Hemostatic compositions and methods

Abstract

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

Description

[0001] Cross-citation of related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 530,618, filed August 3, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0003] Uncontrolled bleeding during surgery or trauma can have adverse consequences for patients. Several topical hemostatic products are available, but biodegradable and biocompatible compositions are crucial for internal application. There is a need for a fully degradable and biocompatible composition that can achieve hemostasis or reduce blood loss. Summary of the Invention

[0004] In summary, this disclosure provides compositions, kits, methods for preparing compositions, and methods for using compositions and kits.

[0005] The foregoing and additional features of this disclosure, and the manner in which they are obtained, will become apparent, and this disclosure will be best understood by reference to the following more detailed description. All references disclosed herein are hereby incorporated in their entirety by reference, as if each were individually incorporated.

[0006] This summary is provided to present certain concepts in a simplified form, which will be described in further detail in the following detailed description. Unless expressly stated otherwise, this 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.

[0007] Details of one or more aspects are set forth in the following description. Features shown or described in conjunction with an exemplary aspect may be combined with features of other aspects. Thus, any of the various aspects described herein may be combined to provide further aspects. If desired, aspects of an aspect may be modified to provide even further aspects by employing the concepts of the various patents, applications, and publications identified herein. Other features, objects, and advantages will be apparent from the specification, drawings, and claims. Detailed Implementation

[0008] This disclosure can be more readily understood by referring to the following detailed description of preferred aspects of the disclosure and examples included herein. In one aspect, this disclosure provides a fully degradable composition capable of achieving complete hemostasis or reducing blood loss. In another aspect, this disclosure provides a fully degradable composition capable of achieving complete hemostasis or reducing blood loss when applied topically or internally. In yet another aspect, this disclosure provides a fully degradable composition that can achieve blood gelation when applied topically or internally.

[0009] The compositions disclosed herein may comprise biodegradable polymers. In one aspect, the biodegradable polymer is synthesized from a polysaccharide. Exemplary polysaccharide polymers that may be used in this disclosure include, but are not limited to, dextran, hyaluronic acid, hyaluronic acid derivatives, heparin, or chitosan. In one aspect, the biodegradable polymer comprises a polymer derived from hyaluronic acid (HA). In one aspect, the biodegradable polymer comprises a polymer derived from chitosan. In one aspect, the biodegradable polymer comprises a polymer derived from dextran. Polysaccharide derivatives that may be used in this disclosure include, but are not limited to, ether derivatives. Polysaccharide ether derivatives may include, but are not limited to, the derivatives described in US 11,440,976, the entire contents of which are incorporated herein by reference. In one aspect, the hyaluronic acid derivative comprises one or more alkyl groups chemically bonded to the hydroxyl group of hyaluronic acid via an ether bond. In one aspect, the hyaluronic acid derivative comprises one or more alkyl groups chemically bonded to the hydroxyl group of hyaluronic acid via residues of a divinyl sulfone linker. Examples of these derivatives are described in US 11,440,976, the entire contents of which are incorporated herein by reference. "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturation, having one to a specified number of carbon atoms, and being connected to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. In one aspect, hyaluronic acid derivatives contain one or more aromatic groups chemically bonded to the hydroxyl group of hyaluronic acid via ether bonds. In another aspect, hyaluronic acid derivatives contain one or more aromatic groups chemically bonded to the hydroxyl group of hyaluronic acid via residues of a divinyl sulfone linker. An aromatic moiety is a carbocyclic aromatic moiety (also known as an aryl moiety) or a heteroaromatic moiety (also known as a heteroaryl moiety) having 1-20 carbon atoms, the heteroaromatic moiety having at least one heteroatom selected from sulfur, oxygen, and nitrogen. Examples of such derivatives are described in US 11,440,976, the entire contents of which are incorporated herein by reference.

[0010] This disclosure provides a derivative of HA, wherein one or more hydroxyl groups of HA are modified hydroxyl groups, wherein the hyaluronic acid derivative has the structure HA-(OCH2CH2SO2CH2CH2-X-R1-Y). n Where HA is hyaluronic acid, X is S or NH, and R1 is substituted or unsubstituted C5-C. 20 The moiety is 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 its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, a phosphonic acid group or its salt, or an amino group.

[0011] In another aspect, this disclosure provides a derivative of HA, wherein two or more hydroxyl groups of hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid or other multi-component polymer has the structure (Y-R2-X-CH2CH2SO2CH2CH2O). m -HA-(OCH2CH2SO2CH2CH2-X-R1-Y) n Where HA is hyaluronic acid, X is S or NH, and R1 is a substituted or unsubstituted C5-C. 20 Aliphatic, cholesterol, lipid, or aromatic moiety, R2 being a substituted or unsubstituted C5-C 20 The aliphatic or aromatic part, wherein R1 and R2 are different from each other, wherein n and m are each integers, 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 amino group.

[0012] In another aspect, this disclosure provides a derivative of HA, wherein 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-(OCH2CH2SO2CH2CH2-X-R1-Y). n Where HA is hyaluronic acid or other multi-component polymer, X is S or NH, and R1 is a substituted or unsubstituted C5-C. 20 The aliphatic, cholesterol, lipid, or aromatic moiety, where n and m are integers, and n ≥ 1 and m ≥ 1, and Y is H; a carboxylic acid group, or its salt or ester; a hydroxyl group; a sulfonic acid group or its salt; a phosphonic acid group or its salt; or an amino group.

[0013] On the other hand, substituted or unsubstituted aliphatic compounds are C5 to C6. 20 Aliphatic. On the other hand, substituted or unsubstituted aliphatic molecules are C8 to C9. 20 Aliphatic. On the other hand, substituted or unsubstituted aliphatic is C. 10 To C 20 Aliphatic. On the other hand, C5 to C 20 Aliphatic compounds have at least four consecutive -CH2- groups. On the other hand, C8 to C96... 20 Aliphatic compounds have at least six consecutive -CH2- groups. On the other hand, C... 10 To C 20 Aliphatic compounds have at least six consecutive -CH2- groups. On the other hand, C... 10 To C 20 Aliphatic compounds have at least eight consecutive -CH2- groups. On the other hand, R1 is C. 10 To C 20 Unsubstituted aliphatic. On the other hand, R1 is C12 To C 18 Unsubstituted aliphatic. On the other hand, R1 is C 12 C 14 C 16 Or C 18 Unsubstituted aliphatic compounds. On the other hand, R2 is C 10 To C 20 Unsubstituted aliphatic. On the other hand, R2 is C 12 To C 18 Unsubstituted aliphatic. On the other hand, R2 is C 12 C 14 C 16 Or C 18 Unreplaced lipids.

[0014] In a further aspect, this disclosure provides HA derivatives as described above, characterized in that, in the derivative, 0.25%-50% of the sum of hydroxyl groups and modified hydroxyl groups are modified hydroxyl groups. In a further aspect, this disclosure provides HA derivatives such as those described above, characterized in that, in the derivative, about 1% to about 95% of the disaccharide units constituting the HA backbone contain at least one modified hydroxyl group.

[0015] On the other hand, the HA component of the above-mentioned derivatives can be replaced by polysaccharides with available hydroxyl or amino groups that are capable of reacting with divinyl sulfone.

[0016] In one aspect, the degradable polymer may include a cross-linked polymer. In another aspect, the cross-linked polymer may be a cross-linked polysaccharide. In another aspect, the cross-linked polysaccharide is derived from hyaluronic acid, dextran or chitosan, derived hyaluronic acid, or combinations thereof. Cross-linking agents that may be used include, but are not limited to, dicarbodiimides, bisepoxides, divinyl sulfone derivatives, diisocyanates, dihalide chlorides, disuccinimide derivatives, and combinations thereof.

[0017] Dicarbodiimide compounds may include, but are not limited to, p-phenylenebis-(ethyl)-carbodiimide, 1,6-hexamethylenebis(ethylcarbodiimide), 1,8-octamethylenebis(ethylcarbodiimide), 1,10-decamethylenebis(ethylcarbodiimide), 1,12-dodecamethylenebis(ethylcarbodiimide), PEG-bis(propyl(ethylcarbodiimide)), 2,2'-dithioethylbis(ethylcarbodiimide), 1,1'-dithio-p-phenylenebis(ethylcarbodiimide); p-phenylene-bis(ethylcarbodiimide) and 1,1'-dithio-m-phenylenebis(ethylcarbodiimide).

[0018] When using a dicarbodiimide crosslinking agent, the dicarbodiimide is mixed with a buffered aqueous solution of the derived polysaccharide. The target pH of the buffer solution can be between pH 5 and pH 6.5.

[0019] The biepoxide compounds may include, but are not limited to, 1,4-butanediol diglycidyl ether (BDDE), 1,2,7,8-diepoxyoctane (DEO), and poly(ethylene glycol) diepoxides. When using a biepoxide crosslinking agent, the biepoxide is mixed with an aqueous solution of the derived polysaccharide, and the pH is raised to pH > 9. The reaction can be carried out at 40°C for more than 4 hours to produce a crosslinked composition. Alternatively, the crosslinking reaction can be carried out at room temperature. Alternatively, the crosslinking reaction can be carried out at temperatures above 4°C.

[0020] Divinyl sulfone crosslinking agents may include, but are not limited to, divinyl sulfone and poly(ethylene glycol) divinyl sulfone.

[0021] On one hand, crosslinking can be generated by Michael addition reactions. Examples of Michael addition reactions include, but are not limited to, reactions between vinyl groups and amines, hydroxyl groups, thiols, or combinations thereof. On the other hand, crosslinking can be generated by free radical reactions of photopolymerization or thermal polymerization.

[0022] On one hand, HA derivatives containing residual available vinyl sulfone functional groups, as described above, can be crosslinked in the presence of an external crosslinking agent having at least two free thiol functional groups. These free thiol groups can be located on the "C" of the central molecule. The central molecule can be a straight-chain or cyclic alkane, a polyethylene glycol (PEG) oligomer or polymer, or any other suitable central molecule of this kind. In the case of a PEG-based crosslinking agent, the PEG can be straight-chain, branched (with two polymer arms), or multi-armed (e.g., having 3, 4, 5, 6, 7, 8, or more polymer arms). Thus, in this case, the central molecule will typically be a straight-chain PEG, a branched PEG with two arms, or a multi-armed PEG with PEG arms emanating from a central core.

[0023] Exemplary cores of such multi-armed polymers include erythritol, pentaerythritol, trimethylolpropane, glycerol, glycerol dimer (3,3'-oxodipropane-1,2-diol), glycerol oligomer, sorbitol, hexaglycerol, etc.

[0024] Exemplary thiol crosslinking agents include PEG-dithiol (HS-PEG-SH), 3-arm PEG-trithiol (glycerol core), 4-arm PEG-tetrathiol (pentaerythritol core), or 8-arm PEG-octathiol (hexaglycerol core). The aforementioned multi-arm PEG reagents may also have fewer than all the arms functionalized with thiols. Other suitable thiol reagents with PEG as the central molecule are available from LaysanBio (Alabama, Arabia), as well as aromatic dithiols, such as those available from NanoScience. Other suitable thiol crosslinking agents include dimercaptosuccinic acid, 2,3-dimercapto-1-propanesulfonic acid, trimethylolpropane tris(3-mercaptopropionate), dithiol-functionalized pluronics F127, dithiol-functionalized F68, dihydrolipoic acid, peptides containing at least two cysteine ​​amino acids, thiol-functionalized dextran, and thiol-functionalized hyaluronic acid.

[0025] On the other hand, a mixture of at least two different thioether-derived HAs can be combined, and a crosslinking agent can be added and the reaction conditions adjusted to crosslink the derived HA polymer. The relative proportions of the different derived HAs can be varied to obtain crosslinked derived HA polymers with different properties. These properties include, but are not limited to, equilibrium swelling, swelling rate, drug release characteristics, elastic modulus, storage modulus, loss modulus, degradation, tensile strength, tissue adhesion, and lubricity. As used herein, "derived HA polymer" may also include compositions comprising one or more derived HA polymers.

[0026] On the other hand, at least two different crosslinking agents can be used to crosslink the derived HA. Specifically, two different crosslinking agents from the same group can be used to crosslink the derived HA polymer. For example, divinyl sulfone and poly(ethylene glycol) divinyl sulfone or 1,4-butanediol diglycidyl ether (BDDE) and poly(ethylene glycol) diepoxide can be used.

[0027] On the other hand, two different crosslinking agents from different groups can be used. For example, divinyl sulfone and 1,4-butanediol diglycidyl ether (BDDE) can be used to crosslink the derived HA. Alternatively, crosslinking agents can be added sequentially, causing initial crosslinking in the presence of a first crosslinking agent, followed by the addition of a second crosslinking agent, resulting in secondary crosslinking. Reaction conditions can be changed after the first crosslinking reaction and before the second crosslinking reaction. Reaction conditions such as temperature, pH, buffer solution, ionic strength, and solvent composition can be varied.

[0028] In one aspect, the cross-linked derived HA polymer can be prepared by ionic cross-linking. This can be achieved by mixing a negatively charged derived polyhydroxy polymer of this disclosure with a compound having two or more positive charges. In another aspect, a solution of a negatively charged derived HA polymer of this disclosure can be prepared, and then the solution can be mixed with a solution of a compound having 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 containing more than two lysine, arginine, or histidine amino acids; chitosan and chitosan derivatives; deacetylated hyaluronic acid; polyethyleneimine (PEI); poly(N,N-dimethylaminoethyl methacrylate); poly(4-vinylpyridine); polyethylene glycol-polylysine block copolymer (PEG-PLL); dextran-grafted polylysine copolymer; or combinations thereof.

[0029] Solutions of derived HA polymers can be prepared by dissolving the derived HA polymer in a suitable solvent or combination of solvents. For example, water or a combination of water and water-miscible solvents can be used. When water is used as the solvent, the water can include, but is not limited to, deionized water, distilled water, and water prepared by reverse osmosis. In one aspect, the water may further contain 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, dimethylformamide (DMF), acetone, 1,4-dioxane, pyridine, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and acetonitrile. The prepared solution can be sterilized by filtration through a 0.2 µm sterile filter. In one aspect, a solution can be prepared using one derived HA. In another aspect, a solution can be prepared using two different derived HA materials. The concentration of the prepared solution can range from, for example, 0.01% (w / v) to about 50% (w / v). On one hand, the concentration can be from about 0.1% (w / v) to 10% (w / v). On the other hand, the concentration is between about 0.75% (w / v) and about 3% (w / v). On the other hand, the concentration is between about 0.75% (w / v) and about 1.5% (w / v).

[0030] The compositions disclosed herein can be in the form of solutions, foams, gels, slurries, membranes, discontinuous membranes, powders, particles, spheres, three-dimensional shapes, lyophilized matrices, nonwoven matrices, electrospun matrices, or combinations thereof. In one aspect, the median particle size (Dv50) is in the range of about 10 µm to about 2000 µm. In another aspect, the median particle size (Dv50) is in the range of about 10 µm to about 200 µm. In another aspect, the median particle size (Dv50) is in the range of about 200 µm to about 600 µm. In another aspect, the median particle size (Dv50) is in the range of about 600 µm to about 1200 µm. In another aspect, the median particle size (Dv50) is in the range of about 1200 µm to 2000 µm. In one aspect, the membrane, discontinuous membrane, or lyophilized matrix may have a thickness of about 40 µm to about 3000 µm. In one aspect, the membrane, discontinuous membrane, or lyophilized matrix may have a thickness of about 40 µm to about 300 µm. In another aspect, the membrane, discontinuous membrane, or lyophilized matrix may have a thickness of about 300 µm to about 600 µm. In another aspect, the membrane, discontinuous membrane, or lyophilized matrix may have a thickness of about 600 µm to about 1200 µm. In another aspect, the membrane, discontinuous membrane, or lyophilized matrix may have a thickness of about 1200 µm to about 3000 µm. In another aspect, the membrane, discontinuous membrane, or lyophilized matrix may have a thickness greater than about 3000 µm. In one aspect, the compositions disclosed herein may be porous.

[0031] In one aspect, the compositions disclosed herein may further comprise buffers, complexing agents, tension modifiers, ionic strength modifiers, solvents, antioxidants, preservatives, viscosity modifiers, pH modifiers, surfactants, emulsifiers, phospholipids, stabilizers, or combinations thereof.

[0032] Buffers that may be used include aqueous solutions prepared using one or more of the following materials: potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate or sodium dihydrogen phosphate, dipotassium hydrogen phosphate or disodium hydrogen phosphate, phosphoric acid, boric acid, sodium acetate, acetic acid, ammonium chloride, ammonium acetate, and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid).

[0033] Complexing agents may include, but are not limited to, α-cyclodextrin, β-cyclodextrin (2-hydroxypropyl)-β-cyclodextrin, sodium sulfobutyl ether β-cyclodextrin, or ethylenediaminetetraacetic acid (EDTA) or its salts.

[0034] The phospholipids that can be used include, but are not limited to, hydrogenated soybean phosphatidylcholine, distearate phosphatidylglycerol, L-α-dimyristoyl phosphatidylcholine or L-α-dimyristoyl phosphatidylglycerol.

[0035] Surfactants that can be used include ionic surfactants and nonionic surfactants. Ionic surfactants can include cationic, anionic, and amphoteric surfactants. Nonionic surfactants may include, but are not limited to, polyoxyethylene castor oil (Cremophor EL), polyoxyethylene hydrogenated castor oil (Cremophor RH) 40, polyoxyethylene hydrogenated castor oil 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, and Softigen. 767. Octyl-β-D-glucopyranoside (OGP), hexyl-β-D-glucopyranoside (HGP), octyl-β-D-1-thioglucopyranoside (TGP), decyl-β-D-glucopyranoside (DGP), dodecyl-β-D-glucopyranoside (DdGP), N-octyl-β-D-maltose glycoside (ODM), decyl-β-D-maltose glycoside (DMP), cyclohexyl-acetyl-maltose glycoside, n-decyl- and n-dodecyl-sucrose, and mono- and di-fatty acid esters of PEG 300, 400, or 1750. Anionic surfactants may include, but are not limited to, sodium dodecyl sulfate, fatty acid salts, sodium lauryl ether sulfate, and sodium dioctyl sulfosuccinate. Cationic surfactants may include, but are not limited to, phosphatidylcholine (lecithin), trimethylammonium bromide, cetrimonium bromide, benzyl chloride, dimethyl dioctadecyl ammonium chloride, tetradecyltrimethylammonium bromide, cetylpyridinium chloride, ester quaternary ammonium salts, and benzalkonium chloride. Amphoteric surfactants may include, but are not limited to, cocamidopropyl betaine, (3-[(3-cholamidopropyl)dimethylammonium]-1-propanesulfonate), cocamidopropyl hydroxysulfonate betaine, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin.

[0036] Solvents that may be used include water-soluble organic solvents. Water-soluble organic solvents include, but are not limited to, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0037] Tension modifiers that can be used include, but are not limited to, dextrose, sucrose, mannitol, glycerol, sodium chloride, and potassium chloride.

[0038] The pH adjusters that can be used include, but are not limited to, salts of citric acid and its salts, phosphoric acid, tartaric acid, lactic acid, glycolic acid, sodium hydroxide, phosphoric acid, sulfuric acid, oxalic acid, and hydrochloric acid.

[0039] Antioxidants that may be used include, but are not limited to, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, vitamin A, vitamin E, α-tocopherol, thioglycerol, cysteine, acetylcysteine, cystine, dithioerythritol, dithiothreitol, glutathione, sodium bisulfite, sodium metabisulfite, thiourea, uric acid, melatonin, propyl gallate, tert-butylhydroquinone, and combinations thereof.

[0040] Emulsifiers that may be used include, but are not limited to, glyceryl monostearate, isopropyl palmitate, polyethylene glycol 400 monostearate, and compounds and combinations thereof listed as surfactants.

[0041] Preservatives that may be used include, but are not limited to, benzoic acid, sorbic acid, boric acid, methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, sodium propionate, phenylethanol, chlorobutanol, benzyl alcohol, potassium sorbate, phenol, chlorocresol, o-phenylphenol, thimerosal, nitrosylmercuric acid, phenylmercuric nitrate, phenylmercuric acetate, benzalkonium chloride, and combinations thereof.

[0042] In one 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, poloxamer 188, poloxamer 124, poloxamer 407, poloxamer 338, poloxamer 237, Pluronic F127, and Pluronic F68.

[0043] The composition may further comprise a bioactive agent. In one aspect, the composition may comprise more than one bioactive agent. Exemplary bioactive agents include, but are not limited to, small molecule drugs, peptides, proteins, growth factors, hormones, antibodies, agonists, antagonists, antibacterial agents, and / or antifungal agents.

[0044] Bioactive agents that can be incorporated into formulations having the aforementioned composition include: antiandrogens, antibacterial agents, antiestrogens, androgens and anabolic agents, antibiotics, anti-migraine drugs, antihistamines, anti-anxiety drugs, antidiuretics, antihistamines, antirheumatic agents, antigens, analgesics, antidepressants, anti-inflammatory agents, anesthetics, aminoglycoside antibodies, antiviral drugs, adrenaline stimulants, anticonvulsants, antianginal drugs, antiarrhythmic drugs, antimalarial drugs, antimitotic drugs, anthelmintics, anorexia nervosa, antitussives, antipruritics, antipyretics, and anti-Alzheimer's drugs. Drugs, anti-Parkinson's drugs, antiemetics and antiemetics, antihypertensives, anticoagulants, antifungals, antibacterial agents, allergens, antidiarrheals, antihyperuricemic drugs, adrenergic stimulants, antiparasitics, antiproliferative agents, antipsychotics, antithyroid drugs, beta-adrenergic blockers, bronchodilators; bronchospasm relaxants, coagulation factors, blood clotting factors, cytotoxic agents, cell inhibitors, chemotherapeutic agents, clot inhibitors, clot dissolving agents, cells, CNS stimulants, corticosteroids, calcium channel blockers, cofactors, ceramides Cardiac glycosides, cytokines (e.g., lymphokines, monokines, chemokines); colony-stimulating factors (e.g., GCSF, GM-CSF, MCSF); dermatological agents, decongestants, diuretics, expectorants, internal and external anthelmintics, growth factors, hemostatic agents, hypoglycemic agents, hormones and hormone analogs, hypercalcemia, hypnotics, interleukins (IL-2, IL-3, IL-4, IL-6); interferons (β-IFN, α-IFN, and γ-IFN); immunosuppressants, muscle relaxants, microorganisms, nonsteroidal anti-inflammatory drugs (NSAIDs). Anti-inflammatory agents, nucleic acids, nutritional supplements, neuromuscular blocking agents, tranquilizers, neurotoxins, nutritional supplements, oligonucleotides, estrogens, obstetric drugs, ovulation inducers, opioids, progestins, pituitary hormones, pituitary inhibitors, proteins, peptides, polysaccharides, protease inhibitors, prostaglandins, quinolones, reductase inhibitors, sulfonamides, sclerosing agents, sedatives, sodium channel blockers, steroids, steroidal anti-inflammatory agents, smoking cessation agents, toxins, thrombolytics, thyroid hormones, tumor necrosis factor; vesicles, vitamins, viruses, vasodilators, and vaccines.Other representative examples of bioactive agents suitable for use in the compositions of the present invention include, but are not limited to: antidiarrheal agents, such as diphenoxylate, loperamide, and hyoscine; antihypertensive agents, such as hydralazine, minoxidil, captopril, enalapril, clonidine, prazosin, isoquinoline, diazoxide, guanethidine, methyldopa, reserpine, and trimefenadine; calcium channel blockers, such as diltiazem, felodipine, amlodipine, nifedipine, nifedipine, and verapamil; antiarrhythmic agents, such as amiodarone, flecainide, disopyramide, procainamide, mexiletine, and quinidine; and antianginal agents, such as nitroglycerin trinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, and mannitol hexanitrate. Piperoxirine, isosorbide dinitrate, and nicorandil; β-adrenergic blockers, such as apravolol, atenolol, blavolol, carteolol, labetalol, metoprolol, nadolol, naproxilol, oxenolol, indololol, propranolol, sotalol, timolol, and timolol maleate; cardiac glycosides, such as digoxin and other cardiac glycosides, and theophylline derivatives; adrenergic stimulants, such as adrenaline, ephedrine, fenoterol, isoproterenol, orsinol, limectin, salbutamol, salmeterol, terbutaline, dobutamine, phenylephrine, phenylpropanolamine, pseudoephedrine, and dopamine; vasodilators, such as cyclomandelate and isocortol. Papaverine, dipyridamole, isosorbide dinitrate, phentolamine, nicotinic acid, dichloroergotamine mesylate (co-dergocrine), nicotinic acid, nitroglycerin trinitrate, pentaerythritol tetranitrate, and zentinol; antiproliferative agents such as paclitaxel, estradiol, actinomycin D, sirolimus, tacrolimus, everolimus, 5-fluorouracil, and dexamethasone; anti-migraine agents such as ergotamine, dihydroergotamine, mexiergot, phenthiazide, and sumatriptan; anticoagulants and thrombolytics such as warfarin, dicumarol, low molecular weight heparin such as enoxaparin, streptokinase, and its active derivatives; hemostatic agents such as aprotinin, tranexamic acid, and protamine; analgesics and antipyretics, including... This includes opioid analgesics such as buprenorphine, dextromethorphan, dextropropoxyphene, fentanyl, alfentanil, sufentanil, hydromorphone, methadone, morphine, oxycodone, total opioids, pentazocine, meperidine, phenopefidine, codeine, and dihydrocodeine; acetylsalicylic acid (aspirin), acetaminophen, synthetic α2-adrenergic receptor agonists, dexmedetomidine hydrochloride, flunixin meglumine, meperidine, phenylbutazone, and antipyrine; immunosuppressants, antiproliferative agents, and cell inhibitors such as rapamycin (sirolimus) and its analogues (everolimus and tacrolimus); and neurotoxins such as capsaicin and botulinum toxin (Botox). TMHypnotics and sedatives, such as barbiturates, amobarbital, butylbarbital, and pentobarbital, and other hypnotics and sedatives, such as chloral hydrate, chlormetrazazole, hydroxyzine, and meprobamate; anxiolytics, such as benzodiazepines alprazolam, bromazepam, nitrazepam, clonazepam, loratadine, diazepam, flunitrazepam, lorazepam, nitrazepam, oxazepam, temazepam, and triazolam; tranquilizers and antipsychotics, such as phenothiazines, chlorpromazine, fluphenazine, cyanazine, perphenazine, promethazine, perphenazine acetate, thioridazine, trifluoperazine; and butyrophenone, droperidol, and haloperidol; and other antipsychotics, such as pimozide, tevothixeol, and lithium; anti- Depressants, such as tricyclic antidepressants amitriptyline, clomipramine, desipramine, duthiramine, doxepin, imipramine, nortriptyline, octopiol, protriptyline, and trimipramine; tetracyclic antidepressants such as mianserin; monoamine oxidase inhibitors such as isocarboxazid, phenelzine, transphenylcyclopromine, and moclobemide; and selective serotonin reuptake inhibitors such as fluoxetine, paroxetine, citalopram, fluvoxamine, and sertraline; CNS stimulants such as caffeine and 3-(2-aminobutylindole); and antipruritics may include compounds such as synthetic Janus kinase (JAK) inhibitors, NK-1 receptor antagonists, and antibodies that neutralize interleukin-31 (IL-31). These drugs may include olatinib maleate, slopitant, and lokivetmab; anti-Alzheimer's drugs such as tacrine; anti-Parkinson's drugs such as amantadine, benserazide, carbidopa, levodopa, bentropine, biperidone, trihexyphenidyl, propranolol, and dopamine-2 agonists such as S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetrahydronaphthalene (N-0923); anticonvulsants, etc. Examples include phenytoin, valproic acid, primidone, phenobarbital, methyl phenobarbital, carbamazepine, ethosuximide, mesosuximide, phenosuximide, succinylthiazide, and clonazepam; antiemetics and antiemetics such as phenothiazines like prochlorperazine and thiotetramethrin; neurokinin (NK1) receptor antagonists, maropitant citrate; and 5HT-3 receptor antagonists such as ondansetron and granisetron; as well as dimenhydrinate, diphenhydramine, metoclopramide, domperidone, scopolamine, scopolamine hydrobromide, scopolamine hydrochloride, clopazole, and bromipride.Nonsteroidal anti-inflammatory agents, including racemic mixtures or individual enantiomers (if applicable), preferably, can be formulated in combination with skin and / or mucosal penetration enhancers, such as ibuprofen, flurbiprofen, ketoprofen, aceclofenac, diclofenac, aloprol, naproxen, aspirin, diflunisal, fenofosine, indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxicam, salicylamide, salicylic acid, sulindac, desoxysulindac, tenoxicam, tramadol, ketoprofen. Acids, Fluorobenzylsalicylic Acid, Salicylic Acid, Triethanolamine Salicylate, Aminopyrine, Antipyrine, Hydroxyphenylbutazone, Azapronexine, Synpentazocine, Flufenamic Acid, Clonixerl, Clonixin, Meclofenamic Acid, 6-Chloro-α-methyl-9H-carbazole-2-acetic Acid (Carprofen), Flunixin, Colchicine, Dimethicone, Allopurinol, Oxypurinol, Benzalkonium Hydrochloride, Dimethicone, Indoxexole, Indextetrazol, Mimben, Paranylene Hydrochloride Hydrochloride, Tetrahydrodamine, Beninpiline Hydrochloride, Fluprofen, Isobutanol, Naproxol, Fenbufen, Cincofen, Diflumiphenone Sodium, Finamoxetine, Flutetrazine, Metazamido, Letitine Hydrochloride, Nesiglitin Hydrochloride, Otamidine, Molinazole, Neocincofen, Nimazole, Proxazazole Citrate, Texicam, Teximed, Tomilide Butyl and triflumimethicone; antirheumatic agents such as penicillamine, glucosamine, sodium glucosamine malate, methotrexate, and auronorfen; muscle relaxants such as baclofen, diazepam, cyclobenzaline hydrochloride, dantrolene, mesobamoline, olphenadol, and quinine; agents used to treat gout and hyperuricemia such as allopurinol, colchicine, probenecid, and sulfadiazine; estrogens such as estradiol, estriol, estrogen, ethinylestradiol, and metronidazole. Estradiol, diethylstilbestrol, dienoestrol, epiestriellol, piperazine sulfate, and gibberellin; progesterone and other progestins, such as allyl estradiol, dydrogesterone, diethylstilbestrol, linegestrol, norethindrone, isethindrone, norethindrone acetate, gestadione, levonorgestrel, medroxyprogesterone, and megestrol acetate; antiandrogens, such as cyproterone acetate and danazol; antiestrogens, such as tamoxifen and thioandrostol, and aromatized... Enzyme inhibitors exemestane and 4-hydroxyandrostenedione and their derivatives; androgens and anabolic agents, such as testosterone, methyltestosterone, clostib acetate, drotalbutone, furazolidone, nandrolone oxyandrozoline, stanozolol, trenbolone acetate, dihydrotestosterone, 17-(α-methyl-19-nortestosterone and fluoromethyltestosterone); 5-α reductase inhibitors, such as finasteride, trorotredoxin, LY-191704 and MK-306;Corticosteroids, such as betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinolone acetonide, fluocinolone acetate, fluocinolone, halcinonide, haloprednisolone, hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisolone, triamcinolone, triamcinolone; glycosylated proteins, proteoglycans, glycosaminoglycans such as chondroitin sulfate; chitosan, glucosamine, hyaluronic acid; complex carbohydrates such as dextran; other examples of steroidal anti-inflammatory agents, such as todoxacin, fludrocortisone, fludrocortisone, difluralasone. Diacetate, acetone hydrochlorothiazide, methylhydroxyzine, amcinafel, amcinifex, betamethasone and other esters, chlorprednisolone, chlorclotropone, disilone, desonide, dichlorophenate, difluprednisolone, fluclotropone, flumethasone, flunisolone, fluocinolone, flumethrin, fluperamide, fluprednisolone, methylprednisolone, methylprednisolone, peramisone, cortisone acetate, hydrocortisone cyclopentylpropionate, todoxason, flucetonide, fluhydrocortisone acetate, hydrochlorothiazide, amcinafel, amcinifex, betamethasone, betamethasone benzoate, chlorprednisolone acetate, chlorclotropone acetate, disilone acetone, deshydroxymethasone, dichlorophenate, difluprednisolone, fluclotropone, flumethasone neopentate, acetyl... Flunisolone acetate, fluperidone acetate, fluprednisolone valerate, peramitha acetate, prednisolone valerate, prednisolone valerate, hexamethylenetetramine, cortivazole, formococcal, and nivacosolone; pituitary hormones and their active derivatives or analogs, such as adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH) analogs, dilorelin acetate, cetrorelin acetate, gonadorelin acetate, clomiphene, human chorionic gonadotropin (HCG), luteinizing hormone (LH), and gonadotropin-releasing hormone (GnRH); hypoglycemic agents, such as insulin, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazoline, tolbutamide, and metformin; thyroid hormones, such as calcitonin, Thyroxine and iodine, as well as antithyroid agents such as carbimazole and propylthiouracil; other miscellaneous hormonal drugs such as octreotide; pituitary inhibitors such as bromocriptine; ovulation inducers such as clomiphene; diuretics such as thiazides, related diuretics and loop diuretics, phenoxythiazide, chlorothiazide, chlorothiazide, dopamine, cyclopenthiazine, hydrochlorothiazide, indapamide, mefcitrate, methylchlorothiazide, metoprazine, quinethazine, bumetanide, ethacrynic acid and furosemide, as well as potassium-sparing diuretics, spironolactone, amiloride and triamterene; antidiuretics such as desmopressin, lysine vasopressin and vasopressin, including their active derivatives or analogues; obstetric drugs, including drugs acting on the uterus such as ergonovine, oxytocin and gemcitabine;Prostaglandins, such as prostaglandin E1 (PGE1), prostacyclin (PGI2), dinoprost (prostaglandin F2-α), and misoprostol; antibacterial agents, including cephalosporins, such as cephalexin, cefoxitin, and cefotaxime; penicillins, such as amoxicillin, amoxicillin-clavulanic acid, ampicillin, bamectin, benzathine penicillin, benzylpenicillin, carbenicillin, cloxacillin, methicillin, feneccillin, phenoxymethylpenicillin, flucloxacillin, mezlocillin, piperacillin, and tebufenozide. Carcillin and azlocillin; tetracyclines, such as minocycline, chlortetracycline, tetracycline, demeclocycline, doxycycline, methacycline, and oxytetracycline, as well as other tetracycline antibiotics; aminoglycosides, such as amikacin, amikacin sulfate, gentamicin, kanamycin, neomycin, netilmicin, and tobramycin; antifungals, such as amorolfine, isoconazole, clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole, amphotericin B, griseofulvin, ketoconazole, fluconazole, and flucytosine. The following antibiotics are included: pyridoxine, salicylic acid, fezathion, ticlavone, tonaphthyl ester, triacetin, zinc, pyridoxine, and sodium pyridoxine; quinolones, such as nalidixic acid, sinofloxacin, ciprofloxacin, enoxacin, and norfloxacin; sulfonamides, such as phthalylsulfathiazole, sulfadoxine, sulfadiazine, sulfadimazole, and sulfamethoxazole; sulfones, such as dapsone; and other miscellaneous antibiotics, such as chloramphenicol, clindamycin, erythromycin, ethyl erythromycin carbonate, erythromycin etoritize, erythromycin gluconate, and ethyl succinate. Medications including 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, especially iodine and iodine compounds such as iodine-PVP complexes and diiodohydroxyquine, hexachlorophene; chlorhexidine; chloramine compounds, silver sulfadiazine, silver, silver nanoparticles, silver nitrate, silver zeolite, silver cations, AgPO3, Ag3PO4, Ag4P2O7, and exsalt; TM SD7 (Exciton Technologies) exsalt TMT7 (Exciton Technologies); Lincomycin hydrochloride, tricyclic tetrahydroquinoline antibacterial agent, 8-pyrazinyl-S-spiropyrimidine trione-oxazinquinoline derivative, 3-spiropyrimidine trione-quinoline derivative, thiadiazole-spiropyrimidine trione-quinoline derivative, (2R,4S,4aS)-10-fluoro-2,4-dimethyl-8-(4-methyloxazol-2-yl)-2,4,4a,6-tetrahydro-1H,1'H-spiro[[1,4]oxazinyl[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(-3'H)-trione, (2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-(3-methylisooxazol-5-yl)-2,4,4a,6 -Tetrahydro-1H,1'H-spiro[[1,4]oxazinyl[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-1H-,1'H-spiro[[1,4]oxazinyl[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-1H,1'H-spiro[[1,4]oxazinyl[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-tetrahydro-o-1H,1'H-spiro[[1,4]oxazinyl[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3'H)-trione Ketones, (2R,4S,4aS)-9-fluoro-2,4-dimethyl-8-(4-methyloxazol-2-yl)-2,4,4a,6-tetrahydro-1H,1'H-spiro[[1,4]oxazinyl[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3-'H)-triones, (2R,4S,4aS)-9,10-di Fluoro-8-(4-(4-fluorophenyl)oxazol-5-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1'H-spiro[[1,4]oxazinyl[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-1H,1'H-spiro-[[1,4]oxazinyl[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-1H,1'H-spiro[[1,4]oxazinyl[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-1H,1'H-spiro[[1,4]oxazinyl[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3'H)-trione, benzoyl peroxide; antituberculosis drugs, such as ethambutol, isoniazid, pyrazinamide, rifampin and clofazimine; antimalarial drugs, such as primaquine, pyrimethamine, chloroquine Hydroxychloroquine, quinine, mefloquine, and halopanthone; compounds such as azithromycin, aztreonam, cefaclor, cefadroxil, cefazolin, cefdinir, cefepime hydrochloride, (cefotaxime sodium, cefuroxime axetil, avibactam, ceftazidime sodium, cefbufen, ceftiofur, tazobactam, cefavirenz sodium [(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-3-[(2S)-tetrahydro-2-furanyl]-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid, monosodium salt] cefuroxime axetil Cefuroxime, cephalexin, chloramphenicol sodium, ciprofloxacin hydrochloride, clarithromycin, clindamycin hydrochloride, clindamycin palmitate hydrochloride, clindamycin phosphate, dapavancin hydrochloride, dapoxetine, demeclocycline hydrochloride, dicloxacillin, donipenon, doxycycline, doxycycline calcium, doxycycline hydrochloride, doxycycline monohydrate, ertapenem sodium, erythromycin, ethyl erythromycin succinate, erythromycin lactobionate, erythromycin stearate, erythromycin, fosfomycin tromethamine, gemifloxacin mesylate, gentamicin sulfate, imipenem, kanamycin, levofloxacin, lincomycin hydrochloride, linezolid, meropenem, urotropine hippurate Metronidazole, metronidazole, micafungin sodium, minocycline hydrochloride, minocycline, moxifloxacin hydrochloride, nafcillin, nalidixic acid, neomycin sulfate, nitrofurantoin, norfloxacin, ofloxacin, orivoxil, penicillin G, penicillin G benzathine, penicillin G sodium, penicillin V potassium, piperacillin sodium, polymyxin B sulfate, quinupristin, dalfopristin, spectinomycin hydrochloride, streptomycin, sulfamethoxazole, terdizotamide phosphate, tervacin, telithromycin, tetracycline hydrochloride, ticarcillin disodium, tigecycline, tobramycin sulfate, tobramycin, trimethoprim hydrochloride, tularemia, vancomycin hydrochloride.

[0045] The compositions disclosed herein may comprise antiviral agents, among which exemplary antiviral agents include acyclovir and acyclovir prodrugs, famciclovir, zidovudine, norinosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n-dococaptanol, tremandin, and idoxuridine. Other suitable bioactive agents include anthelmintics such as mebendazole, thiabendazole, niclosamide, praziquantel, pyrantel pamoate, and dimethoprim; and cytotoxic agents such as procainamide, cyclophosphamide, dacarbazine, fluorouracil, and their prodrugs (described, for example, in the International Journal of Pharmaceutics, 111, 223-233). (1994)), methotrexate, procarbazine, 6-mercaptopurine and mycophenolic acid; anorexia nervosa and weight loss agents, including dexfenfluramine, fenfluramine, diethylamine acetone, macindo and phentermine; drugs for hypercalcemia, such as calcitriol, dihydrotachysterol and their active derivatives or analogs; antitussives, such as ethylmorphine, dextromethorphan and pholcodine; antiparasitic and anthelmintic agents, such as moxicillin, ivermectin, niclosamide, praziquantel, pyrimethamine, pyrifos, albendazole, flubendazole, mebendazole, thiabendazole.

[0046] The compositions disclosed herein may include: expectorants such as carbocysteine, bromhexine, emidine, guaifenesin, ipecac, and saponins; decongestants such as phenylephrine, phenylpropanolamine, and pseudoephedrine; and bronchospasmodics such as ephedrine, fenoterol, orsinol, limpetrol, salbutamol, sodium cromoglycate, cromoglycine, and their prodrugs (described, for example, in the International Journal of Pharmaceutics 7, 63-75 (1980)), terbutaline, ipratropium bromide, salmeterol, and theophylline and theophylline derivatives; antihistamines, such as meclopramide, cycladine, chlorpheniramine, hydroxyzine, brompheniramine, chlorpheniramine, chlormastine, cyproheptadine, dextromethorphan, diphenhydramine, diphenylamine, doxylamine, mepheniramine, feniramine, triprolidine, atazatidine, diphenhydramine, medelazizine, terfenadine, astemizole, loratadine, and cephalosporins. Tirizine; local anesthetics such as benzocaine, bupivacaine, tetracaine, lidocaine, cocaine, cincocaine, debucaine, mepivacaine, prilocaine, eticaine, veratrine (a specific C-fiber blocker), and procaine; stratum corneum lipids such as ceramides, cholesterol, and free fatty acids, for improving skin barrier repair [Man et al. J. Invest. Dermatol., 106(5), 1096,

[1996] ; neuromuscular blocking agents, such as succinylcholine, acuronium, pancuronium bromide, atracurium, galaiodine, tubocurarine, and vecuronium bromide; sclerosing agents or tissue sclerosing agents may be surfactants or may be selected from the group consisting of: ethanol, dimethyl sulfoxide, sucrose, sodium chloride, dextran, glycerol, minocycline, tetracycline, doxycycline, polydocaine, sodium tetradecyl sulfate, sodium morrhuate, and sodium tetradecyl sulfate (sotradecol); angiogenesis inhibitors; 5-lipoxygenase inhibitors or antagonists; chemokine receptor antagonists; cell cycle inhibitors; taxanes; antimicrotubule agents; paclitaxel; analogues or derivatives of paclitaxel; vinca alkaloids; camptothecin or its analogues or derivatives; Podophyllotoxin, which may be etoposide or its analogues or derivatives; anthracyclines, which may be doxorubicin or its analogues or derivatives, or mitoxantrone or its analogues or derivatives; platinum compounds; nitrosoureas; nitroimidazoles; folic acid antagonists; cytidine analogues; pyrimidine analogues; fluoropyrimidine analogues; purine analogues; nitrogen mustard or its analogues or derivatives; hydroxyurea; mitomycin or its analogues or derivatives; alkyl sulfonates; benzamide or its analogues or derivatives; nicotinamide or its analogues or derivatives; halogenated sugars or their analogues or derivatives; DNA alkylating agents; anti-microtubule agents; topoisomerase inhibitors; DNA cleaving agents; antimetabolites; nucleotide tautomerization inhibitors;Dihydroorotate dehydrogenase inhibitors; DNA intercalators; RNA synthesis inhibitors; pyrimidine synthesis inhibitors; cyclin-dependent protein kinase inhibitors; epidermal growth factor kinase inhibitors; elastase inhibitors; factor Xa inhibitors; farnesyltransferase inhibitors; fibrinogen antagonists; guanylate cyclase agonists; heat shock protein 90 antagonists; which may be guldysin or its analogues or derivatives; guanylate cyclase agonists; HMGCoA reductase inhibitors, which may be simvastatin or its analogues or derivatives; IKK2 inhibitors; IL-1 antagonists; ICE antagonists; IRAK antagonists; IL-4 agonists; immunomodulators; sirolimus or its analogues or derivatives; everolimus Or its analogues or derivatives; tacrolimus or its analogues or derivatives; biolmus or its analogues or derivatives; tropelimus or its analogues or derivatives; auronoxine or its analogues or derivatives; 27-O-desmethylrapamycin or its analogues or derivatives; guanitolimus or its analogues or derivatives; pimecrolimus or its analogues or derivatives; ABT-578 or its analogues or derivatives; inosine monophosphate dehydrogenase (IMPDH) inhibitors, which may be mycophenolic acid or its analogues or derivatives or 1-α-25-dihydroxyvitamin D.sub.3 or its analogues or derivatives; leukotriene inhibitors; MCP-1 antagonists; MMP inhibitors; NFκB inhibitors, which may be Bay 11-7082; NO antagonists; p38 MAP kinase inhibitors, which may be SB 202190; Phosphodiesterase inhibitors; TGF-β inhibitors; Thromboxane A2 antagonists; TNF-α antagonists; TACE inhibitors; Tyrosine kinase inhibitors; Pleconin inhibitors; Fibroblast growth factor inhibitors; Protein kinase inhibitors; PDGF receptor kinase inhibitors; Endothelial growth factor receptor kinase inhibitors; Retinoic acid receptor antagonists; Platelet-derived growth factor receptor kinase inhibitors; Fibrinogen antagonists; Antifungal agents; Sulfonazole; Bisphosphonates; Phospholipase A1 inhibitors; Histamine H1 / H2 / H3 receptor antagonists; Macrolide antibiotics; GPIIb / IIIa receptor antagonists; Endothelin receptor antagonists; Peroxisome proliferator-activated receptors Agonists; estrogen receptor agonists; somatostatin analogs; neurokinin 1 antagonists; neurokinin 3 antagonists; VLA-4 antagonists; osteoclast inhibitors; DNA topoisomerase ATP hydrolysis inhibitors; angiotensin I converting enzyme inhibitors; angiotensin II antagonists; neprilysin inhibitors; peroxisome proliferator-activated receptor γ agonists; insulin sensitizers; protein kinase C inhibitors; ROCK (rho-associated kinase) inhibitors; CXCR3 inhibitors; Itk inhibitors; cytophospholipase A2-α inhibitors; PPAR agonists; immunosuppressants; Erb inhibitors; apoptosis agonists; lipocortin agonists; VCAM-1 antagonists; collagen antagonists;α-2 integrin antagonists; TNF-α inhibitors; nitric oxide inhibitors; and cathepsin inhibitors, antifibrinogens, and fibrinolytic agents, including plasminogen, streptokinase, single-chain urokinase, urokinase, t-PA (tissue plasminogen activator), and aminocaproic acid; antiplatelet drugs, including aspirin, prostacyclin (and analogues); glycoprotein IIb / IIIa drugs, including monoclonal antibodies, peptides (e.g., ReoPro, cilatagal, epitubatide, tirofiban, ticlopidine, vapaporst, dipyridamole, telangiol, angiotensin, and vasoactive peptides). Antithrombin and anticoagulants, including dextran, heparin, LMW heparin (enoxaparin, dalteparin), hirudin, recombinant hirudin, antithrombin, synthetic antithrombin, thrombin inhibitors, warfarin (and other coumarins); antimitotics, antiproliferative agents and cell inhibitors, including vincristine, vinblastine, paclitaxel, methotrexate, cisplatin, fluorouracil, rapamycin, azathioprine, cyclophosphamide, mycophenolic acid, corticosteroids, colchicine, sodium nitroprusside; antiangiogenic agents and angiogenesis inhibitors, including argatroban, thromboxane, antithrombin inhibitors; anti-angiogenic agents and angiogenesis inhibitors, including dextran, heparin, LMW heparin (enoxaparin, dalteparin), hirudin, recombinant hirudin, antithrombin, synthetic antithrombin, thrombin inhibitors, warfarin (and other coumarins); antimitotics, antiproliferative agents and cell inhibitors, including vincristine, vinblastine, paclitaxel, tadalafil, cisplatin, fluorouracil, rapamycin, azathioprine, cyclophosphamide, mycophenolic acid, corticosteroids, colchicine, sodium nitroprusside; antiangiogenic agents and angiogenesis inhibitors, including argatroban, tadalafil ...cyclophosphamide, Taxol, angiostatin, and endostatin; genetic material 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 (ω3-fatty acids); phosphodiesterase inhibitors (e.g., dipyridamole); nitrate donors (e.g., madol); somatostatin analogs (e.g., angiopeptidase); immunosuppressants and anti-inflammatory drugs (e.g., prednisolone, glucocorticoids, and dexamethasone); antibacterial agents. Agents (e.g., rifamycin) and radionuclides, including α, β, and γ emission isotopes (e.g., Re-188, Re-186, I-125, Y-90); COX-2 inhibitors, such as celecoxib and nifedipine; kinase inhibitors, such as epidermal growth factor kinase inhibitors, tyrosine kinase inhibitors, MAP kinase inhibitors, proteotransferase inhibitors, Resten-NG; smoking cessation agents such as nicotine, bupropion, and edocaine; insecticides and other pesticides suitable for topical application; dermatological agents, such as vitamins A, C, B1, B2, B6, and B6. 12. Vitamins B12α and E, vitamin E acetate and vitamin E sorbate; allergens used for desensitization, such as house dust or dust mite allergens; nutrients and health supplements, 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, etc.; bone-strengthening biochemicals, such as calcium carbonate, calcium phosphate, tricalcium phosphate, hydroxyapatite or bone morphogenetic protein (BMP); angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EFG), cytokines interleukins, fibroblasts and cytotoxic chemicals;And keratolytic agents, such as alpha-hydroxy acids, glycolic acid, and salicylic acid; DNA, RNA, or other oligonucleotides; vaccines containing 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, porcine reproductive and respiratory syndrome virus antigen, and Mycoplasma hyopneumoniae protein antigen; proteins or protein fragments, such as ORFI Torque teno virus protein or other TTV proteins or fragments, antigens against Aeromonas salmonicida, antigens against Vibrio anguillarum, and antigens against Aeromonas salmonicida; growth factors including but not limited to vascular endothelial growth factor (VEGF) and epidermal growth factor (EFG), growth differentiation factor (GDF), fibroblast growth factor (FGF-1 to FGF-23), osteoprotegerin, cartilage-derived morphogenetic protein (CDMP, which may be based on soft or hard tissue), Lim mineralization protein (LMP), interleukins (IL-1 to IL-13), and islets of Langerhans. Growth factor-like factor-1, connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), nerve growth factor, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), transforming growth factor (TGF-α, TGF-β), tumor necrosis factor (TNF); growth factor agonists or antagonists and antibodies against these growth factors; bioactive agents that can be used to treat macular degeneration, including but not limited to bevacizumab and ranibizumab. Bioactive agents may include the antibiotic anisoxamine. Ansarmycin antibiotics may include, but are not limited to, rifampin, germectin, rifabutin, rifaximin, and rifamycin S.

[0047] On one hand, the active agent is a protein, wherein the term includes peptides and polypeptides, sugar-modified proteins such as glycoproteins, and functional descriptions of protein classes such as antigens, enzymes, immunoglobulins, and antibodies. The composition may include a specific delivery medium for the active agent, such as a virus or a modified virus, wherein the active agent (such as a protein or polynucleotide) is contained within or expressed by the specific delivery medium.

[0048] On one hand, the active agent is a PD-L1 inhibitor. PD-L1 inhibitors can include, but are not limited to, atezolizumab, avelumumab, durvalumab, LY3300054 (Eli Lilly and Company), and monoclonal antibodies or monoclonal antibody conjugates that act as PD-L1 inhibitors.

[0049] On one hand, the active agent is a PD-1 inhibitor. PD-1 inhibitors may include, but are not limited to, pembrolizumab, nivolumab, cimipril, and monoclonal antibodies or monoclonal antibody conjugates that act as PD-1 inhibitors.

[0050] On one hand, the active agent is a CTLA-4 inhibitor. CTLA-4 inhibitors may include, but are not limited to, ipilimumab, AGEN1884, and monoclonal antibodies or monoclonal antibody conjugates that act as CTLA-4 inhibitors.

[0051] On one hand, the active agent is a compound used to treat non-muscle-invasive bladder cancer. Compounds that may be used include, but are not limited to, non-live immune-active BCG subfractions, which include the BCG cell wall and various BCG proteins and antigens, IL-2 fusion proteins such as ALT-801 (Altor Bioscience), Oportuzumab monatox (Sesen Bio), sunitinib (Pfizer), enzalutamide, ethacrynic acid, imiquimod and tamoxifen, ALT-803 (Altor Bioscience), and lenalidomide.

[0052] On one hand, the active agent is an antibody-drug conjugate. Antibody-drug conjugates may include, but are not limited to, trastuzumab emtansine, goxatuzumab, enfortumab vedotin, ASG-15ME, gemtuzumab ozomicin, bentuximab, trastuzumab emtansine, and ozatotuzumab.

[0053] On one hand, the active agent is a small molecule protein kinase inhibitor. Small molecule protein kinase inhibitors may include, but are not limited to, abexicinib, acalabrutinib, afatinib, alectinib, axitinib, baricitinib, bimetinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobitinib, crizotinib, dabrafenib, dacomitinib, dasatinib, cannefenib, erdatinib, erlotinib, everolimus, fantatinib, gefitinib, gipritinib, etc. Ibrutinib, imatinib, lapatinib, larotrectinib, lenvatinib, lorlatinib, midotolin, neratinib, natesudil, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sirolimus, sorafenib, sunitinib, tesimolilimus, tofacitinib, trametinib, vandetanib, and vemurafenib.

[0054] In one aspect, the compositions of this disclosure may comprise collagen, gelatin, chitosan, chitosan derivatives, or thrombin. In one aspect, the compositions of this disclosure may comprise hyaluronic acid derivatives and chitosan as described in this disclosure. In one aspect, the compositions of this disclosure may comprise hyaluronic acid derivatives and collagen as described in this disclosure. In one aspect, the compositions of this disclosure may comprise chitosan derivatives as described in this disclosure and unmodified chitosan. In one aspect, the chitosan derivatives may include those derivatives described in U.S. Patent 10,179,145, the entire teachings of which are incorporated herein by reference. In one aspect, the compositions of this disclosure may comprise dextran derivatives and chitosan as described in this disclosure. In one aspect, chitosan or chitosan derivatives may comprise at least about 5% (w / w) of the composition. In one aspect, chitosan or chitosan derivatives may comprise at least about 10% (w / w) of the composition. In one aspect, chitosan or chitosan derivatives may comprise at least about 20% (w / w) of the composition. In one aspect, chitosan or a chitosan derivative may constitute at least about 30% (w / w) of the composition. In another aspect, chitosan or a chitosan derivative may constitute at least about 40% (w / w) of the composition. In another aspect, chitosan or a chitosan derivative may constitute between about 5% (w / w) and about 40% (w / w) of the composition. In another aspect, chitosan or a chitosan derivative may constitute between about 20% (w / w) and about 80% (w / w) of the composition. In another aspect, chitosan or a chitosan derivative may constitute between about 50% (w / w) and about 90% (w / w) of the composition.

[0055] In one aspect, the compositions of this disclosure may comprise hyaluronic acid derivatives and gelatin as described herein. In one aspect, the gelatin may be cross-linked. In one aspect, the gelatin or cross-linked gelatin is in particulate form. In one aspect, the cross-linked gelatin particles may be in a hydrated form. In one aspect, the gelatin or cross-linked gelatin may constitute at least about 5% (w / w) of the composition. In one aspect, the gelatin or cross-linked gelatin may constitute at least about 10% (w / w) of the composition. In one aspect, the gelatin or cross-linked gelatin may constitute at least about 20% (w / w) of the composition. In one aspect, the gelatin or cross-linked gelatin may constitute at least about 30% (w / w) of the composition. In one aspect, the gelatin or cross-linked gelatin may constitute at least about 40% (w / w) of the composition. In one aspect, the gelatin or cross-linked gelatin may constitute between about 5% (w / w) and about 40% (w / w) of the composition. In one aspect, the gelatin or cross-linked gelatin may constitute between about 20% (w / w) and about 80% (w / w) of the composition. In one respect, gelatin or cross-linked gelatin may comprise between about 50% (w / w) and about 90% (w / w) of the composition.

[0056] In one aspect, the compositions of this disclosure comprise the hyaluronic acid derivatives of this disclosure, wherein R1 is an aliphatic C8 to C12 aliphatic group.18 Chain. In another aspect, the composition comprises a hyaluronic acid derivative of this disclosure and water, wherein R1 is an aliphatic C8 to C1 chain. 18 Chain. In one aspect, the composition comprises a hyaluronic acid derivative of the present disclosure and chitosan, wherein R1 is an aliphatic C8 to C1 chain. 18 Chain. In one aspect, the chitosan in the composition exists in the form of a solid powder. In another aspect, the compositions of this disclosure comprise the hyaluronic acid derivative of this disclosure, chitosan, and an aqueous saline solution, wherein R1 is an aliphatic C8 to C12 chain. 18 Chain. In one aspect, the composition comprises a cross-linked hyaluronic acid derivative of the present disclosure, wherein R1 is an aliphatic C8 to C1 chain. 18 Chain. In one aspect, the composition comprises a cross-linked hyaluronic acid derivative and chitosan of the present disclosure, wherein R1 is an aliphatic C8 to C1 chain. 18 chain.

[0057] In one aspect, the compositions of this disclosure comprise the hyaluronic acid derivative of this disclosure, wherein R1 is an aliphatic C 12 To C 18 The aliphatic chain has at least eight consecutive -CH2- groups. In one aspect, the composition comprises a hyaluronic acid derivative of this disclosure, wherein R1 is an aliphatic C8 to C12 chain. 18 The aliphatic chain has at least eight consecutive -CH2- groups and water. In one aspect, the composition comprises a hyaluronic acid derivative of this disclosure and chitosan, wherein R1 is an aliphatic C8 to C1 chain. 18 The aliphatic chain has at least eight consecutive -CH2- groups. In one aspect, the compositions of this disclosure comprise the hyaluronic acid derivative of this disclosure, chitosan, and an aqueous solution, wherein R1 is an aliphatic C8 to C12 chain. 18 The aliphatic chain has at least eight consecutive -CH2- groups. In one aspect, the composition comprises a cross-linked hyaluronic acid derivative of this disclosure, wherein R1 is an aliphatic C8 to C12 chain. 18 The aliphatic chain has at least eight consecutive -CH2- groups. In another aspect, the composition comprises a cross-linked hyaluronic acid derivative of this disclosure and chitosan, wherein R1 is an aliphatic C8 to C12 chain. 18 The aliphatic chain has at least eight consecutive -CH2- groups. In one aspect, the compositions of this disclosure comprise the hyaluronic acid derivative of this disclosure and gelatin or cross-linked gelatin, wherein R1 is an aliphatic C8 to C12 chain. 18 The aliphatic chain has at least eight consecutive -CH2- groups. In one aspect, the compositions of this disclosure comprise the hyaluronic acid derivative of this disclosure, gelatin or cross-linked gelatin, and water, wherein R1 is an aliphatic C8 to C1 chain. 18 A chain, wherein the aliphatic chain has at least eight consecutive -CH2- groups.

[0058] In one aspect, the compositions of this disclosure comprise the hyaluronic acid derivative of this disclosure, wherein R1 is an aliphatic C 18 A chain (i.e., an aliphatic chain having 18 carbon units), wherein the aliphatic chain has at least eight consecutive -CH2- groups. In one aspect, the compositions of this disclosure comprise the hyaluronic acid derivative of this disclosure, wherein R1 is an aliphatic C 18 The aliphatic chain has at least eight consecutive -CH2- groups and water. In one aspect, the compositions of this disclosure comprise the hyaluronic acid derivative of this disclosure, chitosan, and water, wherein R1 is an aliphatic C... 18 The aliphatic chain has at least eight consecutive -CH2- groups. In one aspect, the compositions of this disclosure comprise the hyaluronic acid derivative of this disclosure, gelatin or cross-linked gelatin, and water, wherein R1 is an aliphatic C 18 A chain, wherein the aliphatic chain has at least eight consecutive -CH2- groups.

[0059] In one aspect, the compositions of this disclosure comprise two or more of the hyaluronic acid derivatives of this disclosure. In another aspect, the first hyaluronic acid derivative of this disclosure comprises, as an aliphatic C... 18 The chain (i.e., an aliphatic chain with 18 carbon units) contains R1, and the second hyaluronic acid derivative of this disclosure contains as an aliphatic C 16 R1 of the chain (i.e., an aliphatic chain having 16 carbon units). In one aspect, the first hyaluronic acid derivative of this disclosure comprises as an aliphatic C 18 The chain (i.e., an aliphatic chain with 18 carbon units) contains R1, and the second hyaluronic acid derivative of this disclosure contains as an aliphatic C 12 or aliphatic C 14 R1 of the chain.

[0060] In one aspect, the compositions of this disclosure are part of a medical device comprising a delivery system containing the compositions of this disclosure. Examples of delivery systems include, but are not limited to, syringes, manual nebulizers, gas-assisted nebulizers, aerosol cans, or combinations thereof. In one aspect, the compositions of this disclosure are sterile. In one aspect, the medical devices of this disclosure are sterile.

[0061] The compositions disclosed herein can be placed at a location within the body or on the surface of a tissue or organ. In one aspect, the compositions disclosed herein can be placed in or on muscle, adipose tissue, lung tissue, brain tissue, 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 another aspect, the compositions disclosed herein can be placed within an aneurysm. In another aspect, the compositions disclosed herein can be placed at a site of injury. In another aspect, the compositions disclosed herein can be placed at a surgical site. In another aspect, the compositions disclosed herein can be placed in or on burns, ulcers, or wounds.

[0062] In one aspect, the compositions of this disclosure can be formulated for (and can be used for) reducing or stopping blood flow from or through tissues or organs. In another aspect, the compositions of this disclosure can be formulated for (and can be used for) achieving hemostasis at surgical or trauma sites. In another aspect, the compositions of this disclosure can be formulated for (and can be used for) coagulating blood at surgical or trauma sites. In another aspect, the compositions of the present invention can be applied in the form of solutions, dry powders, slurries, films, foams, gels, lyophilized matrices, or combinations thereof. In another aspect, after applying the compositions of this disclosure, a compressive force can be applied to the application site and held there for at least 10 seconds before the compressive force is removed.

[0063] Methods of using the compositions disclosed herein may include placing or applying the compositions of the disclosed herein to a bleeding site of a subject. Methods of using the compositions of the disclosed herein may include placing the compositions of the disclosed herein at the bleeding site and then applying compressive force to the site.

[0064] The compositions disclosed herein can be used to coat a medical device, or can be applied to a medical device before, during, or after placement of the medical device. Medical devices that can be coated with or used in combination with the compositions disclosed herein include, but are not limited to, catheters, needles, biopsy needles, sutures, cannulas, tissue markers, guidewires and endovascular sheaths, sutures, braids, cannulas, mesh bags, electrospun sheets, electrospun bags, electrospun materials, hernia meshes, surgical meshes, meshes for breast reconstruction, contact lenses, intraocular lenses, stents (e.g., vascular stents, esophageal stents, bile duct stents, coronary stents, kidney stents, peripheral vascular stents, urinary stents, ureteral stents), nasal splints, vascular grafts, stent grafts, aneurysm coils, catheter sheaths, balloon catheters, vascular closure devices, inferior vena cava filters, artificial joints, replacement tendons, tendon repair patches, devices for achieving spinal fusion, pacemakers, pacemaker leads, implantable cardiac electronic devices, implantable cardioverter defibrillators, spinal cord stimulators, leads for implantable electronic devices, and hydrocephalus shunts. In one aspect, a medical device may be a pouch or sheath into which another medical device is inserted. In one aspect, the pouch or envelope contains a biodegradable polymer. In another aspect, the biodegradable polymer is synthesized from one or more monomers selected from l-lactide, dl-lactide, glycolide, ε-caprolactone, trimethylene carbonate, morpholino-dione, p-dioxanone, and 1,5-dioxane-2-one. In another aspect, the biodegradable polymer includes glycolide copolymers. In another aspect, the biodegradable polymer includes lactide copolymers. In another aspect, the biodegradable polymer includes polydioxanone polymers or copolymers.

[0065] This document discloses a method for hemostasis control, comprising providing a subject with a composition comprising derived hyaluronic acid, wherein the derived hyaluronic acid comprises an aliphatic chain of 18 carbon units, 16 carbon units, 14 carbon units, 12 carbon units, 10 carbon units, 20 carbon units, 22 carbon units, 24 carbon units, 26 carbon units, 28 carbon units, or 30 carbon units. The disclosed composition may further comprise water, chitosan, gelatin, cross-linked derived hyaluronic acid, or mixtures or combinations thereof. The composition may be provided to the subject via a medical device. The medical device may include a syringe containing the disclosed composition. One method may include providing the disclosed composition to one or more sites of bleeding in the subject or to sites of active loss of hemostasis or hydrostatic fluid in the subject. One method may include providing a kit comprising the disclosed composition, wherein the kit and its components are used to improve hemostasis in the subject.

[0066] As used herein, a subject refers to any living organism that maintains fluid levels to survive. Subjects may include, but are not limited to, humans, animals, mammals, livestock, plants, worms, multicellular and single-celled organisms. For example, an organism or a portion thereof may be immersed in the compositions disclosed herein to prevent or inhibit the loss of one or more fluids (such as cellular fluid, tissue fluid, blood and / or plasma) from the organism, or the subject may administer, apply, inject, or contact the compositions disclosed herein to one or more sites of fluid loss in the subject.

[0067] This document discloses a kit comprising the disclosed composition and optional instructions for use. In one aspect, the kit may comprise the disclosed composition and an applicator for delivering the composition to a site, and optional instructions for use. In another aspect, the kit may comprise the disclosed composition and a medical device, and optional instructions for use. In yet another aspect, one or more components of the kit may be sterile.

[0068] The following examples are provided for illustrative purposes only and not for limitation.

[0069] Example 1

[0070] HA modified by DVS (DVS2)

[0071] Add 2.5 g of sodium hyaluronate (900 kDa) to a 4 L glass reactor. Attach the lid, top stirrer, and anchor impeller to the reactor. Stir the solution at approximately 200 rpm. Add 250 g of deionized (DI or D2O) water to the reactor. Stir the solution for approximately 18 hours. Add 166.5 g of 0.25 M NaOH solution to the dissolved sodium hyaluronate. Measure the pH of the solution after 2 minutes; the result is 12.69. Then, rapidly add a freshly prepared solution of 10.6 g of divinyl sulfone in 66 g of DI water to the stirred solution. After 75 seconds, add 50 g of 1 M HCl solution to the reaction mixture. Then, add 1 M NaOH dropwise until the pH of the solution is between 5 and 7. Then, add 6 g of NaCl to the solution. Once the NaCl has dissolved, slowly add 1.25 L of acetone over 20 minutes. Stir the suspension for approximately 3 hours. Add 200 mL of denatured ethanol and stir the solution for approximately 30 minutes. Filter the precipitate under vacuum through a 0.22 µm PTFE filter membrane using a sintered glass funnel. Once all the solution has been filtered, disconnect the vacuum and rinse the precipitate with 100 mL of ethanol. Then remove the ethanol by vacuum filtration. Repeat this process three times. Vacuum dry the product (sample) in a vacuum oven at room temperature. Add approximately 10–20 mg of the dried sample to a vial. Add D2O to the sample to bring the final concentration of the solution to approximately 6 mg / mL. Shake the sample on an orbital oscillator until dissolved. Once dissolved, transfer the sample to an NMR tube and record the sample on an NMR spectrometer. 1 ¹H-NMR spectra. The spectra were printed, revealing specific peaks in the regions of 6.3–6.5 ppm (two peaks from the 2 CH₂= protons of vinyl sulfone residues), 6.8–7.0 ppm (CH peak of vinyl groups), and 1.8–2.5 ppm (single peak from the 3 CH₃ protons of the N-acetyl group of HA). The percentage of modification was calculated based on the molar ratio of vinyl CH protons (6.8–7 ppm) to acetamide protons (1.8–2.5 ppm). The substitution percentage was found to be approximately 8.9%.

[0072] Example 2

[0073] HA modified by DVS (DVS13)

[0074] 3.5 g of sodium hyaluronate (approximately 800 kDa; 1.4 m³ / kg IV) was added to a 4 L glass reactor. The lid, top stirrer, and anchor impeller were attached to the reactor. 350 g of deionized water was added to the reactor. The solution was then stirred at approximately 300 rpm. The solution was stirred for approximately 18 hours. The stirring speed was then increased to 750 rpm, and approximately 233 g of 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2 minutes and found to be 12.95. A freshly prepared solution of 15.5 g of divinyl sulfone in 92.4 g of DI water was then rapidly added to the stirred solution. After 4.5 minutes, 63 g of 1 M HCl solution was added to the reaction mixture. Then, 1 M NaOH was added dropwise until the pH of the solution was between 5 and 7. 8.4 g of NaCl was then added to the solution. Once the NaCl had dissolved, 1.5 L of acetone was slowly added over 30 minutes. The suspension was stirred for approximately 3 hours. 300 mL of denatured ethanol was added, and the solution was stirred for approximately 30 minutes. The precipitate was filtered under vacuum through a 0.22 µm PTFE membrane using a sintered glass funnel. Once all the solution had been filtered, the vacuum was removed, and the precipitate was washed with 150 mL of ethanol. The ethanol was then removed by vacuum filtration. This process was repeated three times. The product was vacuum-dried in a vacuum oven at room temperature. The substitution percentage was determined to be approximately 25% using the procedure described in Example 1.

[0075] Example 3

[0076] HA modified by DVS (DVS14)

[0077] The reaction was carried out using a 6-minute reaction time as described in Example 2. Based on the procedure described in Example 1, a substitution percentage of approximately 31% was found.

[0078] Example 4

[0079] The reaction of HA-DVS with 1-octylthiol (HA-DVS2-oct)

[0080] 0.5 g of vinyl sulfone-derived HA (approximately 9%, according to Example 1) was added to 50 g of DI water in a 250 mL round-bottom flask. The reaction was stirred at room temperature for approximately 4 hours. Approximately 15.8 g of denatured ethanol was added and the mixture was stirred for approximately 18 hours, at which point the material had dissolved. The flask was then purged with nitrogen. A 7.9 g ethanol solution of 0.023 g of 1-octylthiol was then added to the HA-derived solution. The pH of the reaction mixture was adjusted to approximately 9 using 0.25 M NaOH. The solution was stirred for 4 hours, and then the pH was adjusted to approximately 7 using 0.25 M HCl. 0.5 g of NaCl was added to the reaction solution. The solution was stirred until the NaCl dissolved. 150 mL of cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was separated using vacuum filtration. The precipitate was washed four times with 25 mL of ethanol, ensuring the filter funnel did not dry out. The precipitate was vacuum dried at room temperature. A sample of the material was dissolved in D2O and the determination was performed. 1 ¹H-NMR spectra. 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-) confirm the presence of octahthiol substitution. The molar degree of octahthiol was calculated to be 5.4% based on the integrals at 2.6–2.7 ppm (Oct – CH₂-S-) and 1.7–2 ppm (HA – acetamide).

[0081] Example 5

[0082] The reaction of HA-DVS with 1-octylthiol (HA-DVS2-oct-DMF)

[0083] Add 0.5 g of vinyl sulfone-derived HA (approximately 9%, according to Example 1) to 50 g of DI water in a 250 mL round-bottom flask. Stir the reaction at room temperature for approximately 4 hours. Add approximately 18.88 g of dimethylformamide (DMF) and stir the mixture for approximately 18 hours, until the material is dissolved. Then purge the flask with nitrogen. Add 0.029 g of 1-octylthiol from 9.4 g of DMF to the HA-derived solution. Adjust the pH of the reaction mixture to approximately 9 using 0.25 M NaOH. Stir the solution for 4 hours, then adjust the pH to approximately 7 using 0.25 M HCl. Add approximately 0.25 g of NaCl to the reaction solution. Stir the solution until the NaCl dissolves. Slowly add 150 mL of cold acetone to the solution. Stir the reaction mixture for 1.5 hours. Add 25 mL of ethanol and stir the resulting mixture for 15 minutes. Separate the precipitate using vacuum filtration. Wash the precipitate four times with 25 mL of ethanol, ensuring the filter funnel does not dry out. Dry the precipitate under vacuum at room temperature. The material sample was dissolved in D2O and measured. 1 The H-NMR spectrum shows that the molar degree of substitution of octylthiol is 5.5% calculated based on the integrals at 2.4–2.5 ppm (Oct – CH2-S-) and 1.7–2 ppm (HA – acetamide).

[0084] Example 6

[0085] The reaction of HA-DVS with 1-dodecylthiol (HA-DVS2-dod)

[0086] 0.5 g of vinyl sulfone-derived HA (approximately 9%, according to Example 1) was added to 50 g of DI water in a 250 mL round-bottom flask. The reaction was stirred at room temperature for approximately 4 hours. Approximately 15.8 g of denatured ethanol was added and the mixture was stirred for approximately 18 hours, at which point the material had dissolved. The flask was then purged with nitrogen. 0.04 g of a 7.9 g ethanol solution of 1-dodecanethiol was then added to the HA-derived solution. The pH of the reaction mixture was adjusted to approximately 9 using 0.25 M NaOH. The solution was stirred for 4 hours, and then the pH was adjusted to approximately 7 using 0.25 M HCl. 0.25 g of NaCl was added to the reaction solution. The solution was stirred until the NaCl dissolved. 150 mL of cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was separated using vacuum filtration. The precipitate was washed four times with 25 mL of ethanol, ensuring the filter funnel did not dry out. The precipitate was vacuum dried at room temperature. A sample of the material was dissolved in D2O and the determination was performed. 1¹H-NMR spectra. 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-) confirm the presence of octahthiol substitution. The molar degree of octahthiol substitution was calculated to be 5.2% based on the integrals at 2.6–2.7 ppm (Oct – CH₂-S-) and 1.7–2 ppm (HA – acetamide).

[0087] Example 7

[0088] HA modified by DVS – (DVS5 – 800 kDa)

[0089] Add 3.5 g of sodium hyaluronate (1.4 m³ / kg, approximately 800 kDa) to a 4 L glass reactor. Attach the lid, top stirrer, and anchor impeller to the reactor. Add 350 g of deionized water to the reactor. Stir the solution at approximately 200 rpm for approximately 18 hours. Add 233 g of 0.25 M NaOH solution to the dissolved sodium hyaluronate. Measure the pH of the solution after 2 minutes; the result is 12.85. Then, rapidly add a freshly prepared solution of 14.8 g of divinyl sulfone in 92.4 g of DI water to the stirred solution. After 75 seconds, add 63 g of 1 M HCl solution to the reaction mixture. Then, add 1 M NaOH or 1 M HCl dropwise as needed until the pH of the solution is between 5 and 7. Then, add 8.4 g of NaCl to the solution. Once the NaCl dissolves, slowly add 1.5 L of acetone over a 30-minute period. Stir the suspension for approximately 3 hours. Add 200 mL of ethanol (ethanol, alcohol reagent, denatured anhydrous 94%–96%) and stir the solution for approximately 30 minutes. Filter the precipitate under vacuum through a 0.22 µm PTFE filter membrane using a sintered glass funnel. Wash the precipitate with 150 mL of ethanol. Then remove the ethanol by vacuum filtration. Repeat this process three times. Dry the product under vacuum in a vacuum oven at room temperature. The percentage of substitution was found to be approximately 8.9%, as determined in Example 1.

[0090] Example 8

[0091] The reaction of HA-DVS with 1-decylthiol (HA-DVS5-dec)

[0092] Add 0.5 g of vinyl sulfone-derived HA (approximately 9%, according to Example 7) to 20 DI water in a 250 mL round-bottom flask. Stir the reaction at room temperature for approximately 4 hours. Add 19.7 g of denatured ethanol and stir the mixture for approximately 18 hours, at which point the material has dissolved. Then purge the flask with nitrogen. Then add a 4 g ethanol solution of 0.035 g of 1-decathiol to the HA-derived solution. Adjust the pH of the reaction mixture to approximately 9 using 0.25 M NaOH. Stir the solution for 4 hours, then adjust the pH to approximately 7 using 0.25 M HCl. Add 0.25 g of NaCl to the reaction solution. Stir the solution until the NaCl dissolves. Slowly add 150 mL of cold acetone to the solution. Stir the reaction mixture for 1.5 hours. Separate the precipitate using vacuum filtration. Wash the precipitate four times with 25 mL of ethanol, ensuring the filter funnel does not dry out. Vacuum dry the precipitate at room temperature. Dissolve a sample of the material in D2O and determine its composition. 1 ¹H-NMR spectra. Peaks at 0.6–0.8 ppm (CH₃-), 1.1–1.6 ppm (-CH₂-), 2.4–2.6 ppm (-CH₂-S-), and 2.7–2.9 ppm (-S-CH₂-) confirm the presence of decanethiol substitution. The molar degree of substitution of decanethiol was calculated to be 6.5% based on the integrals at 2.3–2.7 ppm (pent – ​​CH₂-S-) and 1.7–2 ppm (HA – acetamide).

[0093] Example 9

[0094] HA modified by DVS – (DVS18 – 800 kDa)

[0095] 3.5 g of sodium hyaluronate (IV = 1.4 m) 3Add sodium hyaluronate (approximately 800 kDa / kg) to a 4 L glass reactor. Attach the lid, top stirrer, and anchor impeller to the reactor. Add 350 g of deionized water to the reactor. Stir the solution at approximately 750 rpm for approximately 18 hours. Add 233 g of 0.25 M NaOH solution to the dissolved sodium hyaluronate. Measure the pH of the solution after 2 minutes; the result is 12.92. Then, rapidly add a freshly prepared solution of 15.5 g of divinyl sulfone in 92 g of DI water to the stirred solution. After 15 minutes, add 63 g of 1 M HCl solution to the reaction mixture. Then, add 1 M NaOH or 1 M HCl dropwise as needed until the pH of the solution is between 5 and 7. Then, add approximately 8.4 g of NaCl to the solution. Once the NaCl has dissolved, slowly add 1.5 L of acetone over 30 minutes. Stir the suspension for approximately 3 hours. Add 300 mL of ethanol (ethanol, alcohol reagent, denatured anhydrous 94%–96%) and stir the solution for approximately 30 minutes. Filter the precipitate under vacuum through a 0.22 µm PTFE filter membrane using a sintered glass funnel. Once all the solution has been filtered, disconnect the vacuum and wash the precipitate with 150 mL of ethanol. Then remove the ethanol by vacuum filtration. Repeat this process three times. Dry the product under vacuum in a vacuum oven at room temperature. The substitution percentage was found to be 71.3%, as determined by the procedure described in Example 1.

[0096] Example 10

[0097] The reaction of HA-DVS with octylthiol

[0098] HA-DVS was prepared in a manner similar to that in Example 9, and converted to an octylthiol derivative in a manner similar to that in Example 6. The sample of the material was dissolved in D₂O, and the determination was performed. 1 The 1H-NMR spectrum shows that the molar degree of substitution of octylthiol was calculated to be 69.8% based on the integrals at 2.4–2.5 ppm (Oct – CH2-S-) and 1.7–2 ppm (HA – acetamide).

[0099] Example 11

[0100] HA modified with octadecylthiol (DVS6-2)

[0101] Add 500 g of deionized water to a 4 L reaction vessel. Set the top stirrer to 200 rpm. Add 5 g of sodium hyaluronate [HA] (approximately 200 kDa) to the 4 L reaction vessel. Stir the solution until the HA dissolves. Add 21.2 g of divinyl sulfone [DVS] to 132 g of deionized water and stir the solution for approximately 15 minutes. Add 333 g of 0.25 M NaOH to the HA solution. Adjust the pH of the HA solution to approximately 12.8 using NaOH and HCl. Then quickly add the DVS solution and allow the reaction to proceed for 180 seconds. Add 90 g of 1 M HCl to quench the reaction. Then adjust the pH of the solution to between 5 and 7 using 1 M NaOH. Add 12 g of NaCl to the solution and continue stirring until the NaCl dissolves. Slowly add 2 L of acetone to the reaction mixture. Stir the reaction mixture for 3 hours, then add approximately 400 mL of ethanol and stir the solution for 30 minutes. Filter the precipitated composition and wash with four 200 mL aliquots of ethanol. Add DVS-derived HA to a 1 L reaction vessel. Add approximately 300 g of deionized water. Set the top stirrer to approximately 300 rpm and heat the system to approximately 30°C. Add approximately 200 g of ethanol to the reaction mixture. Once the material has dissolved, increase the stirring speed to approximately 500 rpm and add approximately 3.6 g of 1-octadecylthiol (Sigma) to the reaction mixture. After 10 minutes, adjust the pH of the reaction mixture to approximately pH 9.0 using 1M NaOH and 1M HCl. Allow the reaction to proceed for approximately 16–18 hours. Then adjust the pH to approximately pH 6.7–7.3 and turn off the heating. Then add approximately 2.3 g of NaCl to the reaction mixture. Once the NaCl has dissolved, add approximately 500 mL of acetone to the mixture. Stir the mixture for approximately 90 minutes. Turn off the stirrer and filter the settled precipitate. Wash the precipitate four times with 200 mL of ethanol. Dry the product under vacuum. Dissolve a sample of the product in D₂O and determine its composition. 1 ¹H-NMR spectra revealed that the degree of substitution of octadecylthiol was approximately 4.1% based on the disaccharide unit and approximately 1.0% based on the HA hydroxyl group.

[0102] Example 12

[0103] In vitro coagulation test

[0104] A 1% solution of octadecyl mercaptan HA derivative (Example 11) was prepared in deionized water. A 1% solution of octadecyl mercaptan HA derivative (Example 11) was also prepared in 0.9% NaCl / water. 1% hyaluronic acid (800 kDa) was prepared in deionized water. 1 mL of the 1% octadecyl mercaptan HA derivative solution was added to a glass vial. 1 mL of citrate sheep blood (a hemostatic agent) was added to the glass vial. The mixture was vortexed for 10 seconds, and a timer was started at the beginning of the vortex. The vial was then placed in a water bath set to 37°C. The vial was inverted periodically. After 30 seconds, the mixture gelled and did not flow after inversion. This study was repeated using octadecyl mercaptan HA derivative / saline solution, unmodified HA solution, and deionized water. The octadecyl mercaptan HA derivative / saline solution gelled within approximately 3 minutes to 3 minutes and 30 seconds, while the unmodified HA solution and deionized water samples did not gel after 10 minutes.

[0105] Example 13

[0106] freeze-dried sponge

[0107] A 1% solution of octadecyl mercaptan HA derivative (Example 11) was prepared in deionized water. 8 g of the solution was aliquoted into glass vials and 80 mg of glycerol was added. The solutions were mixed and poured into rectangular plastic molds. The process was repeated using 1) 8 g of octadecyl mercaptan HA derivative solution and 25 mg of glycerol, and 2) 8 g of octadecyl mercaptan HA derivative solution. The three samples were then frozen at -80°C and subsequently lyophilized to produce a foamy solid material.

[0108] Example 14

[0109] HA modified with octadecylthiol

[0110] The reaction in Example 11 was repeated, with the divinyl sulfone reaction used for 80 seconds and 360 seconds. It was found that the octadecyl mercaptan substitution in the 80-second reaction was about 2.5% based on the disaccharide unit and about 0.63% based on the HA hydroxyl group, while the octadecyl mercaptan substitution in the 360-second reaction was about 4.3% based on the disaccharide unit and about 1.1% based on the HA hydroxyl group.

[0111] Example 15

[0112] HA modified with hexadecylthiol

[0113] The reaction described in Example 11 was repeated using hexadecylthiol. The hexadecylthiol reaction was carried out twice consecutively to produce the final material. The degree of substitution of hexadecylthiol was found to be approximately 3.8% based on the disaccharide unit and approximately 0.95% based on the HA hydroxyl group.

[0114] Example 16

[0115] Prepare 1.5% (w / v) octylthiol-derived HA using deionized water (Example 10). Add approximately 2 g of low molecular weight chitosan (Sigma-Aldrich Cat#448869) to approximately 10 g of solution in a 20 mL scintillation vial. Mix the mixture using a spatula. Transfer a portion of the mixture into a 3 mL plastic syringe. Insert the syringe plunger and remove as much headspace as possible. Then expel the mixture from the syringe.

[0116] Example 17

[0117] Prepare a 1% (w / v) octadecyl mercaptan-derived HA (Example 11) solution using deionized water. Transfer the solution to a 3 mL syringe and cap it. Then heat-seal the syringe in a foil pouch.

[0118] Example 18

[0119] Prepare a 1% (w / v) octadecyl mercaptan-derived HA solution (Example 11) using deionized water. Prepare a 1% (w / v) hexadecyl mercaptan-derived HA solution (Example 15). Mix the three solutions at mass ratios of 0.5:1, 1:1, and 1:0.5, respectively, with the octadecyl mercaptan-derived HA solution. Transfer each solution to a separate 3 mL syringe and cap it. Then heat-seal each syringe in a foil bag.

[0120] Example 19

[0121] Gel samples were prepared by adding approximately 3.4 g of a 0.25 M NaOH / 5% (v / v) ethanol solution containing 0.5% (v / v) BDDE to approximately 0.5 g of octadecyl mercaptan-derived HA (Example 11) in a 20 mL glass scintillation vial. The pH of the final mixture was adjusted to approximately 13.1. The sample was placed in an oven at approximately 50 °C for approximately 3 hours. The sample was washed and equilibrated in PBS (pH 7.4). The gel was then treated by adding a 2% (w / v) HA solution at an 80:20 coagulation:HA solution (w / w) ratio to the gel, followed by passing the gel mixture through a 120 µm sieve (in a syringe filter setting) multiple times to produce particles. Approximately half of the sample was dried in an oven and then ground to produce a solid powder.

[0122] Example 20

[0123] A gel sample was prepared by adding approximately 3.4 g of a 0.25 M NaOH / 5% (v / v) ethanol solution containing 0.5% (v / v) BDDE to approximately 0.5 g of octadecyl mercaptan-derived HA (Example 11) in a 20 mL glass scintillation vial. The pH of the final mixture was adjusted to approximately 13.1. The sample was placed in an oven at approximately 50 °C for approximately 3 hours. The sample was washed and equilibrated in PBS (pH 7.4). The gel was then treated by adding a 1% (w / v) octadecyl mercaptan-derived HA (Example 11) solution (in deionized water) at an 80:20 gel:solution (w / w) ratio to the gel, and then passing the gel mixture through a 120 µm sieve (in a syringe filter setting) multiple times to produce particles. Approximately half of the sample was dried in an oven and then ground to produce a solid powder.

[0124] Example 21

[0125] A gel sample was prepared by adding approximately 3.4 g of a 0.25 M NaOH / 5% (v / v) ethanol solution containing 0.5% (v / v) BDDE to approximately 0.5 g of octadecyl mercaptan-derived HA (Example 11) in a 20 mL glass scintillation vial. The pH of the final mixture was adjusted to approximately 13.1. The sample was placed in an oven at approximately 50 °C for approximately 3 hours. The sample was washed and equilibrated in PBS (pH 7.4). The gel was processed by passing the gel mixture through a 120 µm sieve (in a syringe filter device) multiple times to produce particles. Approximately 2 g of low molecular weight chitosan (Sigma-Aldrich Cat#448869) was added to approximately 10 g of the particle mixture and mixed with a spatula. Approximately half of the sample was dried in an oven and then ground to produce a solid powder.

[0126] All references disclosed in this article, including patent references and non-patent references, are hereby incorporated in their entirety by reference as if each reference were incorporated individually.

[0127] It should be understood that the terminology used herein is for descriptive purposes only and is not intended to be restrictive. It should also be understood that, unless specifically defined herein, the terms used herein will be given their conventional meanings known in their respective fields.

[0128] Throughout this specification, references to "an aspect" or "aspect" and its variations mean that a particular feature, structure, or characteristic described in connection with that aspect is included in at least one aspect. Therefore, the phrases "in an aspect" or "in one aspect" appearing in various places in this specification do not necessarily refer to the same aspect. Furthermore, a particular feature, structure, or characteristic may be combined in one or more aspects in any suitable manner.

[0129] As used in this specification and the appended claims, unless the content and context clearly indicate otherwise, the singular forms “a” and “the / said” include plural referents, i.e., one or more. It should also be noted that the conjunctions “and” and “or” are generally used in the broadest sense to include “and / or” unless the content and context clearly indicate inclusion or exclusivity as the specific circumstances warrant. Therefore, the use of alternatives (e.g., “or”) should be understood to mean one, both, or any combination of the alternatives. Furthermore, the composition of “and” and “or” when expressed herein as “and / or” is intended to cover aspects including all related items or concepts as well as one or more other alternative aspects including fewer than all related items or concepts.

[0130] Unless the context otherwise requires, throughout the specification and appended claims, the word “comprising” and its synonyms and variations (such as “having” and “including”) and its variants such as (containing) shall be interpreted in an open-ended, inclusive sense, for example, “including, but not limited to”. The term “consisting substantially of” limits the scope of the claims to the specified materials or steps, or to materials or steps that do not substantially affect the essential and novel characteristics of the claimed disclosure.

[0131] Any subheadings used in this document are for the convenience of the reader only and should not be construed as limiting this disclosure or the claims in any way. Therefore, the subheadings and abstracts provided herein are for convenience only and do not define the scope or meaning of any aspect.

[0132] Where value ranges are provided herein, it should be understood that every intermediate value between the upper and lower limits of the range (one-tenth of a unit to the lower limit, unless otherwise expressly stated) and any other stated or intermediate value within the range is included within this disclosure. The upper and lower limits of these smaller ranges may be independently included within that smaller range and are also covered by this disclosure, subject to any expressly excluded limitations within the specified range. Where a stated range includes one or both of the included limits, the range excluding any one or both of the included limits is also included within this disclosure.

[0133] For example, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range provided herein shall be understood to include any integer value within the stated range, and, where appropriate, to include fractions (such as one-tenth and one-hundredth of an integer). Additionally, unless otherwise indicated, any numerical range set forth herein relating to any physical characteristic (such as polymer subunits, size, or thickness) shall be understood to include any integer within the stated range. As used herein, unless otherwise indicated, the term “about” means ±20% of the indicated range, value, or structure.

[0134] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in and / or listed in the application data sheets 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 methods described in publications that may be used in conjunction with the disclosures currently described. The publications discussed above and throughout this document are provided only for their disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that the inventor has no right to make any of the cited publications prior to previous disclosures.

[0135] All patents, publications, scientific articles, websites, and other documents and materials cited or referenced herein demonstrate the technical skill of a person skilled in the art to which this disclosure pertains, and each such cited document and material is hereby incorporated in the same manner as if it had been individually incorporated in its entirety or set forth herein in its entirety. The applicant reserves the right to actually incorporate any and all materials and information from any such patents, publications, scientific articles, websites, electronically available information, and other cited materials or documents into this specification.

[0136] Generally, the terminology used in the following claims should not be construed as limiting the claims to the specific aspects disclosed in this specification and claims, but should be interpreted as encompassing all possible aspects and the full scope of equivalents obtained under the ownership of these claims. Therefore, the claims are not limited by this disclosure.

[0137] Furthermore, the written description portion of this patent includes all claims. Moreover, all claims, including all original claims and all claims from any and all priority documents, are hereby incorporated in their entirety by reference into the written description portion of the specification, and the applicant reserves the right to actually incorporate any and all such claims into the written description of this application or any other portion thereof. Therefore, by way of example, in any case where the precise wording of the claimed claims is not set forth in the same terms in the written description portion of the patent, the patent shall not be construed as a written description that allegedly does not provide claims.

[0138] The claims shall be interpreted in accordance with the law. However, and although it is claimed or considered that interpreting any claim or any part thereof is easy or difficult, in no event shall any adjustment or amendment to the claims or any part thereof during the examination of one or more applications that give rise to this patent be construed as a waiver of any rights to any and all equivalents that do not constitute part of the prior art.

[0139] Other limiting aspects are set forth in the following claims. This patent should not be construed as being limited to the specific examples or non-limiting aspects or methods specifically and / or explicitly disclosed herein. In no event should this patent be construed as being limited by any statement made by any examiner or any other officer or employee of the Patent and Trademark Office, unless the applicant expressly and unconditionally or reservedly adopts such a statement in responsive writing.

Claims

1. A method for hemostasis control, the method comprising providing a subject with a composition comprising derived hyaluronic acid, wherein the derived 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 according to claim 1, wherein the derived hyaluronic acid is cross-linked.

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 the subject includes providing the composition of claim 1 to one or more sites of bleeding in the subject.

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 administering the composition to a subject.