Hemostatic compositions and methods

Abstract

Disclosed herein are hemostatic compositions and methods of making and using such disclosed hemostatic compositions.

Description

HEMOSTATIC COMPOSITIONS AND METHODSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 530,618, filed on August 3, 2023, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Uncontrolled bleeding in a surgical or trauma situation can result is adverse outcomes for the patient. Several topical hemostatic products are available but having a composition that is biodegradable and biocompatible is essential for use in internal applications. What is needed is a composition that is fully degradable and biocompatible that can bring about hemostasis or reduce the rate of blood loss.SUMMARY

[0003] In brief, the present disclosure provides compositions, kits, methods of preparing compositions, and methods of using the compositions and kits.

[0004] The above-mentioned and additional features of the present disclosure and the manner of obtaining them will become apparent, and the disclosure will be best understood by reference to the following more detailed description. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.

[0005] This Brief Summary has been provided to introduce certain concepts in a simplified form that are further described in detail below in the Detailed Description. Except where otherwise expressly stated, this Brief Summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.

[0006] The details of one or more aspects are set forth in the description below. The features illustrated or described in connection with one exemplary aspect may be combined with the features of other aspects. Thus, any of the various aspects described herein can be combined to provide further aspects. Aspects of the aspects can be modified, if necessary to employ concepts of the various patents, applications andpublications as identified herein to provide yet further aspects. Other features, objects and advantages will be apparent from the description, the drawings, and the claims.DETAILED DESCRIPTION OF THE DISCLOSURE

[0007] The present disclosure may be understood more readily by reference to the following detailed description of preferred aspects of the disclosure and the Examples included herein. In an aspect, the present disclosure provides a fully degradable composition that can bring about completed hemostasis or a reduction in blood loss . In an aspect, the present disclosure provides a fully degradable composition that can bring about completed hemostasis or a reduction in blood loss when applied topically or internally. In an aspect, the present disclosure provides a fully degradable composition that can bring about gelation of blood when applied topically or internally.

[0008] A composition of the present disclosure may comprise a degradable polymer. In an aspect, a degradable polymer is synthesized from a polysaccharide. Exemplary polysaccharide polymers useful in the present disclosure include, but are not limited to, dextran, hyaluronic acid, hyaluronic acid derivatives, heparin, or chitosan. In an aspect, a degradable polymer comprises a polymer derived from hyaluronic acid (HA). In an aspect, a degradable polymer comprises a polymer derived from chitosan. In an aspect, a degradable polymer comprises a polymer derived from dextran. Polysaccharide derivatives that can be used in the present disclosure include but are not limited to ether derivatives. Polysaccharide ether derivatives can include but are not limited to derivatives described in US 11,440,976 which is incorporated in its entirety herein by reference. In an aspect, hyaluronic acid derivatives comprise one or more alkyl groups that are chemically bound to a hydroxyl group of the hyaluronic acid through an ether bond. In an aspect, hyaluronic acid derivatives comprise one or more alkyl groups that are chemically bound to a hydroxyl group of the hyaluronic acid through the residue of a divinyl sulfone linker. Examples of these derivatives are described in US 11,440,976 which is incorporated in its entirety herein by reference. "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to the specified number of carbon atoms, and which is attached to the rest ofthe molecule by a single bond, e.g., methyl, ethyl, n propyl, 1- methylethyl (iso propyl), n- butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3methylhexyl, 2- methylhexyl, and the like. In an aspect, hyaluronic acid derivatives comprise one or more aromatic groups that are chemically bound to a hydroxyl group of the hyaluronic acid through an ether bond. In an aspect, hyaluronic acid derivatives comprise one or more aromatic groups that are chemically bound to a hydroxyl group of the hyaluronic acid through the residue of a divinyl sulfone linker. An aromatic moiety refers to a carbocyclic aromatic moiety, a.k.a., an aryl moiety, or a heteroaromatic moiety, a.k.a., a heteroaryl moiety, either having 1-20 carbon atoms, the heteroaromatic moiety having at least one heteroatom selected from sulfur, oxygen and nitrogen. Examples of these derivatives are described in US 11,440,976 which is incorporated in its entirety herein by reference.

[0009] The present disclosure provides a derivative of HA in which one or more hydroxyl groups of HA is a modified hydroxyl group, wherein the derivative of hyaluronic acid has the structure HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)nwhere HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20, a cholesterol moiety, a lipid moiety or an aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, a phosphonic acid group or a salt thereof, or an amine group.

[0010] In another aspect, the present disclosure provides a derivative of HA in which two or more hydroxyl groups of hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid or other polyhydric polymer has the structure (Y-R2-X- CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)r, where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, R2 is a substituted or unsubstituted C5-C20 aliphatic or aromatic moiety wherein Ri and R2 are different from each other, wherein n and m are each integers, and n > land m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group or a salt thereof; a phosphonic acid group or a salt thereof; or an amine group.

[0011] In another aspect, the present disclosure provides a derivative of HA in which two or more hydroxyl groups of hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (CH2=CH-SO2CH2CH2O)m-HA- (OCH2CH2SC>2CH2CH2-X-Ri-Y)nwhere HA is hyaluronic acid or other polyhydric polymer, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, each of n and m is an integer, and n > 1 and m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group, or a salt thereof; a phosphonic acid group or a salt thereof; or an amine group.

[0012] In another aspect, the substituted or unsubstituted aliphatic, is a Cs to C20 aliphatic. In another aspect, the substituted or unsubstituted aliphatic, is a Cs to C20 aliphatic. In another aspect, the substituted or unsubstituted aliphatic, is a C10 to C20 aliphatic. In another aspect, the C5 to C20 aliphatic has at least four consecutive -CH2- groups. In another aspect, the Cs to C20 aliphatic has at least six consecutive -CH2- groups. In another aspect, the C10 to C20 aliphatic has at least six consecutive -CH2- groups. In another aspect, the C10 to C20 aliphatic has at least eight consecutive -CH2- groups. In another aspect, the Ri, is a C10 to C20 unsubstituted aliphatic. In another aspect, the Ri, is a C12 to Cis unsubstituted aliphatic. In another aspect, the Ri, is a C12 , C14, Cig or Cis unsubstituted aliphatic. In another aspect, the R2, is a C10 to C20 unsubstituted aliphatic. In another aspect, the R2, is a C12 to Cis unsubstituted aliphatic. In another aspect, the R2, is a C12, C14, Cig or Cis unsubstituted aliphatic.

[0013] In further aspects, the present disclosure provides derivatives of HA such as described above, which are further characterized by the derivative wherein 0.25-50% of a sum of the hydroxyl groups and the modified hydroxyl groups are a modified hydroxyl group. In further aspects, the present disclosure provides derivatives of HA such as described above, which are further characterized by the derivative wherein about 1% to about 95% of the disaccharide units that make up the HA backbone comprise at least one modified hydroxyl group.

[0014] In another aspect, the HA component of the derivatives described above can be replaced by a polysaccharide that has an available hydroxyl or amine group that iscapable of reacting with divinyl sulfone.

[0015] In an aspect, a degradable polymer can comprise a crosslinked polymer. In an aspect, a crosslinked polymer can be a crosslinked polysaccharide. In an aspect, a crosslinked polysaccharide is derived from hyaluronic acid, dextran, or chitosan, a derivatized hyaluronic acid or a combination thereof. Crosslinking agents that can be used include but are not limited to biscarbodiimides, bisepoxides, divinyl sulfone derivatives, diisocyanates, dihalide chlorides, disuccinimidyl derivatives and combinations thereof.

[0016] Biscarbodiimide compounds can include but are not limited to para-phenylene bis-(ethyl)-carbodiimide, 1,6-hexamethylene bis(ethylcarbodiimide), 1,8-octamethylene bis(ethylcarbodiimide), 1,10 decamethylene bis(ethylcarbodiimide), 1,12 dodecamethylene bis(ethylcarbodiimide), PEG-bis(propyl(ethylcarbodiimide)), 2,2'- dithioethyl bis(ethylcarbodiimide), l,l'-dithio-p-phenylene bis(ethylcarbodiimide); para- phenylene-bis(ethylcarbodiimide), and l,l'-dithio-m-phenylene bis(ethylcarbodiimide).

[0017] When utilizing a biscarbodiimide crosslinker, the biscarbodiimide is mixed with a buffered aqueous solution of the derivatized polysaccharide. The target pH of the buffered solution can be between pH 5 and pH 6.5.

[0018] Bisepoxide compounds can include but are not limited to 1,4-butanediol diglycidyl ether (BDDE), 1,2,7,8-diepoxyoctane (DEO), poly(ethylene glycol) diepoxide. When utilizing a bisepoxide crosslinker, the bisepoxide is mixed with an aqueous solution of the derivatized polysaccharide and the pH is raised to a pH > 9. The reaction can be carried out at 40°C for greater than 4 hours to produce a crosslinked composition. In an aspect, the crosslinking reaction can be performed at room temperature. In an aspect, the crosslinking reaction can be performed at greater than 4 °C.

[0019] Divinyl sulfone crosslinkers can include but are not limited to divinyl sulfone and poly(ethylene glycol) bisvinyl sulfone.

[0020] In an aspect, the crosslinking can result from a Michael addition reaction. Examples of a Michael addition reaction include but are not limited to the reaction between a vinyl group and an amine, hydroxyl, thiol group or a combination thereof. In an aspect, the crosslinking can result from a radical reaction from a photopolymerizationreaction or a thermal polymerization reaction.

[0021] In an aspect, a HA derivative as described above that comprises residual available vinyl sulfone functional groups can be crosslinked in the presence of an external crosslinking agent that has at least two free thiol functional groups. These free thiol groups may be positioned upon a central molecule, "C". The central molecule may be a linear or cyclic alkane, a polyethylene glycol (PEG) oligomer or polymer, or any other such suitable central molecule. In the case of PEG-based crosslinking agents, the PEG may be linear, branched (having two polymer arms), or multi-armed (e.g., having 3, 4, 5, 6, 7, 8 or more polymer arms). Thus, in such instances, the central molecule will typically be a linear PEG, a branched PEG having 2 arms, or a multi-armed PEG having PEG arms emanating from a central core.

[0022] Illustrative cores for such multi-armed polymers include erythritol, pentaerythritol, trimethylolpropane, glycerol, glycerol dimer (3,3'-oxydipropane-l,2-diol), glycerol oligomers, sorbitol, hexaglycerol, and the like.

[0023] Illustrative thiol crosslinking agents include PEG-dithiol (HS-PEG-SH), 3-arm PEG-tri-thiol (glycerine core), 4-arm PEG-tetrathiol (pentaerythritol core), or 8-arm PEG- octa-thiol (hexaglycerine core). The foregoing multi-armed PEG reagents may also have fewer than all arms functionalized with thiol. Additional suitable thiol reagents having PEG as the central molecule are available from Laysan Bio (Arab, Ala.), as well as aromatic dithiols such as those available from NanoScience. Other suitable thiol crosslinking agents include dimercaptosuccinic acid, 2,3-dimercapto-l-propanesulfonic acid, trimethylolpropane tris(3-mercaptopropionate), dithiol functionalized pluronics F127, dithiol functionalized F68, dihydrolipoic acid, peptides containing at least 2 cysteine amino acids, thiol functionalized dextran, and thiol-functionalized hyaluronic acid.

[0024] In another aspect, a mixture of at least 2 different thioether derivatized HA can be mixed together, a crosslinking agent can be added and the reactions conditions adjusted such that the derivatized HA polymers are crosslinked. The relative ratios of the different derivatized HA can be altered such that crosslinked derivatized HA polymers with different properties are obtained. These properties include but are not limited toequilibrium swelling, swelling rate, drug release characteristics, elastic modulus, storage modulus, loss modulus, degradation, tensile strength, tissue adhesiveness and lubricity. As used herein "derivatized HA polymers" may also include compositions comprising one or more derivatized HA polymers.

[0025] In another aspect, at least 2 different crosslinking agents can be used to crosslink the derivatized HA. In one aspect, two different crosslinking agents from the same group could be used to crosslink the derivatized HA polymers. For example, divinyl sulfone and polyethylene glycol) bisvinyl sulfone or 1,4-butanediol diglycidyl ether (BDDE) and poly(ethylene glycol) diepoxide could be used.

[0026] In another aspect, two different crosslinking agents from different groups could be used. For example, divinyl sulfone and 1,4-butanediol diglycidyl ether (BDDE) may be used to crosslink the derivatized HA. In another aspect, the crosslinker can be added sequentially such that initial crosslinking occurs in the presence of the first crosslinked and then the second crosslinker is added such that secondary crosslinking occurs. The reaction conditions may be changed after the first crosslinking reaction and prior to the second crosslinking reaction. Reaction conditions such as temperature, pH, buffer, ionic strength and solvent composition can be altered.

[0027] In an aspect, crosslinked derivatized HA polymers can be prepared though ionic crosslinking. This can be accomplished by mixing a derivatized polyhydric polymer of this disclosure that has a negative charge with a compound that has two or more positive charges. In one aspect, a solution of the derivatized HA polymer of this disclosure that has a negative charge can be prepared and then mixed with a solution of a compound that has two or more positive charges. Inorganic compounds that can be used include but are not limited to ferric chloride, aluminum chloride, chromium sulfate, and aluminum sulfate. Positively charged polymers that can be used include polymers that comprise more than two lysines, arginine or histidine amino acids, chitosan and chitosan derivatives, deacetylated hyaluronic acid, polyethyleneimine (PEI), poly( / V, / V- dimethylaminoethylmethacrylate), poly(4-vinylpyridine), polyethylene glycol-polylysine block copolymers (PEG-PLL), dextran grafted polylysine copolymers, or combinationsthereof.

[0028] A solution of the derivatized HA polymer can be prepared by dissolving the derivatized HA polymer in an appropriate solvent or a combination of solvents. For example, water or a combination of water and water-miscible solvent can be used. When water is used as a solvent, the water can include but is not limited to deionized water, distilled water, water prepared through reverse osmosis. In one aspect, the water can further comprise a salt, a buffer or a combination thereof. In another aspect, the salt is sodium chloride. In another aspect, the buffer is a phosphate buffer or a citrate buffer. Water-miscible solvents can include but are not limited to methanol, ethanol, isopropanol, dimethyl formamide (DMF) acetone, 1,4-dioxane, pyridine, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) and acetonitrile. The prepared solutions can be sterilized by filtering through a 0.2 pm sterile filter. In an aspect, a solution can be prepared using one derivatized HA. In an aspect, a solution can be prepared using 2 different derivatized HA materials. The concentration of the prepared solutions can range from, e.g., 0.01% (w / v) to about 50% (w / v). In an aspect, the concentration may be from about 0.1% (w / v) to 10% (w / v). In an aspect, the concentration is between about 0.75% (w / v) and about 3% (w / v). In another aspect, the concentration is between about 0.75% (w / v) and about 1.5% (w / v).

[0029] The composition of the present disclosure can be in the form of a solution, a foam, a gel, a slurry, a film, a non-continuous film, a powder, particles, spheres, three- dimensional shape, a lyophilized matrix, a non-woven matrix, an electrospun matrix, or a combination thereof. In an aspect, median size (Dv50) of particles are in the range of about 10 pm to about 2000 pm. In an aspect, the median size (Dv50) of particles is in the range of about 10 pm to about 200 pm. In an aspect, the median size (Dv50) of particles is in the range of about 200 pm to about 600 pm. In an aspect, the median size (Dv50) of particles is in the range of about 600 pm to about 1200 pm. In an aspect, the median size (Dv50) of particles is in the range of about 1200 pm to 2000 pm. In an aspect, a film, non-continuous film or lyophilized matrix can have a thickness of about 40 pm to about 3000 pm. In an aspect, a film, non-continuous film or lyophilized matrix can have a thickness of about 40 pm to about 300 pm. In an aspect, a film, non-continuous film or lyophilized matrix canhave a thickness of about 300 pm to about 600 pm. In an aspect, a film, non-continuous film or lyophilized matrix can have a thickness of about 600 pm to about 1200 pm. In an aspect, a film, non-continuous film or lyophilized matrix can have a thickness of about 1200 pm to about 3000 pm. In an aspect, a film, non-continuous film or lyophilized matrix can have a thickness greater than about 3000 pm. In an aspect, a composition of the present disclosure may be porous.

[0030] In an aspect, a composition of the present disclosure may further comprise a buffer, complexing agent, tonicity modulator, ionic strength modifier, solvent, antioxidant, preservative, viscosity modifier, pH modifier, surfactant, emulsifier, phospholipid, stabilizer or a combination thereof.

[0031] Buffers that can be used include aqueous solutions prepared using one or more of the following materials: potassium hydrogen phthalate, sodium hydrogen phthalate, potassium or sodium dihydrogen phosphate, dipotassium or disodium hydrogen phosphate, phosphoric acid, boric acid, sodium acetate, acetic acid, ammonium chloride, ammonium acetate, (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid).

[0032] Complexing agents can include but are not limited to a-cyclodextrin, 0- cyclodextrin (2-hydroxypropyl)-beta-cyclodextrin, sulfobutylether beta cyclodextrin sodium, or ethylenediaminetetraacetic acid (EDTA) or salts thereof.

[0033] Phospholipids that can be used include but are not limited to hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-a-dimyristoyl phosphatidylcholine, or L-a-dimyristoyl phosphatidylglycerol.

[0034] Surfactants that can be used include ionic and non-ionic surfactants. Ionic surfactants can include cationic, anionic and zwitterionic surfactants. Non-ionic surfactants can include but are not limited to (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-tocopherol polyethylene glycol 1000 succinate, Brij, Myrj, polysorbate 20, polysorbate 80, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 85, Solutol HS 15, sorbitan monooleate (Span 80), Sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan trioleate (Span 8) poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, nonoxynol-9, Softigen767 , octyl beta-D-glycopyranoside (OGP), hexyl beta-D-glucopyranoside (HGP), Octyl beta- D-l-thioglucopyranoside (TGP), Decyl-beta-D-glucopyranoside (DGP), Dodecyl-beta-D- glucopyranoside (DdGP), N-octyl beta-D-Maltoside (ODM), decyl beta-D-maltopyranoside (DMP), cyclohexyl-ethanoyl-maltoside, n-decyl- and n-dodecyl-sucrose, and mono- and difatty acid esters of PEG 300, 400, or 1750. Anionic surfactants can include but are not limited to sodium lauryl sulfate, fatty acid salts, sodium laureth sulfate, dioctyl sodium sulfosuccinate. Cationic surfactants can include but are not limited to Phosphatidylcholine (Lecithin), cetrimide, cetrimonium bromide, benethonium chloride, dimethyldioctadecyl ammonium chloride, tetradecyl trimethyl ammonium bromide, cetylpyridinium chloride, esterquat, and benzalkonium chloride. Zwitterionic surfactants can include but are not limited to Cocamidopropyl betaine, (3-[(3-Cholamidopropyl)dimethylammonio]-l- propanesulfonate) and cocamidopropyl hydroxysultaine, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins.

[0035] Solvents that can be used include water-soluble organic solvents. Watersoluble organic solvents include but are not limited to polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N- methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide.

[0036] Tonicity modifiers that can be used include but are not limited to dextrose, sucrose, mannitol, glycerin, sodium chloride, and potassium chloride.

[0037] pH modifiers that can be used include but are not limited to citric acid and its salts, salts of phosphoric acid, tartaric acid, lactic acid, glycolic acid, sodium hydroxide, phosphoric acid, sulfuric acid, oxalic acid and hydrochloric acid.

[0038] Anti-oxidants that can be used include but are not limited to ascorbic acid, butylated hydroxyanisole, Butylhydroxytoluene, Vitamin A, vitamin E, a-tocopherol, thioglycerol, cysteine, acetylcysteine, cystine, dithioerythritol, dithiothreitol, glutathione, Sodium bisulfite, Sodium metabisulfite, thiourea, uric acid, melatonin, propyl gallate, tertiary butylhydroquinone and combinations thereof.

[0039] Emulsifiers that can be used include but are not limited to glyceryl monostearate, isopropyl palmitate, polyethylene glycol 400 monostearate, as well as thecompounds listed as surfactants and combinations thereof.

[0040] Preservatives that can be used include but are not limited to benzoic acid, sorbic acid, boric acid, methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, sodium propionate, phenyl ethyl alcohol, chlorobutanol, benzyl alcohol, potassium sorbate, phenol, chlorocresol, o-phenyl phenol, thiomersal, nitromersol, phenylmercuric nitrate, phenylmercuric acetate, benzalkonium and combinations thereof.

[0041] In an aspect, the composition may further comprise a polyethylene oxide - polypropylene oxide block copolymer. Examples of polyethylene oxide - polypropylene oxide block copolymers include but are not limited to Polonamer 188, Poloxamer 124, Poloxamer 407, Poloxamer 338, Poloxamer 237, Pluronics F127 and Pluronics F68.

[0042] A composition can further comprise a biologically active agent. In an aspect, a composition can comprise more than one biologically active agent. Exemplary biologically active agents include, without limitation, small molecule drugs, peptides, proteins, growth factors, hormones, antibodies, agonists, antagonists, anti-bacterial, and / or anti-fungal agents.

[0043] Biologically active agents that can be incorporated into formulations with the compositions described include: antiandrogens, antibacterial, antioestrogens, androgens and anabolic agents, antibiotics, antimigraine drugs, antihistamines, antianxiety drugs, antidiuretics, antihistamines, antirheumatic agents, antigens, analgesics, antidepressants, anti-inflammatories, anesthetics, aminoglycosides antibodies, antiviral, adrenergic stimulants, anticonvulsants, antianginal agents, antiarrhythmics, antimalarials, antimitotic, anthelmintics, anorectic agents, antitussives, antipruritics, antipyretics, antiAlzheimer's agents, anti-Parkinson's agents, antiemetics and antinauseants, antihypertensives, anticoagulants, antifungals, antimicrobials, allergens, antidiarrheals, antihyperuricemic agents, adrenergic stimulants, antiparasitic agents, antiproliferative agents, antipsychotic drugs, antithyroid agents, beta-adrenergic blocking agents, bronchodilators; bronchospasm relaxants, blood clotting factors, blood coagulation factors, cytotoxic agents, cytostatic agents, chemotherapeutics, clot inhibitors, clot dissolving agents, cells, CNS stimulants, Corticosteroids, calcium channel blockers,cofactors, ceramides, cardiotonic glycosides, cytokines (e.g., lymphokines, monokines, chemokines); colony stimulating factors (e.g., GCSF, GM-CSF, MCSF); dermatological agents, decongestants, diuretics, expectorants, endectocide agents, growth factors, hemostatic agents, hypoglycemic agents, hormones and hormone analogs, hypercalcemia, Hypnotics, interleukins (IL-2, IL-3, IL-4, IL-6); interferons (.beta.-IFN, . alpha. -IFN and .gamma.-IFN); immunosuppressants, muscle relaxants, microorganisms, non-steroidal anti-inflammatory agents, nucleic acids, nutritional agents, neuromuscular blocking agents, neuroleptics, Neurotoxins , nutraceuticals, oligonucleotides, oestrogens, obstetric drugs, ovulation inducers, opioids, progestogens, pituitary hormones, Pituitary inhibitors proteins, peptides, polysaccharides, protease inhibitors, prostaglandins, quinolones, reductase inhibitors, sulfa drugs, sclerosant, sedatives, sodium channel blockers, steroids, steroidal anti-inflammatory agents, smoking cessation agents, toxins, thrombolytic agents, thyroid hormones, tumor necrosis factor; vesicles, vitamins, viruses, vasodilators, and vaccines. Additional representative examples of biologically active agents that may be suitable for use in the compositions of the present invention include, but are not limited to, antidiarrheals such as diphenoxylate, loperamide and hyoscyamine; antihypertensives such as hydralazine, minoxidil, captopril, enalapril, clonidine, prazosin, debrisoquine, diazoxide, guanethidine, methyldopa, reserpine, trimethaphan; calcium channel blockers such as diltiazem, felodipine, amlodipine, nitrendipine, nifedipine and verapamil; antiarrhythmics such as amiodarone, flecainide, disopyramide, procainamide, mexiletine and quinidine, antianginal agents such as glyceryl trinitrate, erythrityl tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate, perhexiline, isosorbide dinitrate and nicorandil; beta-adrenergic blocking agents such as alprenolol, atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol, nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol and timolol maleate; cardiotonic glycosides such as digoxin and other cardiac glycosides and theophylline derivatives; adrenergic stimulants such as adrenaline, ephedrine, fenoterol, isoprenaline, orciprenaline, rimiterol, salbutamol, salmeterol, terbutaline, dobutamine, phenylephrine, phenylpropanolamine, pseudoephedrine and dopamine; vasodilators such as cyclandelate, isoxsuprine, papaverine, dipyridamole,isosorbide dinitrate, phentolamine, nicotinyl alcohol, co-dergocrine, nicotinic acid, glyceryl trinitrate, pentaerythritol tetranitrate and xanthinol; Antiproliferative agents such as paclitaxel, estradiol, actinomycin D, sirolimus, tacrolimus, everolimus, 5-fluorouracil and dexamethasone; Antimigraine preparations such as ergotamine, dihydroergotamine, methysergide, pizotifen and sumatriptan; Anticoagulants and thrombolytic agents such as warfarin, dicoumarol, low molecular weight heparins such as enoxaparin, streptokinase and its active derivatives; Hemostatic agents such as aprotinin, tranexamic acid and protamine; analgesics and antipyretics including the opioid analgesics such as buprenorphine, dextromoramide, dextropropoxyphene, fentanyl, alfentanil, sufentanil, hydromorphone, methadone, morphine, oxycodone, papaveretum, pentazocine, pethidine, phenopefidine, codeine, dihydrocodeine; acetylsalicylic acid (aspirin), paracetamol, synthetic alpha? -adrenoreceptor agonist, dexmedetomidine hydrochloride, flunixin meglumine, meperidine, phenylbutazone and phenazone; immunosuppressants, antiproliferatives and cytostatic agents such as rapamycin (sirolimus) and its analogs (everolimus and tacrolimus); neurotoxins such as capsaicin, botulinum toxin (Botox™); Hypnotics and sedatives such as the barbiturates amylobarbitone, butobarbitone and pentobarbitone and other hypnotics and sedatives such as chloral hydrate, chlormethiazole, hydroxyzine and meprobamate; antianxiety agents such as the benzodiazepines alprazolam, bromazepam, chlordiazepoxide, clobazam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam, temazepam and triazolam; neuroleptic and antipsychotic drugs such as the phenothiazines, chlorpromazine, fluphenazine, pericyazine, perphenazine, promazine, thiopropazate, thioridazine, trifluoperazine; and butyrophenone, droperidol and haloperidol; and other antipsychotic drugs such as pimozide, thiothixene and lithium; antidepressants such as the tricyclic antidepressants amitriptyline, clomipramine, desipramine, dothiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline and trimipramine and the tetracyclic antidepressants such as mianserin and the monoamine oxidase inhibitors such as isocarboxazid, phenelzine, tranylcypromine and moclobemide and selective serotonin reuptake inhibitors such as fluoxetine, paroxetine, citalopram, fluvoxamine and sertraline;CNS stimulants such as caffeine and 3-(2-aminobutyl) indole; antipruritics can include compounds such as synthetic Janus Kinase (JAK) inhibitors, NK-1 receptor antagonists, antibodies that neutralize interleukin-31 (IL-31). These can include oclacitinib maleate, Serlopitant, and Lokivetmab, anti-Alzheimer's agents such as tacrine; anti-Parkinson’s agents such as amantadine, benserazide, carbidopa, levodopa, benztropine, biperiden, benzhexol, procyclidine and dopamine-2 agonists such as S(-)-2-(N-propyl-N-2- thienylethylamino)-5-hydroxytetralin (N-0923), anticonvulsants such as phenytoin, valproic acid, primidone, phenobarbitone, methylphenobarbitone and carbamazepine, ethosuximide, methsuximide, phensuximide, sulthiame and clonazepam, antiemetics and antinauseants such as the phenothiazines prochlorperazine, thiethylperazine, a neurokinin (NK1) receptor antagonist, maropitant citrate and 5HT-3 receptor antagonists such as ondansetron and granisetron, as well as dimenhydrinate, diphenhydramine, metoclopramide, domperidone, hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, clebopride and bromopride; non-steroidal anti-inflammatory agents including their racemic mixtures or individual enantiomers where applicable, preferably which can be formulated in combination with dermal and / or mucosal penetration enhancers, such as ibuprofen, flurbiprofen, ketoprofen, aceclofenac, diclofenac, aloxiprin, naproxen, aspirin, diflunisal, fenoprofen, indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxicam, salicylamide, salicylic acid, sulindac, desoxysulindac, tenoxicam, tramadol, ketorolac, flufenisal, salsalate, triethanolamine salicylate, aminopyrine, antipyrine, oxyphenbutazone, apazone, cintazone,flufenamic acid, clonixerl, clonixin, meclofenamic acid, 6-chloro-a-methyl-9H-carbazole-2-acetic acid (carprofen), flunixin, colchicine, demecolcine, allopurinol, oxypurinol, benzydamine hydrochloride, dimefadane, indoxole, intrazole, mimbane hydrochloride, paranylene hydrochloride, tetrydamine, benzindopyrine hydrochloride, fluprofen, ibufenac, naproxol, fenbufen, cinchophen, diflumidone sodium, fenamole, flutiazin, metazamide, letimide hydrochloride, nexeridine hydrochloride, octazamide, molinazole, neocinchophen, nimazole, proxazole citrate, tesicam, tesimide, tolmetin, and triflumidate; antirheumatic agents such as penicillamine, aurothioglucose, sodium aurothiomalate, methotrexate andauranofin; muscle relaxants such as baclofen, diazepam, cyclobenzaprine hydrochloride, dantrolene, methocarbamol, orphenadrine and quinine; agents used in gout and hyperuricemia such as allopurinol, colchicine, probenecid and sulphinpyrazone; estrogens such as estradiol, oestriol, estrone, ethinylestradiol, mestranol, stilbestrol, dienestrol, epiestriol, estropipate and zeranol; Progesterone and other progestogens such as allylestrenol, dydrogesterone, lynestrenol, norgestrel, norethynodrel, norethisterone, norethisterone acetate, gestodene, levonorgestrel, medroxyprogesterone and megestrol; antiandrogens such as cyproterone acetate and danazol; Antioestrogens such as tamoxifen and epitiostanol and the aromatase inhibitors, exemestane and 4-hydroxy- androstenedione and its derivatives; androgens and anabolic agents such as testosterone, methyltestosterone, clostebol acetate, drosta noIone, furazabol, nandrolone oxandrolone, stanozolol, trenbolone acetate, dihydro-testosterone, 17-(. alpha. -methyl-19- noriestosterone and fluoxymesterone; 5-alpha reductase inhibitors such as finasteride, turosteride, LY-191704 and MK-306; Corticosteroids such as betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisone, triamcinolone, triamcinolone acetonide; Glycosylated proteins, proteoglycans, glycosaminoglycans such as chondroitin sulfate; chitin, acetyl-glucosamine, hyaluronic acid; Complex carbohydrates such as glucans; Further examples of steroidal antiinflammatory agents such as cortodoxone, fludroracetonide, fludrocortisone, diflorasone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and its other esters, chloroprednisone, clocortolone, descinolone, desonide, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide, fluocortolone, fluoromethoIone, fluperolone, fluprednisolone, meprednisone, methylprednisolone, paramethasone, cortisone acetate, hydrocortisone cyclopentylpropionate, cortodoxone, flucetonide, fludrocortisone acetate, flurandrenolone, aincinafal, amcinafide, betamethasone,betamethasone benzoate, chloroprednisone acetate, clocortolone acetate, descinolone acetonide, desoximetasone, dichlorisone acetate, difluprednate, flucloronide, flumethasone pivalate, flunisolide acetate, fluperolone acetate, fluprednisolone valerate, paramethasone acetate, prednisolamate, prednival, triamcinolone hexacetonide, cortivazol, formocortal and nivazol; pituitary hormones and their active derivatives or analogs such as corticotrophin, thyrotropin, follicle stimulating hormone (FSH), a gonadotropin-releasing hormone (GnRH) analog, deslorelin acetate, cetrorelix acetate, gonadorelin acetate , clomiphene, Human chorionic gonadotropin (HCG), luteinizing hormone (LH) and gonadotrophin releasing hormone (GnRH); Hypoglycemic agents such as insulin, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide and metformin; thyroid hormones such as calcitonin, thyroxine and liothyronine and antithyroid agents such as carbimazole and propylthiouracil; other miscellaneous hormone agents such as octreotide; pituitary inhibitors such as bromocriptine; ovulation inducers such as clomiphene; diuretics such as the thiazides, related diuretics and loop diuretics, bendrofluazide, chlorothiazide, chlorthalidone, dopamine, cyclopenthiazide, hydrochlorothiazide, indapamide, mefruside, methyclothiazide, metolazone, quinethazone, bumetanide, ethacrynic acid and frusemide and potassium sparing diuretics, spironolactone, amiloride and triamterene; antidiuretics such as desmopressin, lypressin and vasopressin including their active derivatives or analogs; obstetric drugs including agents acting on the uterus such as ergometrine, oxytocin and gemeprost; prostaglandins such as alprostadil (PGE1), prostacyclin (PGI2), dinoprost (prostaglandin F2- alpha) and misoprostol; antimicrobials including the cephalosporins such as cephalexin, cefoxitin and cephalothin; Penicillins such as amoxycillin, amoxycillin with clavulanic acid, ampicillin, bacampicillin, benzathine penicillin, benzylpenicillin, carbenicillin, cloxacillin, methicillin, phenethicillin, phenoxymethylpenicillin, flucloxacillin, mezlocillin, piperacillin, ticarcillin and azlocillin; tetracyclines such as minocycline, chlortetracycline, tetracycline, demeclocycline, doxycycline, methacycline and oxytetracycline and other tetracyclinetype antibiotics; aminoglycosides such as amikacin, amikin sulfate, gentamicin, kanamycin, neomycin, netilmicin and tobramycin; antifungals such as amorolfine, isoconazole,clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, zinc, pyrithione and sodium pyrithione; quinolones such as nalidixic acid, cinoxacin, ciprofloxacin, enoxacin and norfloxacin; sulfonamides such as phthalylsulfathiazole, sulfadoxine, sulphadiazine, sulfamethizole and sulfamethoxazole; sulphones such as dapsone; other miscellaneous antibiotics such as chloramphenicol, clindamycin, erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin gluceptate, erythromycin ethylsuccinate, erythromycin lactobionate, roxithromycin, lincomycin, natamycin, nitrofurantoin, spectinomycin, vancomycin, aztreonam, colistin IV, metronidazole, tinidazole, secnidazole, ornidazole, fusidic acid, trimethoprim, and 2-thiopyridine N-oxide; halogen compounds, particularly iodine and iodine compounds such as iodine-PVP complex and diiodohydroxyquin, hexachlorophene; chlorhexidine; chloroamine compounds, silver sulfadiazine, silver, nanoparticulate silver, silver nitrate, silver zeolites, silver cations, AgPO3 Ag3PO4, Ag4P2O7, exsalt™SD7 (Exciton Technologies) exsalt™T7 (Exciton Technologies); lincomycin Hydrochloride, tricyclic tetrahydroquinoline antibacterial agents, 8-pyrazinyl-S-spiropyrimidinetrione- oxazinoquinoline derivatives, 3-spiropyrimidinetrione-quinoline derivatives, thiadiazol- spiropyrimidinetrione-quinoline derivatives, (2R,4S,4aS)-10-fluoro-2,4-dimethyl-8-(4- methyloxazol-2-yl)-2,4,4a,6-tetra-hydro-lH,l'H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'- pyrimidine]-2',4',6'(-3'H)-trione, (2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-(3- methylisoxazol-5-yl)-2,4,4a,6-tetrahydro-lH,l'H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'- pyrimidine]-2',-4',6'(3'H)-trione, (2R,4S,4aS)-10-fluoro-2,4-dimethyl-8-(oxazol-2-yl)- 2,4,4a,6-tetrahydro-lH-,l'H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]- 2',4',6'(3'H)-trione, (2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-(2-methyloxazol-5-yl)- 2,4,4a,6-tetrahydro-lH,l'H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4'- ,6'(3'H)-trione, (2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-(oxazol-4-yl)-2,4,4a,6-tetrahydr- o-lH,l'H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3'H)-trione, (2R,4S,4aS)-9-fluoro-2,4-dimethyl-8-(4-methyloxazol-2-yl)-2,4,4a,6-tetrahydro-lH,l'H- spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3-'H)-trione, (2R,4S,4aS)-9,10-difluoro-8-(4-(4-fluorophenyl)oxazol-5-yl)-2,4-dimethyl-2,4,4a,6-tetrahyd ro-lH,l'H- spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3'H)-trione, (2S,4R,4aR)-2,4- dimethyl-8-(oxazol-5-yl)-2,4,4a,6-tetrahydro-lH,l'H-spiro-[[l,4]oxazino[4,3-a]quinoline- 5,5'-pyrimidine]-2',4',6'(3'H)-trione, (2S,4R,4aR)-8-(4-ethyloxazol-2-yl)-9,10-difluoro-2,4- dimethyl-2,4,4a,6-tetrahydro-lH, H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]- 2',4',-6'(3'H)-trione, (2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-(oxazol-2-yl)-2,4,4a,6- tetrahydro-lH, H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3'H)-trione, benzoyl peroxide; antituberculosis drugs such as ethambutol, isoniazid, pyrazinamide, rifampicin and clofazimine; antimalarials such as primaquine, pyrimethamine, chloroquine, hydroxychloroquine, quinine, mefloquine and halofantrine; compounds such as azithromycin, aztreonam, cefaclor, Cefadroxil , Cefazolin, Cefdinir, Cefepime Hydrochloride, (cefoperazone sodium, Ceftaroline fosamil, avibactam, Ceftazidime sodium, Ceftibuten, ceftiofur, Tazobactam, cefovecin sodium [(6R,7R)-7-[[(2Z)-(2-amino- 4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-3-[(2S)-tetrahydro-2-furanyl]-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, monosodium salt] Cefuroxime Axetil, Cefuroxime, Cephalexin, Chloramphenicol Sodium, Ciprofloxacin HCI, Clarithromycin, Clindamycin hydrochloride, Clindamycin palmitate hydrochloride, Clindamycin phosphate, Dalbavancin Hydrochloride, Daptomycin, Demeclocycline hydrochloride, Dicloxacil lin, Doripenem, Doxycycline, Doxycycline calcium, Doxycycline hyclate, Doxycycline monohydrate, Ertapenem sodium, Erythromycin, Erythromycin Ethylsuccinate, Erythromycin lactobionate, Erythromycin stearate, Erythromycin, Fosfomycin tromethamine, Gemifloxacin mesylate, Gentamicin Sulfate, Imipenem, Kanamycin, Levofloxacin, Lincomycin hydrochloride, Linezolid, Meropenem, Methenamine Hippurate, Metronidazole , Metronidazole, Micafungin sodium, Minocycline Hydrochloride, Minocycline, Moxifloxacin hydrochloride, Nafcillin, Nalidixic acid, Neomycin Sulfate, Nitrofurantoin, Norfloxacin, Ofloxacin, Oritavancin diphosphate, Oxacillin, Penicillin G, Penicillin G benzathine, Penicillin G Sodium, Penicillin V Potassium, Piperacillin Sodium, Polymyxin B Sulfate, Quinupristin, dalfopristin, Spectinomycin hydrochloride, Streptomycin, Sulfamethoxazole, Tedizolid Phosphate, Telavancin, Telithromycin,Tetracycline Hydrochloride, Ticarcillin disodium, Tigecycline, Tobramycin Sulfate, Tobramycin, Trimethoprim hydrochloride, tulathromycin, Vancomycin hydrochloride.

[0044] Antiviral agents may be included in the compositions of the present disclosure, where exemplary antiviral agents include acyclovir and acyclovir prodrugs, famciclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol, tromantadine and idoxuridine. Other suitable biologically active agents include anthelmintics such as mebendazole, thiabendazole, niclosamide, praziquantel, pyrantel embonate and diethylcarbamazine; cytotoxic agents such as plicamycin, cyclophosphamide, dacarbazine, fluorouracil and its prodrugs (described, for example, in International Journal of Pharmaceutics, 111, 223-233 (1994)), methotrexate, procarbazine, 6-mercaptopurine and mycophenolic acid; anorectic and weight reducing agents including dexfenfluramine, fenfluramine, diethylpropion, mazindol and phentermine; agents used in hypercalcemia such as calcitriol, dihydrotachysterol and their active derivatives or analogs; antitussives such as ethylmorphine, dextromethorphan and pholcodine; antiparasitic and endectocide agents such as moxidectin, Ivermectin, Niclosamide, Praziquantel, Pyrantel, Pyrvinium, Albendazole, Flubendazole, Mebendazole, Thiabendazole.

[0045] Compositions of the present disclosure may include: an expectorant such as carbocysteine, bromhexine, emetine, quanifesin, ipecacuanha and saponins; Decongestants such as phenylephrine, phenylpropanolamine and pseudoephedrine; bronchospasm relaxants such as ephedrine, fenoterol, orciprenaline, rimiterol, salbutamol, sodium cromoglycate, cromoglicic acid and its prodrugs (described, for example, in International Journal of Pharmaceutics 7, 63-75 (1980)), terbutaline, ipratropium bromide, salmeterol and theophylline and theophylline derivatives; antihistamines such as meclizine, cyclizine, chlorcyclizine, hydroxyzine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine, diphenhydramine, diphenylamine, doxylamine, mebhydrolin, pheniramine, triprolidine, azatadine, diphenylpyraline, methdilazine, terfenadine, astemizole, loratadine and cetirizine; Local anesthetics such as benzocaine, bupivacaine, amethocaine, lignocaine, lidocaine, cocaine,cinchocaine, dibucaine, mepivacaine, prilocaine, etidocaine, veratridine (specific c-fiber blocker) and procaine; stratum corneum lipids, such as ceramides, cholesterol and free fatty acids, for improved skin barrier repair [Man, et al. J. Invest. Dermatol., 106(5), 1096, (1996)]; neuromuscular blocking agents such as suxamethonium, alcuronium, pancuronium, atracurium, gallamine, tubocurarine and vecuronium; sclerosing agents or sclerosants may be a surfactant or it may be selected from the group consisting of ethanol, dimethyl sulfoxide, sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate, and sotradecol; an angiogenesis inhibitor; a 5-lipoxygenase inhibitor or antagonist; a chemokine receptor antagonist; a cell cycle inhibitor; a taxane; an anti-microtubule agent; paclitaxel; an analogue or derivative of paclitaxel; a vinca alkaloid; camptothecin or an analogue or derivative thereof; a podophyllotoxin, wherein the podophyllotoxin may be an etoposide or an analogue or derivative thereof; an anthracycline, wherein the anthracycline may be doxorubicin or an analogue or derivative thereof or the anthracycline may be mitoxantrone or an analogue or derivative thereof; a platinum compound; a nitrosourea; a nitroimidazole; a folic acid antagonist; a cytidine analogue; a pyrimidine analogue; a fluoropyrimidine analogue; a purine analogue; a nitrogen mustard or an analogue or derivative thereof; a hydroxyurea; a mitomycin or an analogue or derivative thereof; an alkyl sulfonate; a benzamide or an analogue or derivative thereof; a nicotinamide or an analogue or derivative thereof; a halogenated sugar or an analogue or derivative thereof; a DNA alkylating agent; an anti-microtubule agent; a topoisomerase inhibitor; a DNA cleaving agent; an antimetabolite; a nucleotide interconversion inhibitor; a dihydroorotate dehydrogenase inhibitor; a DNA intercalation agent; an RNA synthesis inhibitor; a pyrimidine synthesis inhibitor; a cyclin dependent protein kinase inhibitor; an epidermal growth factor kinase inhibitor; an elastase inhibitor; a factor Xa inhibitor; a farnesyltransferase inhibitor; a fibrinogen antagonist; a guanylate cyclase stimulant; a heat shock protein 90 antagonist; which may be a geldanamycin or an analogue or derivative thereof; a guanylate cyclase stimulant; a HMGCoA reductase inhibitor, which may be simvastatin or an analogue or derivative thereof; an IKK2 inhibitor; an IL-1 antagonist; anICE antagonist; an IRAK antagonist; an IL-4 agonist; an immunomodulatory agent; sirolimus or an analogue or derivative thereof; everolimus or an analogue or derivative thereof; tacrolimus or an analogue or derivative thereof; bioImus or an analogue or derivative thereof; tresperimus or an analogue or derivative thereof; auranofin or an analogue or derivative thereof; 27-0-demethylrapamycin or an analogue or derivative thereof; gusperimus or an analogue or derivative thereof; pimecrolimus or an analogue or derivative thereof; ABT-578 or an analogue or derivative thereof; an inosine monophosphate dehydrogenase (IMPDH) inhibitor, which may be mycophenolic acid or an analogue or derivative thereof or l-.alpha.-25 dihydroxy vitamin D.sub.3 or an analogue or derivative thereof; a leukotriene inhibitor; an MCP-1 antagonist; an MMP inhibitor; an NF kappa B inhibitor, which may be Bay 11-7082; an NO antagonist; a p38 MAP kinase inhibitor, which may be SB 202190; a phosphodiesterase inhibitor; a TGF-.beta. inhibitor; a thromboxane A2 antagonist; a TNF-alpha antagonist; a TACE inhibitor; a tyrosine kinase inhibitor; vitronectin inhibitor; a fibroblast growth factor inhibitor; a protein kinase inhibitor; a PDGF receptor kinase inhibitor; an endothelial growth factor receptor kinase inhibitor; a retinoic acid receptor antagonist; a platelet derived growth factor receptor kinase inhibitor; a fibrinogen antagonist; an antimycotic agent; sulconazole; a bisphosphonate; a phospholipase Al inhibitor; a histamine H1 / H2 / H3 receptor antagonist; a macrolide antibiotic; a GPIIb / llla receptor antagonist; an endothelin receptor antagonist; a peroxisome proliferator-activated receptor agonist; an estrogen receptor agent; a somatostatin analogue; a neurokinin 1 antagonist; a neurokinin 3 antagonist; a VLA-4 antagonist; an osteoclast inhibitor; a DNA topoisomerase ATP hydrolyzing inhibitor; an angiotensin I converting enzyme inhibitor; an angiotensin II antagonist; an enkephalinase inhibitor; a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer; a protein kinase C inhibitor; a ROCK (rho-associated kinase) inhibitor; a CXCR3 inhibitor; Itk inhibitor; a cytosolic phospholipase A2-.alpha. inhibitor; a PPAR agonist; an immunosuppressant; an Erb inhibitor; an apoptosis agonist; a lipocortin agonist; a VCAM- 1 antagonist; a collagen antagonist; an alpha-2 integrin antagonist; a TNF-alpha inhibitor; a nitric oxide inhibitor; and a cathepsin inhibitor, anti-fibrin and fibrinolytic agents,including plasmin, streptokinase, single chain urokinase, urokinase, t-PA (tissue type plasminogen activator), aminocaproic acid; anti-platelet agents including, aspirin, prostacyclins (and analogues); glycoprotein llb / llla agents including monoclonal antibodies, peptides (e.g. ReoPro, Cilastagel, eptifibatide, tirofiban, ticlopidine, Vapiprost, dipyridamole, forskolin, angiopeptin, argatroban), thromboxane inhibitors; anti-thrombin and anti-coagulant agents, including dextran, heparin, LMW heparin (Enoxaparin, Dalteparin), hirudin, recombinant hirudin, anti-thrombin, synthetic antithrombins, thrombin inhibitors, Warfarin (and other coumarins); anti-mitotic, antiproliferative and cytostatic agents, including vincristine, vinblastine, paclitaxel, methotrexate, cisplatin, fluorouracil, rapamycin, azathioprine, cyclophosphamide, mycophenolic acid, corticosteroids, colchicine, nitroprusside; antiangiogenic and angiostatic agents, including paclitaxel, angiostatin and endostatin; genetic materials and oligonucleotides; ACE inhibitors (e.g. Cilazapril, Lisinopril, Captopril); growth factor (e.g. VEGF, FGF) antagonists; antioxidants and vitamins (e.g. Probucol, Tocopherol); calcium channel blockers (e.g. nifedipine); fish oil (omega 3-fatty acid); phosphodiesterase inhibitors (e.g. dipyridamole); nitric acid donor (e.g. Molsidomine); somatostatin analogues (e.g. angiopeptin); immunosuppressives and anti-inflammatory agents (e.g. prednisolone, glucocorticoid and dexamethasone); antimicrobials (e.g. rifamycin) and radionuclides, including alpha, beta and gamma emitting isotopes (e.g. Re-188, Re-186, 1-125, Y-90); COX-2 inhibitors such as Celecoxib and Vioxx; kinase inhibitors, such as epidermal growth factor kinase inhibitor, tyrosine kinase inhibitors, MAP kinase inhibitors protein transferase inhibitors, Resten-NG, Smoking cessation agents such as nicotine, bupropion and ibogaine; Insecticides and other pesticides which are suitable for local application; Dermatological agents, such as vitamins A, C, Bl, B2, B6, B 12, B 12 alpha, and E, vitamin E acetate and vitamin E sorbate; allergens for desensitization such as house, dust or mite allergens; nutritional agents and nutraceuticals, such as vitamins, essential amino acids and fats; macromolecular pharmacologically active agents such as proteins, enzymes, peptides, polysaccharides (such as cellulose, amylose, dextran, chitin), nucleic acids, cells, tissues, and the like; Bone mending biochemicals such as calcium carbonate, calcium phosphate, tricalciumphosphate, hydroxyapatite or bone morphogenic protein (BMP); angiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF) and epidermal growth factor (EFG), cytokines interleukins, fibroblasts and cytotoxic chemicals; and Keratolytics such as the alpha-hydroxy acids, glycolic acid and salicylic acid; and DNA, RNA or other oligonucleotides; vaccines that contain Hendra virus (HeV) G glycoprotein and / or Nipah virus G glycoprotein, Luteinizing Hormone Releasing Hormone (LHRH) peptide, LHRH- diphtheria toxoid conjugate, porcine circovirus type 2 (PCV2) antigen, a porcine reproductive and respiratory syndrome virus antigen, mycoplasma hyopneumoniae protein antigen; proteins or protein fragments, for example ORFI Torque teno virus protein, or other TTV proteins or fragments, antigens against Aeromonas salmonicida, antigens against Vibrio anguillarum, and antigens against V. salmonicida; growth factors include but are not limited to Vascular Endothelial Growth Factor (VEGF) and epidermal growth factor (EFG), Growth Differentiation Factors (GDFs), Fibroblast Growth Factors (FGF-1 through FGF-23), Osteoprotegerin, Cartilage Derived Morphogenic Proteins (CDMPs, which can be a foundation for soft or hard tissue), Lim Mineralization Proteins (LMPs)lnterleukins (IL-1 through IL-13), Insulin-like Growth Factor-1, Connective Tissue Growth Factor (CTGF), platelet derived growth factor (PDGF), nerve growth factors, neutrophins Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4 (NT-4)], Transforming growth factors (TGF-a, TGF- P), Tumor necrosis factor (TNF); growth factor agonists or antagonists as well as antibodies against these growth factors; biologically active agents that can be used to treat macular degeneration include but are not limited to bevacizumab and ranibizumab. Biologically active agents can include ansamycin antibiotics. Ansamycin antibiotics can include but are not limited to rifampicin, geldanamycin, rifabutin, rifaximin, and rifamycin S.

[0046] In an aspect, an active agent is a protein, where that term includes peptides and polypeptides, sugar-modified protein such as glycoprotein, as well as functional descriptions of protein classes such as antigen, enzyme, immunoglobulin and antibody. A composition may include a special delivery vehicle for the active agent, such as a virus or modified virus, where the active agent, such as a protein or polynucleotide, is containedwithin or expressed by the special delivery vehicle.

[0047] In an aspect, an active agent is a PD-L1 inhibitor. A PD-L1 inhibitor can include but is not limited to Atezolizumab, Avelumab, Durvalumab, LY3300054 (Eli Lilly and Company), and monoclonal antibodies or monoclonal antibody conjugates that act as a PD-L1 inhibitor

[0048] In an aspect, an active agent is a PD-1 inhibitor. A PD-1 inhibitor can include but is not limited to pembrolizumab, Nivolumab, Cemiplimab and monoclonal antibodies or monoclonal antibody conjugates that act as a PD-1 inhibitor.

[0049] In an aspect, an active agent is a CTLA-4 inhibitor. A CTLA-4 inhibitor can include but is not limited to Ipilimumab, AGEN1884 and monoclonal antibodies or monoclonal antibody conjugates that act as a CTLA-4 inhibitor.

[0050] In an aspect, an active agent is a compound that is used to treat non-muscle invasive bladder cancer. The compounds that can be used include but are not limited to non-live immunologically active Bacillus Calmette-Guerin (BCG) subcomponents that include BCG cell wall and various BCG proteins and antigens, an IL-2 fusion protein such as ALT-801 (Aitor Bioscience), Oportuzumab monatox (Sesen Bio), sunitinib (Pfizer), enzalutamide, ethacrynic acid, Imiquimod and tamoxifen, ALT-803 (Aitor Bioscience), and Lenalidomide.

[0051] In an aspect, an active agent is an antibody drug conjugate. The antibody drug conjugate can include but is not limited to trastuzumab emtansine, Sacituzumab govitecan, Enfortumab vedotin, ASG-15ME, Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, and Inotuzumab ozogamicin.

[0052] In an aspect, an active agent is a small molecule protein kinase inhibitor. The small molecule protein kinase inhibitor can include but is not limited to abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, baricitinib, binimetinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, encorafenib, erdafitinib, erlotinib, everolimus, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, lapatinib, larotrectinib, lenvatinib, lorlatinib, midostaurin, neratinib, netarsudil, nilotinib, nintedanib, osimertinib, palbociclib, Pazopanib, Ponatinib,Regorafenib, Ribociclib, Ruxolitinib, Sirolimus, Sorafenib, Sunitinib, Temsirolimus, Tofacitinib, Trametinib, Vandetanib, and Vemurafenib.

[0053] In an aspect, a composition of the present disclosure can comprise collagen, gelatin, chitosan, a chitosan derivative or thrombin. In an aspect, a composition of the present disclosure can comprise a hyaluronic acid derivative as described in the present disclosure and chitosan. In an aspect, a composition of the present disclosure can comprise a hyaluronic acid derivative as described in the present disclosure and collagen. In an aspect, a composition of the present disclosure can comprise a chitosan derivative as described in the present disclosure and unmodified chitosan. In an aspect, chitosan derivatives can include those described in US patent 10,179,145, which is herein incorporated in its entirety for its teachings. In an aspect, a composition of the present disclosure can comprise a dextran derivative as described in the present disclosure and chitosan. In an aspect, a chitosan or chitosan derivative can comprise at least about 5% (w / w) of the composition. In an aspect, a chitosan or chitosan derivative can comprise at least about 10% (w / w) of the composition. In an aspect, a chitosan or chitosan derivative can comprise at least about 20% (w / w) of the composition. In an aspect, a chitosan or chitosan derivative can comprise at least about 30% (w / w) of the composition. In an aspect, a chitosan or chitosan derivative can comprise at least about 40% (w / w) of the composition. In another aspect, the chitosan or chitosan derivative can comprise at between about 5% (w / w) and about 40% (w / w) of the composition. In an aspect, a chitosan or chitosan derivative can comprise at between about 20% (w / w) and about 80% (w / w) of the composition. In an aspect, a chitosan or chitosan derivative can comprise at between about 50% (w / w) and about 90% (w / w) of the composition.

[0054] In an aspect, a composition of the present disclosure can comprise a hyaluronic acid derivative as described in the present disclosure and gelatin. In an aspect, gelatin can be crosslinked. In an aspect, gelatin or crosslinked gelatin is in the form of particles. In an aspect, crosslinked gelatin particles can be in a hydrated form. In an aspect, gelatin or crosslinked gelatin can comprise at least about 5% (w / w) of a composition. In an aspect, gelatin or crosslinked gelatin can comprise at least about 10% (w / w) of a composition. Inan aspect, gelatin or crosslinked gelatin can comprise at least about 20% (w / w) of a composition. In an aspect, gelatin or crosslinked gelatin can comprise at least about 30% (w / w) of a composition. In an aspect, the gelatin or crosslinked gelatin can comprise at least about 40% (w / w) of a composition. In an aspect, gelatin or crosslinked gelatin can comprise between about 5% (w / w) and about 40% (w / w) of a composition. In an aspect, gelatin or crosslinked gelatin can comprise between about 20% (w / w) and about 80% (w / w) of a composition. In an aspect, gelatin or crosslinked gelatin can comprise between about 50% (w / w) and about 90% (w / w) of a composition.

[0055] In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cs to Cis chain. In another aspect, a composition comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cs to Cis chain and water. In an aspect, a composition comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cs to Cis chain and chitosan. In an aspect, chitosan of a composition is present as a solid powder. In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cs to Cis chain, chitosan and an aqueous saline solution. In an aspect, a composition comprises a crosslinked hyaluronic acid derivative of the present disclosure, where R1 is an aliphatic Cs to Cis chain. In an aspect, a composition comprises a crosslinked hyaluronic acid derivative of the present disclosure, where R1 is an aliphatic Cs to Cis chain and chitosan.

[0056] In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic C12 to Cis chain wherein the aliphatic chain has at least eight consecutive -CH2- groups. In an aspect, a composition comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cs to Cis chain wherein the aliphatic chain has at least eight consecutive -CH2- groups and water. In an aspect, a composition comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cs to Cis chain wherein the aliphatic chain has at least eight consecutive -CH2- groups and chitosan. In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is analiphatic Cg to Cis chain wherein the aliphatic chain has at least eight consecutive -CH2- groups, chitosan and an aqueous solution. In an aspect, a composition comprises a crosslinked hyaluronic acid derivative of the present disclosure, where R1 is an aliphatic Cg to Cig chain wherein the aliphatic chain has at least eight consecutive -CH2- groups. In another aspect, the composition comprises a crosslinked hyaluronic acid derivative of the present disclosure, where R1 is an aliphatic Cg to Cig chain wherein the aliphatic chain has at least eight consecutive -CH2- groups and chitosan. In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cg to Cig chain wherein the aliphatic chain has at least eight consecutive -CH2- groups, and gelatin or crosslinked gelatin. In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cg to Cig chain wherein the aliphatic chain has at least eight consecutive -Cogroups, gelatin or crosslinked gelatin and water.

[0057] In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cig chain (i.e. an aliphatic chain of 18 carbon units) wherein the aliphatic chain has at least eight consecutive -CH2- groups. In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Ci chain wherein the aliphatic chain has at least eight consecutive -CH2- groups and water. In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cig chain wherein the aliphatic chain has at least eight consecutive -CH2- groups, chitosan and water. In an aspect, a composition of the present disclosure comprises a hyaluronic acid derivative of the present disclosure where R1 is an aliphatic Cis chain wherein the aliphatic chain has at least eight consecutive -CH2- groups, gelatin or crosslinked gelatin and water.

[0058] In an aspect, a composition of the present disclosure comprises two or more hyaluronic acid derivative of the present disclosure. In an aspect, the first hyaluronic acid derivative of the present disclosure comprises R1 as an aliphatic Cig chain (i.e. an aliphatic chain of 18 carbon units) and the second hyaluronic acid derivative of the presentdisclosure comprises R1 as an aliphatic Ci6 chain (i.e. an aliphatic chain of 16 carbon units). In an aspect, the first hyaluronic acid derivative of the present disclosure comprises R1 as an aliphatic Cis chain (i.e. an aliphatic chain of 18 carbon units) and the second hyaluronic acid derivative of the present disclosure comprises R1 as an aliphatic C12 or an aliphatic C14 chain.

[0059] In an aspect, a composition of the present disclosure is part of a medical device wherein the medical device comprises a delivery system that contains the composition of the present disclosure. Examples of a delivery system include but are not limited to a syringe, a manual sprayer, a gas assisted sprayer, an aerosol can or a combination thereof. In an aspect, the composition of the present disclosure is sterile. In an aspect, the medical device of the present disclosure is sterile.

[0060] A composition of the present disclosure can be placed into a location within a body or onto the surface of a tissue or organ. In an aspect, a composition of the present disclosure can be placed in or onto muscle, fat tissue, lung tissue, brain matter, liver tissue, kidney tissue, spleen tissue, breast tissue, prostate tissue, arterial tissue, venous tissue, soft tissue, abdominal tissue, spinal tissue, nasal tissue, tumor, lesion or bone. In an aspect, a composition of the present disclosure can be placed within an aneurysm. In an aspect, a composition of the present disclosure can be placed into a trauma site. In an aspect, a composition of the present disclosure can be placed into a surgical site. In an aspect, a composition of the present disclosure can be placed into or onto a burn, an ulcer or a wound.

[0061] In an aspect, compositions of the present disclosure may be formulated for, and are useful for, reducing orstoppingthe flow of blood from orthrough a tissue ororgan. In an aspect, compositions of the present disclosure may be formulated for, and are useful for bring about hemostasis at a surgical or trauma site. In an aspect, compositions of the present disclosure may be formulated for, and are useful for gelling blood at a surgical or trauma site. In an aspect, a composition of the present disclosure can be applied as a solution, a dry powder, a slurry, a film, a foam, a gel, a lyophilized matrix or a combination thereof. In an aspect, following application of a composition of the present disclosure, acompressive force can be applied to the application site and held there for at least 10 seconds prior to removal of the compressive force.

[0062] A method of use of a composition of the present disclosure can comprise placing or providing a composition of the present disclosure at the site of bleeding of a subject. A method of use of a composition of the present disclosure can comprise placing composition of the present disclosure at the site of bleeding and then applying a compressive force to that site.

[0063] A composition of the present disclosure can be used to coat a medical device, or can be applied to a medical device prior to, or simultaneously with placement of a medical device or after placement of a medical device. Medical devices that can be coated with or used in combination with a disclosed composition herein include but are not limited to a catheter, a needle, a biopsy needle, a suture, a trocar, a tissue marker, a guide wire, and endoluminal sheath, a suture, a braid, a trocar, a mesh pouch, an electrospun sheet, an electrospun pouch, an electrospun material, a hernia mesh, a surgical mesh, a mesh for breast reconstruction, a contact lens, an intra-ocular lens, a stent (for example vascular stent, esophageal stent, biliary stent coronary stent, renal stent, peripheral vascular stent, urinary stent, ureteral stent) , a nasal splint, a vascular graft, a stent-graft, aneurysm coils, introducer sheaths, balloon catheters, vascular closure devices, inferior vena cava filter, an artificial joint, a replacement tendon, a tendon repair patch, a device that is used to achieve spinal fusion device, a pace maker, pace maker leads, cardiac implantable electronic devices, implantable cardioverter defibrillators, spinal cord stimulator, leads for implantable electronic devices, and hydrocephalic shunts. In an aspect, a medical device can be a pouch or envelope into which another medical device is inserted. In an aspect, a pouch or envelope comprises a degradable polymer. In an aspect, degradable polymers are synthesized from one or more monomers of l-lactide, dl-lactide, glycolide, e-caprolactone, trimethylene carbonate, morpholine-dione, p-dioxanone and l,5-dioxapan-2-one. In an aspect, a degradable polymer comprises a glycolide copolymer. In an aspect, a degradable polymer comprises a lactide copolymer. In an aspect, a degradable polymer comprises a polydioxanone polymer or copolymer.

[0064] Disclosed herein is a method for hemostatic control, comprising providing to a subject a composition comprising a derivatized hyaluronic acid wherein the derivatized hyaluronic acid comprises an aliphatic chain of 18 carbon units, an aliphatic chain of 16 carbon units, an aliphatic chain of 14 carbon units, an aliphatic chain of 12 carbon units, an aliphatic chain of 10 carbon units, an aliphatic chain of 20 carbon units, an aliphatic chain of 22 carbon units, an aliphatic chain of 24 carbon units, an aliphatic chain of 26 carbon units, an aliphatic chain of 28 carbon units, or an aliphatic chain of 30 carbon units. A composition disclosed herein may further comprise water, chitosan, gelatin, a derivatized hyaluronic acid that is crosslinked, or mixtures or combinations thereof. A composition may be provided to a subject a medical device. A medical device may comprise a syringe containing a disclosed composition. A method may comprise providing a disclosed composition to one or more sites of the subject that are bleeding or where there is active loss of the subject's hemostatic or hydrostatic fluid. A method may comprise providing a kit comprising a disclosed composition, wherein the kit and its components are used to improve the hemostatic status of the subject.

[0065] As used herein, subject means any living organism that maintains a fluid level for survival. A subject may include, but is not limited to, a human, an animal, a mammal, domestic animals, plants, worms, multicellular and single cellular organisms. For example, an organism or a portion of an organism may be immersed in a composition disclosed herein to prevent or inhibit loss of one or more fluids, such as cellular fluid, interstitial fluid, blood, and / or plasma, from the organism, or a subject may have a composition disclosed herein provided, applied, injected, contacted with one or more sites of the subject from which a fluid is being lost.

[0066] Disclosed herein are kits comprising a composition disclosed herein and optionally, directions for use of the kit. In an aspect, a kit may comprise a composition disclosed herein and an applicator for providing the composition to a site, and optionally, directions for use of the kit. In an aspect, a kit may comprise a composition disclosed herein and a medical device, and optionally directions for use of the kit. In an aspect, one or more components of a kit may be sterile.The following Examples are offered by way of illustration and not by way of limitation.Example 1DVS modified HA (DVS2)

[0067] 2.5 g sodium hyaluronate (900 KDa) was added to a glass 4L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. The solution was then stirred at about 200 rpm. 250 g deionized (DI or D2O) water was added to the kettle. The solution was stirred for about 18 hrs. 166.5 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2 min and was found to be 12.69. A freshly prepared solution of 10.6 g divinyl sulfone in 66g of DI water was then rapidly added to the stirring solution. After 75 seconds, 50 g of a IM HCI solution was added to the reaction mixture. 1 M NaOH was then added dropwise until the solution pH was between 5 and 7. 6 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.25 L acetone was slowly added over a period of 20 minutes. The suspension was stirred for about 3 hours. 200 mL denatured ethanol was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. Once all the solution had been filtered, the vacuum was disconnected and 100 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product (sample) was dried under vacuum at room temp in a vacuum oven. Approx. 10-20 mg of the dried sample was added to a vial. D2O was added to the sample to make the final concentration of the solution about 6 mg / mL. The sample was shaken on an orbital shaker until dissolved. Once dissolved, the sample was transferred into an NMR tube and the1H-NMR spectrum of the sample was recorded on an NMR spectrometer. The spectrum was printed out with the specific peaks in the 6.3- 6.5 ppm (2 peaks from the 2 CH2= protons from the vinyl sulfone residue), the 6.8-7.0 ppm (CH peak of vinyl group) and 1.8-2.5 ppm (singlet from the 3 CH3 protons from the N-acetyl group of the HA) regions being integrated. The percent modification is calculated on molar ratio of the vinyl CH protons (6.8-7 ppm) to the acetamide (1.8-2.5 ppm) protons. Thepercent substitution was found to be about 8.9%.Example 2DVS modified HA (DVS13)

[0068] 3.5 g sodium hyaluronate (approx. 800kDa; 1.4 m3 / Kg IV) was added to a 4L glass reaction kettle. The lid, overhead stirrer and anchor impeller were attached to the reaction kettle. 350g deionized water was added to the kettle. The solution was then stirred at about 300 rpm. The solution was stirred for about 18 hrs. The stirring speed was then increased to 750 rpm and about 233 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2min and was found to be 12.95. A freshly prepared solution of 15.5 g divinyl sulfone in 92.4 g of DI water was then rapidly added to the stirring solution. After 4.5 minutes, 63 g of a 1 M HCI solution was added to the reaction mixture. 1 M NaOH was then added dropwise until the solution pH was between 5 and 7. 8.4 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.5 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 300 mL denatured ethanol was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. Once all the solution had been filtered, the vacuum was disconnected and 150 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temp in a vacuum oven. The percent substitution, as determined by the procedure described in Example 1, was found to be about 25%.Example 3DVS modified HA (DVS14)

[0069] The reaction as described in Example 2 was performed using a reaction time of 6 minutes. The percent substitution, as determined according to the procedure described in Example 1, was found to be about 31%.Example 4HA-DVS reaction with 1-octanethiol (HA-DVS2-oct)

[0070] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to50 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 15.8 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.023 g 1-octanethiol in 7.9 g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. 0.5g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and theXH-NMR spectrum was measured. The presence of octanethiol substitution was evidenced by peaks at 0.8-0- 9 ppm (-CH3), 1.2-1.6 ppm (-CH2-), 2.6-2.7 ppm (-CH2-S-) and 2.9-3.0 ppm (-S-CH2-). The octanethiol molar substitution, as calculated from the integrals at 2.6-2.7 ppm. (Oct -CH2- S-) and 1.7-2 ppm (HA - acetamide), was 5.4%.Example 5HA-DVS reaction with 1-octanethiol (HA-DVS2-oct-DMF)

[0071] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to50 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 18.88 g dimethylformamide (DMF) was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.029 g 1-octanethiol in 9.4g DMF was then added to the derivatized HA solution. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. About 0.25 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution.The reaction mixture was stirred for 1.5 hours. 25 mL ethanol was added and the resultant mixture was stirred for 15 minutes. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the ^-NMR spectrum was measured. The octanethiol molar substitution, as calculated from the integrals at 2.4-2.5 ppm (Oct - CH2- S-) and 1.7-2 ppm (HA - acetamide), was 5.5%.Example 6HA-DVS reaction with 1-dodecanethiol (HA-DVS2-dod)

[0072] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to50 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 15.8 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.04 g 1-dodecanethiol in 7.9g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. 0.25g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and theXH-NMR spectrum was measured. The presence of octanethiol substitution was evidenced by peaks at 0.8-0- 9 ppm (CH3-), 1.2-1.6 ppm (-CH2-), 2.6-2.7 ppm (-CH2-S-) and 2.9-3.0ppm (-S-CH2-). The octanethiol molar substitution, as calculated from the integrals at 2.6-2.7 ppm (Oct - CH2- S-) and 1.7-2 ppm (HA - acetamide), was 5.2%.Example 7DVS modified HA - (DVS5 - 800kDa)

[0073] 3.5 g sodium hyaluronate (1.4 m3 / kg, approx. 800kDa) was added to a glass 4L reaction kettle. The lid, overhead stirrer and anchor impel lor were attached to the reaction kettle. 350g deionized water was added to the kettle. The solution was stirred at about 200 rpm for about 18 hrs. 233 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2 min and was found to be 12.85. A freshly prepared solution of 14.8 g divinyl sulfone in 92.4 g of DI water was then rapidly added to the stirring solution. After 75 seconds, 63 g of a IM HCI solution was added to the reaction mixture. Either IM NaOH or IM HCI was then added dropwise as needed until the solution pH was between 5 and 7. 8.4g NaCI was then added to the solution. Once the NaCI had dissolved, 1. 5 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 200 mL ethanol (Ethanol, Alcohol Reagent, Denatured anhydrous 94-96%) was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. 150 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temp in a vacuum oven. The percent substitution, determined as described in Example 1, was found to be about 8.9%.Example 8HA-DVS reaction with 1-decanethiol (HA-DVS5-dec)

[0074] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 7) was added to20 DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. 19.7 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.035 g 1-decanethiol in 4 g ethanol was then added to the derivatized HA solution. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. 0.25 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixturewas stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the1H-NMR spectrum was measured. The presence of decanethiol substitution was evidenced by peaks at 0.6-0-8 ppm (CH3-), 1.1- 1.6 ppm (-CH2-), 2. -2.6 ppm (-CH2-S-) and 2.7-2.9 ppm (-S-CH2-). The decanethiol molar substitution, as calculated from the integrals at 2.3-2.7 ppm (pent- CH2-S-) and 1.7-2 ppm (HA - acetamide), was 6.5%.Example 9DVS modified HA - (DVS18 - 800kDa)

[0075] 3.5 g sodium hyaluronate (IV = 1.4 m3 / kg, MW approx. 800 kD) was added to a glass 4 L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 350 g deionized water was added to the kettle. The solution was stirred at about 750 rpm for about 18 hrs. 233 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2 min and was found to be 12.92. A freshly prepared solution of 15.5 g divinyl sulfone in 92 g of DI water was then rapidly added to the stirring solution. After 15 minutes, 63 g of a IM HCI solution was added to the reaction mixture. Either IM NaOH or IM HCI was then added dropwise as needed until the solution pH was between 5 and 7. About 8.4 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.5 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 300 mL ethanol (Ethanol, Alcohol Reagent, Denatured anhydrous 94-96%) was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. Once all the solution had been filtered, the vacuum was disconnected and 150 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temperature in a vacuum oven. The percent substitution, as determined by the procedure described in Example 1, was found to be 71.3%.Example 10HA-DVS reaction with Octanethiol

[0076] HA-DVS was made in a similar manner to Example 9 and the HA-DVS was converted to the octanethiol derivative in a similar manner to Example 6. A sample of the material was dissolved in D2O and the1H-NMR spectrum was measured. The octanethiol molar substitution, as calculated from the integrals at 2.4-2.5 ppm (Oct - CH2-S-) and 1.7- 2 ppm (HA - acetamide), was 69.8%.Example 11Octadecanethiol modified HA (DVS6-2)

[0077] 500g deionized water was added to a 4L reaction vessel. The overhead stirrer was set at 200 rpm. 5g sodium hyaluronate [HA] (approx. 200kDa) was added to the 4L reaction kettle. The solution was allowed to stir until the HA had dissolved. 21.2g divinyl sulfone [DVS] was added to 132 g deionized water and the solution was stirred for about 15 minutes. 333g 0.25M NaOH was added to the HA solution. The pH of the HA solution was adjusted to about 12.8 using NaOH and HCI. The DVS solution was then added rapidly and the reaction was allowed to proceed for 180 seconds. 90g IM HCI was added to quench the reaction. The pH of the solution was then adjusted to between 5-7 using IM NaOH. 12g NaCI was added to the solution and stirring continued until the NaCI was dissolved. 2L acetone was added slowly to the reaction mixture. The reaction mixture was stirred for 3 hrs, then about 400 mL ethanol was added and the solution was stirred for 30 min. The precipitated composition was filtered and then washed with four aliquots of 200mL ethanol. The DVS-derivatized HA was added to a IL reaction vessel. About 300 g deionized water was added. The overhead stirrer was set to about 300 rpm and the system was heated to about 30°C. About 200 g ethanol was added to the reaction mixture. Once the material had dissolved, the stirring speed was increased to about 500 rpm and about 3.6 g 1-octadecanethiol (Sigma) was added to the reaction mixture. After 10 min, the pH of the reaction mixture was adjusted to about pH 9.0 using IM NaOH and IM HCI. The reaction was allowed to run for about 16-18 hours. The pH was then adjusted to about pH 6.7 to 7.3 and the heating was turned off. About 2.3g NaCI wasthen added to the reaction mixture. Once the NaCI was dissolved about 500mL acetone was added to the mixture. The mixture was stirred for about 90 minutes. The stirrer was turned off and the settled precipitate was filtered. The precipitate was washed 4 times with 200mL ethanol. The product was dried under vacuum. A sample of the product was dissolved in D2O and the1H-NMR spectrum was measured. The octadecane thiol substitution was found to be about 4.1% based on the disaccharide unit basis and about 1.0% on a HA hydroxyl basis.Example 12 In-vitro clotting test

[0078] A 1% solution of the octadecane thiol HA derivative (Example 11) was prepared in deionized water. A 1% solution of the octadecane thiol HA derivative (Example 11) was prepared in 0.9% NaCI / water. A 1% hyaluronic acid (800kDa) was prepared in deionized water. 1 mL of the 1% octadecane thiol HA derivative solution was added to a glass vial. 1 mL of citrated sheep blood (Hemostat) was added to the glass vial. The mixture was vortexed to 10 sec with a timer being started when vortexing was initiated. The vial was then placed in a water bath set to 37°C. The vial was inverted periodically. After 30 sec, the mixture had gelled and did not flow after inversion. The study was repeated with the octadecane thiol HA derivative / saline solution, the unmodified HA solution and deionized water. The octadecane thiol HA derivative / saline solution gelled in about 3 min to 3 min 30sec while the unmodified HA solution and deionized water samples had not gelled after 10 minutes.Example 13 Lyophilized Sponge

[0079] A 1% solution of the octadecane thiol HA derivative (Example 11) was prepared in deionized water. 8g of the solution was aliquoted into a glass vial and 80mg glycerol was added. The solution was mixed and poured into a rectangular plastic mold. This process was repeated using 1) 8g octadecane thiol HA derivative solution and 25mg glycerol and2) 8g octadecane thiol HA derivative solution. The 3 samples were then frozen in a -80°C freezer and then lyophilized to produce a foam like solid material.Example 14Octadecanethiol modified HA

[0080] The reaction in example 11 was repeated using 80 second and 360 seconds for the divinylsulfone reaction. The octadecane thiol substitution for the 80 second reaction was found to be about 2.5% based on the disaccharide unit basis and about 0.63% on a HA hydroxyl basis while the octadecane thiol substitution for the 360 second reaction was found to be about 4.3% based on the disaccharide unit basis and about 1.1% on a HA hydroxyl basis.Example 15Hexadecanethiol modified HA

[0081] The reaction described in example 11 was repeated using hexadecane thiol. The Hexadecanethiol reaction was run 2 consecutive times to produce the final material. The hexadecane thiol substitution was found to be about 3.8% based on the disaccharide unit basis and about 0.95% on a HA hydroxyl basis.Example 16

[0082] A 1.5% (w / v) octanethiol derivatized HA (Example 10) was prepared using deionized water. About 2g of low molecular weight chitosan (Sigma-Aldrich Cat # 448869) was added to about 10g of the solution that was in a 20 mL scintillation vial. The mixture was mixed using a spatula. A portion of the mixture was transferred to a 3 mL plastic syringe. The syringe plunger was inserted and as much headspace was removed as possible. The mixture was then extruded from the syringe.Example 17

[0083] A 1 % (w / v) octadecanethiol derivatized HA (Example 11) solution was prepared using deionized water. The solution was transferred to a 3 mL syringe that was then capped. The syringe was then heat sealed in a foil pouch.Example 18

[0084] A 1 % (w / v) octadecanethiol derivatized HA (Example 11) solution is prepared using deionized water. A 1% (w / v) hexadecanethiol derivatized HA (Example 15) solution is prepared. Three solutions are mixed at a mass ratio of 0.5:1, 1:1 and 1:0.5 of the octadecanethiol derivatized HA solution to the hexadecanethiol derivatized HA solution. Each solution is transferred to separate 3 mL syringes that is then capped. Each syringe is then heat sealed in a foil pouch.Example 19

[0085] A gel sample is prepared by adding about 3.4g of a 0.25M NaOH / 5% (v / v) ethanol solution that contains 0.5% (v / v) BDDE to about 0.5 g octadecanethiol derivatized HA (Example 11) in a 20 mL glass scintillation vial. The pH of the final mixture is adjusted to about 13.1. The sample is placed in an oven for about 3 hrs at about 50°C. The sample is washed and equilibrated in PBS (pH 7.4). The gel is processed by adding a 2% (w / v) HA solution to the gel in an 80:20 Gel:HA solution (w / w) and then passing the gel mixture through a 120 pm mesh (in a syringe filter setup) several times to generate particles. About half of the sample is dried in an oven and is then ground to produce a solid powder.Example 20

[0086] A gel sample is prepared by adding about 3.4g of a 0.25M NaOH / 5% (v / v) ethanol solution that contains 0.5% (v / v) BDDE to about 0.5 g octadecanethiol derivatized HA (Example 11) in a 20 mL glass scintillation vial. The pH of the final mixture is adjusted to about 13.1. The sample is placed in an oven for about 3 hrs at about 50°C. The sample is washed and equilibrated in PBS (pH 7.4). The gel is processed by adding a1% (w / v) octadecanethiol derivatized HA (Example 11) solution (in deionized water) to the gel in an 80:20 geksolution (w / w) and then passing the gel mixture through a 120 pm mesh (in a syringe filter setup) several times to generate particles. About half of the sample is dried in an oven and is then ground to produce a solid powder.Example 21

[0087] A gel sample is prepared by adding about 3.4g of a 0.25M NaOH / 5% (v / v) ethanol solution that contains 0.5% (v / v) BDDE to about 0.5 g octadecanethiol derivatized HA (Example 11) in a 20 mL glass scintillation vial. The pH of the final mixture is adjusted to about 13.1. The sample is placed in an oven for about 3 hrs at about 50°C. The sample is washed and equilibrated in PBS (pH 7.4). The gel is processed by passing the gel mixture through a 120 pm mesh (in a syringe filter setup) several times to generate particles. About 2g of low molecular weight chitosan (Sigma-Aldrich Cat # 448869) is added to about 10g of the particle mixture and is mixed in using a spatula. About half of the sample is dried in an oven and is then ground to produce a solid powder.

[0088] All references disclosed herein, including patent references and non-patent references, are hereby incorporated by reference in their entirety as if each was incorporated individually.

[0089] It is to be understood that the terminology used herein is for the purpose of describing specific aspects only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

[0090] Reference throughout this specification to "one aspect" or "an aspect" and variations thereof means that a particular feature, structure, or characteristic described in connection with the aspect is included in at least one aspect. Thus, the appearances of the phrases "in one aspect" or "in an aspect" in various places throughout this specification are not necessarily all referring to the same aspect. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or moreaspects.

[0091] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents, i.e., one or more, unless the content and context clearly dictates otherwise. It should also be noted that the conjunctive terms, "and" and "or" are generally employed in the broadest sense to include "and / or" unless the content and context clearly dictates inclusivity or exclusivity as the case may be. Thus, the use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. In addition, the composition of "and" and "or" when recited herein as "and / or" is intended to encompass an aspect that includes all of the associated items or ideas and one or more other alternative aspects that include fewer than all of the associated items or ideas.

[0092] Unless the context requires otherwise, throughout the specification and claims that follow, the word "comprise" and synonyms and variants thereof such as "have" and "include", as well as variations thereof such as "comprises" and "comprising" are to be construed in an open, inclusive sense, e.g., "including, but not limited to." The term "consisting essentially of" limits the scope of a claim to the specified materials or steps, or to those that do not materially affect the basic and novel characteristics of the claimed disclosure.

[0093] Any headings used within this document are only being utilized to expedite its review by the reader, and should not be construed as limiting the disclosure or claims in any manner. Thus, the headings and Abstract of the Disclosure provided herein are for convenience only and do not interpret the scope or meaning of the aspects.

[0094] Where a range of values is provided herein, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, rangesexcluding either or both of those included limits are also included in the disclosure.

[0095] For example, any concentration range, percentage range, ratio range, or integer range provided herein is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the term "about" means ± 20% of the indicated range, value, or structure, unless otherwise indicated.

[0096] All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. Such documents may be incorporated by reference for the purpose of describing and disclosing, for example, materials and methodologies described in the publications, which might be used in connection with the presently described disclosure. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate any referenced publication by virtue of prior disclosure.

[0097] All patents, publications, scientific articles, web sites, and other documents and materials referenced or mentioned herein are indicative of the levels of skill of those skilled in the art to which the disclosure pertains, and each such referenced document and material is hereby incorporated by reference to the same extent as if it had been incorporated by reference in its entirety individually or set forth herein in its entirety. Applicants reserve the right to physically incorporate into this specification any and all materials and information from any such patents, publications, scientific articles, web sites, electronically available information, and other referenced materials or documents.

[0098] In general, in the following claims, the terms used should not be construed to limit the claims to the specific aspects disclosed in the specification and the claims, butshould be construed to include all possible aspects along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

[0099] Furthermore, the written description portion of this patent includes all claims. Furthermore, all claims, including all original claims as well as all claims from any and all priority documents, are hereby incorporated by reference in their entirety into the written description portion of the specification, and Applicants reserve the right to physically incorporate into the written description or any other portion of the application, any and all such claims. Thus, for example, under no circumstances may the patent be interpreted as allegedly not providing a written description for a claim on the assertion that the precise wording of the claim is not set forth in haec verba in written description portion of the patent.

[0100] The claims will be interpreted according to law. However, and notwithstanding the alleged or perceived ease or difficulty of interpreting any claim or portion thereof, under no circumstances may any adjustment or amendment of a claim or any portion thereof during prosecution of the application or applications leading to this patent be interpreted as having forfeited any right to any and all equivalents thereof that do not form a part of the prior art.

[0101] Other nonlimiting aspects are within the following claims. The patent may not be interpreted to be limited to the specific examples or nonlimiting aspects or methods specifically and / or expressly disclosed herein. Under no circumstances may the patent be interpreted to be limited by any statement made by any Examiner or any other official or employee of the Patent and Trademark Office unless such statement is specifically and without qualification or reservation expressly adopted in a responsive writing by Applicants.

Claims

CLAIMSWhat is claimed is:

1. A method for hemostatic control, comprising providing to a subject a composition comprising a derivatized hyaluronic acid wherein the derivatized hyaluronic acid comprises an aliphatic chain of 18 carbon units.

2. The method of Claim 1, wherein the composition further comprises water.

3. The method of Claim 1, wherein the derivatized hyaluronic acid is crosslinked.

4. The method of Claim 1, wherein the composition further comprises chitosan.

5. The method of Claim 1, wherein the composition further comprises gelatin.

6. The method of Claim 1, wherein the composition is provided by a medical device comprising a syringe containing the composition of Claim 1.

7. The method of Claim 1, wherein providing to a subject comprises providing the composition of Claim 1 to one or more sites of the subject that are bleeding.

8. The method of Claim 7 , wherein the composition further comprises chitosan.

9. The method of Claim 1, further comprising providing a kit comprising the composition of Claim 1 for providing the composition to a subject.