of a 5% aqueous solution of ethanol in water. This embodiment may function as a composition to treat arterial bleeds.

In one embodiment of the invention, the protective coat comprises a solution sing about 0.1% to about 30% by weight of a di- or higher valent cation; 0% to about 90% by weight of a hydrophobic polymer; and about 5% to about 99.9% by weight of a solvent. In one embodiment of the invention, the protective coat comprises a solution comprising about 0.1% to about 1% by weight of a di-valent cation; about 1 to about 5% by weight of a hydrophobic polymer; and about 94% to about 98.9% by weight of a solvent.

In one ment of the invention, composition (114 ) is used as a carrier for a therapeutic agent such as a drug or biologic molecule. The use of composition (114) as a drug delivery system improves the efficiency of the wound healing gel. In one aspect, protective coat (110 ) is ed with a salt of , increasing the antimicrobial properties of the gel.

In one embodiment, the therapeutic agent is selected from the group consisting of: antimicrobial agents, antibiotics, hormones, proteins (such as calreticulin, thrombin, prothrombin, Factor VIII), and iodine, and ations thereof. In one embodiment of the invention, the therapeutic agent is preferably iodine. In another embodiment of the invention, the therapeutic agent is a protein.

In one ment of the invention, the cross-linkable polyanionic polymer may be a yrene sulfonate (such as sodium polystyrene sulfonate), a polyacrylate (such as sodium polyacrylate), a polymethacrylate (such as sodium polymethacrylate), a polyvinyl sulphate (such as sodium polyvinyl te), a polyphosphate (such as sodium polyphosphate), Iota carrageenan, Kappa eenan, gellan gum, carboxyl methyl cellulose, carboxyl methyl agarose, carboxyl methyl dextran, yl methyl chitin, carboxyl methyl chitosan, a polymer modified with a carboxyl methyl group, an alginate (such as sodium alginate), a r containing a plurality of carboxylate groups, a xanthan gum, and combinations thereof. Preferably, the crosslinkable polyanionic polymer is an alginate, more preferably sodium te.

Preferably the cross-linkable polyanionic polymer comprises about 1% to about 95% by weight of the biocompatible polymeric composition; preferably the cross-linkable polyanionic polymer comprises about 5% to about 40% by weight of the biocompatible polymeric composition; preferably the linkable polyanionic r comprises about % to about 30% by weight of the biocompatible polymeric composition.

In one ment of the ion, the non-cross-linkable polyanionic polymer may be a hyaluronate (such as sodium hyaluronate), a polynucleotide (such as RNA), a polypeptide chain having an average e isoelectric point below 7, a glucosaminoglycan, and a proteoglycan, and combinations thereof. Preferably the non-cross-linkable ionic polymer is a hyaluronate, more preferably sodium hyaluronate.

Preferably the non-cross-linkable polyanionic polymer comprises about 0 to about 95% by weight of the patible polymeric composition; preferably the non-crosslinkable polyanionic polymer ses about 5 to about 25% by weight of the biocompatible polymeric composition; preferably the non-cross-linkable polyanionic polymer comprises about 0 to about 5% by weight of the biocompatible polymeric composition; preferably the non-cross-linkable polyanionic polymer comprises about 0 to about 2% by weight of the biocompatible polymeric composition; preferably the non-cross-linkable polyanionic polymer comprises about 1 to about 5% by weight of the biocompatible polymeric composition.

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

Preferably the polycationic polymer is a chitosan, more preferably chitosan chloride.

Preferably the polycationic r is laminoethyl-dextran (DEAE-Dextran).

Preferably the polycationic polymer comprises about 1% to about 90% by weight of the biocompatible polymeric composition; preferably the polycationic r comprises about 2% to about 80% by weight of the biocompatible polymeric composition; preferably the polycationic polymer comprises about 2% to about 25% by weight of the biocompatible polymeric composition.

The individual ents of the biocompatible polymeric composition may be stored in a variety of different containers for a y of different ations, including for example, packets, sachets, tubes, tubs, pumps, syringes, bottles, bags, and aerosol-based spray cans. The components may be stored in containers made of a variety of materials, including for example, c, metal, or glass. The components may be provided in ly connected configurations, or as separate components for a user to set up prior to use.

The compositions and systems described herein may be included in a kit or article of manufacture for forming a biocompatible ric composition comprising one or more of: a solution comprising a polyanionic polymer; a solution comprising a polycationic polymer; a solvent; and a solution comprising a di- or higher valent cation, a hydrophobic polymer, and solvent. The kit or e of manufacture may further contain gauze, bandages, tape, brushes, spatulas, and sponges.

A number of implementations have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of this document. In particular, for example, various compositions of the ons have been described, but varying similar components and elements may be integrated or utilized in substitution to achieve the same or similar effect. Moreover, varying matrices may be employed to target diverse wound locations, internal or external to the dermal layers of the skin, ing organ transplantation, tissue grafting, and/or various surgical incisions and lesions at any site or location external and/or internal to the body. ingly, other implementations are within the scope of the following claims.

Further, the studies described may e one embodiment of the composition to form a rigid matrix while another composition may be designed with an increased elasticity, alone or in combination. Further, the methods of mixing and formulating the composition may be performed in any order and combination so as to achieve the same or similar effects of the embedded solidified matrix, the matrix ating the formation of naturally cturing tissue. In one embodiment, the one or more than one polyanionic polymer is first applied to a wound and then the one or more than one polycationic polymer is applied to the said one or more than one polymeric polymer at the wound site. In one embodiment, the one or more than one polyanionic r is mixed with the one or more than one polycationic polymer and then the mixture is then applied to the wound. In one embodiment, the one or more than one polyanionic r is applied to a wound at the same time, or about the same time, that the one or more than one polycationic polymer is applied to a wound.

In one embodiment, a method of treating a wound comprises applying one or more than one polyanionic polymer to a wound and then applying one or more than one polycationic polymer to the said one or more than one polymeric polymer at the wound site.

In one embodiment, a method of treating a wound comprises mixing one or more than one ionic polymer with one or more than one tionic polymer and then applying the mixture to the wound. In one embodiment, a method of treating a wound comprises applying one or more than one polyanionic polymer to the wound at the same time, or about the same time, as one or more than one polycationic polymer is applied to a wound.

Claims (13)

What is claimed:

1. A composition consisting of: a) 0.1 % to 5% by weight of sodium alginate; b) 2% to 25% by weight of chitosan; and c) water as a solvent.

2. The composition of claim 1, consisting of 2% to 5% by weight of sodium alginate.

3. The composition of claim 1 or claim 2, consisting of 73% to 93% by weight of water.

4. Use of a composition consisting of: a) 0.1 % to 5% by weight of sodium te; b) 2% to 25% by weight of chitosan; and c) water as a solvent, in the preparation of a ment for treating a bleed.

5. The use of claim 4, wherein the composition consists of 2% to 5% by weight of sodium alginate.

6. The use of claim 4 or claim 5, wherein the composition consists of 73% to 93% by weight of water.

7. The use of any one of claims 4 to 6, wherein the bleed is an arterial bleed, a venous bleed, a dental bleed or an oral bleed.

8. The use of claim 7, wherein the bleed is an al bleed.

9. The use of claim 7, wherein the bleed is a venous bleed.

10. The use of any one of claims 4 to 9, wherein the medicament is adapted to treat the bleed without the need to apply pressure.

11. The use of any one of claims 4 to 10, wherein the medicament is adapted to form a hemostatic matrix at a bleed site.

12. The use of any one of claims 4 to 10, wherein the medicament is adapted to solidify at a bleed site.

13. The ition of claim 1, substantially as herein described with reference to any one of the