WO2025245108A1

WO2025245108A1 - Methods and compositions comprising particulate wound matrix

Info

Publication number: WO2025245108A1
Application number: PCT/US2025/030190
Authority: WO
Inventors: David M. Gravett
Original assignee: Pmidg LLC
Current assignee: Pmidg LLC
Priority date: 2024-05-20
Filing date: 2025-05-20
Publication date: 2025-11-27
Anticipated expiration: 2026-11-20

Abstract

Disclosed herein are compositions comprising at least one degradable polymer and a hyaluronic acid-based compound, and methods of making and using such compositions comprising at least one degradable polymer and a hyaluronic acid-based compound.

Description

METHODS AND COMPOSITIONS COMPRISING PARTICULATE WOUND MATRIX

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/649,507, filed May 20, 2024, which is incorporated by reference herein in its entirety.

TECHNICAL FIELD

[0002] The present disclosure relates to compositions and methods comprising one or more degradable polymers in the particulate form for use in treating a medical condition.

BACKGROUND

[0003] The skin functions as a critical barrier to protect the body. Once the skin is compromised, it can have a detrimental health impact on the patient or animal. Chronic wounds and bums are examples of where the skin has been compromised and having the skin barrier function restored as soon as possible has many benefits for the patient or animal. There are several products that have been used to restore the skin barrier function. Many of these are expensive and complex to manufacture. Thus, a simple to manufacture, cost efficient and effective wound healing matrix is needed. The present disclosure provides degradable compositions, related articles, and methods to overcome the challenges with the existing wound healing matrices.

SUMMARY

[0004] Briefly stated, the present disclosure provides compositions, products made therefrom, kits, and methods of making and forming products.

DETAILED DESCRIPTION

[0005] The present disclosure comprises compositions comprising a particulate made from one or more degradable polymers and/or copolymers and methods of making and use of such compositions. Compositions can be in the form of powder, sponge, film, sheet, solution, gel, or a paste.

[0006] Composition of the present disclosure can comprise one or more polymers. Polymers that can be used include degradable polymers. Degradable polymers can be enzymatically degradable, hydrolytically degradable or a combination thereof. In some aspects, the degradable polymer is non-water soluble. In some aspects, the degradable polymer is partially water soluble. Degradable polymers that can be used include but are not limited to polymers that are comprise repeat units derived from at least one of the following monomers: 1-lactide, dl-lactide, glycolide, trimethylene carbonate, epsilon-caprolactone, gamma-caprolactone, p-dioxanone and a morpholinedione.

[0007] In some aspects, a polymer can be a homopolymer or a copolymer. A copolymer can be a random copolymer or a block copolymer. In some aspects, a block copolymer can be a diblock copolymer, a tri block copolymer or a multiblock copolymer. A degradable polymer can be a linear polymer, a branched polymer, a triaxial polymer, a 4-armed polymer, or a multi-axial polymer. A multi-axial polymer is a polymer that is initiated from more than two sites on the same initiator. Initiators that can be used to make polymers disclosed herein include, but are not limited to, compounds that comprise 3 or more hydroxyl or amine groups. Examples of hydroxyl-based initiators include, but are not limited to, triethanolamine, trimethylolpropane, 1,1,1- tris(hydroxymethyl)ethane, pentaerythritol, dipentaerythntol. tripentaerythritol, di(trimethylolpropane), 2,2,6,6-tetrakis(hydroxymethyl)cyclohexanol, glycerol, glucose, 2- hydroxymethyl-l,3-propanediol. triisopropanolamine, l-[N,N-bis(2-hydroxyethyl)amino]-2- propanol, and 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)-l,3-propanediol. Polymers that can be used to prepare disclosed compositions include those described in the patents US6462169, US6794485, US7129319, US7070858, US7026437, US 8299205, EP 1244725, US6342065, US6413539, and US7048753, which are incorporated by reference herein in their entireties.

[0008] Examples of polymers that can be used include but are not limited to polymers that comprise poly(lactide-co-glycolide), poly(lactide-co-trimethylene carbonate), poly(dioxanone), poly(caprolactone), poly(caprolactone-co-glycolide), poly(caprolactone-co-lactide), poly(glycolide), poly(glycolide-co-trimethylene carbonate), poly(lactide), poly(glycolide-co- caprolactone-co-trimethylene carbonate), poly(glycolide-co-lactide-co-trimethylene carbonate), poly(ethylene glycol-co-glycolide), poly(ethylene glycol-co-glycolide-co-lactide), poly(ethylene glycol-co-glycolide-co-trimethylene carbonate), poly(ethylene glycol-co-glycolide-co- caprolactone), blends and combinations thereof.

[0009] In some aspects, a degradable polymer can comprise greater than about 50% glycolide residues. In some aspects, a degradable polymer can comprise greater than about 60% glycolide residues. In some aspects, a degradable polymer can comprise greater than about 70% glycolide residues. In some aspects, a degradable polymer can comprise greater than about 80% glycolide residues. In some aspects, a degradable polymer can comprise greater than about 90% glycolide residues. In some aspects, a degradable polymer can comprise greater than about 95% glycolide residues. In some aspects, a degradable polymer can comprise greater than about 98% glycolide residues. In some aspects, a degradable polymer can comprise between about 50% and about 100% glycolide residues. In some aspects, a degradable polymer can comprise between about 60% and about 98% glycolide residues. In some aspects, a degradable polymer can comprise between about 75% and about 98% glycolide residues. In some aspects, a degradable polymer can comprise between about 85% and about 98% glycolide residues. In some aspects, a degradable polymer can comprise between about 91% and about 100% glycolide residues. In some aspects, a degradable polymer can comprise between about 91% and about 99% glycolide residues.

[0010] A degradable polymer can have a molecular weight. In some aspects, the molecular weight is greater than 200 000 g/mol. In some aspects, the molecular weight is between about 100 000 g/mol and about 200 000 g/mol. In some aspects, the molecular weight is between about 50 000 g/mol and about 100 000 g/mol. In some aspects, the molecular weight is between about 10 000 g/mol and about 50000 g/mol. In some aspects, the molecular weight is between about 1000 g/mol and about 10 000 g/mol.

[0011] A degradable polymer of the present disclosure can be in the form of particles. In some aspects particles are generally round. In some aspects, particles are microspheres. In some aspects, particles have a regular shape. In some aspects, particles have an irregular shape. In some aspects, particles comprise a curved surface. In some aspects, particles comprise a sharp edge surface. In some aspects, particles can be solid. In some aspects, particles can be porous. Particles can be formed by taking a bulk polymer and processing it in such a manner that the desired particles are attained. Processes that can be used to prepare particles include but are not limited to milling, grinding, ball milling, roller milling, jet milling, cryomilling, freezer milling, wet milling, impact milling, immersion milling, hammer milling, pin milling, solvent precipitation, spray drying, micronization, use of emulsions, or a combination thereof. Specific particle size ranges can be obtained by passing the particles through a screen or sieve.

[0012] The particles can have an aspect ratio. In some aspects an aspect ratio is about 1. In some aspects, an aspect ratio is between about 1 and about 1.25. In some aspects, an aspect ratio is between about 1.25 and about 1. 5. In some aspects, an aspect ratio is between about 1. 5 and about 1. 75. In some aspects, an aspect ratio is between about 1.75 and about 2. In some aspects, an aspect ratio is between about 2 and about 3. In some aspects, an aspect ratio is greater than about 3.

[0013] Particles can have a range of sizes and can have an average size. In some aspects, the average particle size is less than about 300 pm. In some aspects, an average particle size is less than about 200 pm. In some aspects, an average particle size is less than about 100 pm. In some aspects, an average particle size is less than about 75 pm. In some aspects, an average particle size is less than about 50 pm. In some aspects, an average particle size is less than about 25 pm. In some aspects, an average particle size is less than about 15 pm. In some aspects, an average particle size is less than about 10 pm. In some aspects, an average particle size is between about 300 pm and about 500 pm. In some aspects, an average particle size is between about 200 pm and about 300 pm. In some aspects, an average particle size is between about 150 pm and about 200 pm. In some aspects, an average particle size is between about 100 pm and about 150 pm. In some aspects, an average particle size is between about 75 pm and about 100 pm. In some aspects, an average particle size is between about 50 pm and about 75 pm. In some aspects, an average particle size is between about 25 pm and about 50 pm. In some aspects, an average particle size is between about 10 pm and about 25 pm. In some aspects, an average particle size is between about 1 pm and about 10 pm.

[0014] A composition can comprise particles of the present disclosure. In some aspects, a composition can comprise one population of particles. In some aspects, a composition can comprise two different populations of particles. In some aspects a composition can comprise more than two different populations of particles. In some aspects, a composition can comprise particles of the same composition and a different average particle size. In some aspects, a composition can comprise particles in which a first population of particles comprises a different composition to that of a second population of particles. In some aspects, a first population of particles can comprise a different average particle size than a second population of particles. In some aspects, a first population of particles can comprise a polymer that has a different molecular weight to a polymer of a second population of particles. In some aspects, a first population of particles can comprise a polymer that has the same composition as a polymer of a second population of particles but wherein as least a molecular weight of the polymer, average particle size, an aspect ratio of the particles, a shape of the particles, a surface morphology or a combination of these parameters are different between a first population of particles as compared to a second population of particles.

[0015] A composition can further comprise hyaluronic acid, a salt of hyaluronic acid, a derivative of hyaluronic acid or a combination thereof. A salt of hyaluronic acid can include a sodium salt, a potassium salt, a calcium salt, a feme salt or a combination thereof. A derivative of hyaluronic acid can include ester derivatives, ether derivatives, amide derivatives, and thioether derivatives. Examples of thioether derivatives include those described in the US 11440976, which is incorporated by reference herein in its entirety. Examples of ester derivatives include benzyl ester derivatives and those described in the US 4851521 and US 4965353, which are incorporated by reference herein in their entireties. Additional examples of hyaluronic acid derivatives include aliphatic derivatives of hyaluronic acid. These include Cs-Cis aliphatic ester derivatives of hyaluronic acid. These aliphatic derivatives include palmitoyl, lauroyl, stearoyl, and undecanoyl derivatives as described in WO 2014082611, which is incorporated by reference herein in its entirety. In some aspects, a derivatized hyaluronic acid comprises an aromatic ring. In some aspects, a derivatized hyaluronic acid comprises a linear or branched aliphatic chain. In some aspects, a derivatized hyaluronic acid comprises an aliphatic chain with at least three consecutive -CH2- groups. In some aspects, a derivatized hyaluronic acid comprises an aliphatic chain with at least seven consecutive -CH2- groups. In some aspects, a derivatized hyaluronic acid comprises an aliphatic chain with at least nine consecutive -CH2- groups. In some aspects, a derivatized hyaluronic acid comprises an aliphatic chain with at least fourteen consecutive -CH2- groups. In some aspects, a derivatized hyaluronic acid comprises a thioether derived from octadecane thiol, hexadecanethiol, dodecane thiol, octane thiol, mercaptobenzoic acid or a combination thereof.

[0016] In some aspects, a molecular weight of a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative is greater than 1 500 000 g/mol. In some aspects, a molecular weight is between about 1 000 000 g/mol and 1 500 000 g/mol. In some aspects, a molecular weight is between about 700 000 g/mol and 1 000 000 g/mol. In some aspects, a molecular weight is between about 300 000 g/mol and 700 000 g/mol. In some aspects, a molecular weight is between about 100 000 g/mol and 300 000 g/mol. In some aspects, a molecular weight is between about 50 000 g/mol and 100 000 g/mol. In some aspects, a molecular weight is less than about 50 000 g/mol.

[0017] A composition can further comprise collagen, gelatin, chitosan, silk protein, tricalcium phosphate, hydroxyapatite, degradable glass fibers, degradable glass particles, sodium alginate, carboxymethyl cellulose, poly(ethylene glycol), polyacrylic acid, or combinations thereof. In some aspects, a composition can further comprise a polymer which has thermoreversible properties when in solution. Examples of a polymer with thermoreversible properties when in solution include but are not limited to Pluronic F127. and Pluronic F68.

[0018] A composition can further comprise water. In some aspects, a composition can further comprise saline. In some aspects, a composition can further comprise a pharmaceutically acceptable excipient. Examples of excipients include but are not limited to a buffer, complexing agent, tonicity modulator, ionic strength modifier, solvent, anti-oxidant, preservative, viscosity modifier, pH modifier, surfactant, humectant, emulsifier, phospholipid, stabilizer, and inorganic compound. An inorganic compound can include but is not limited to silver or a silver salt. In some aspects, the pH modifier is an acid or a base. In some aspects, the pH modifier is acetic acid, glycolic acid, citric acid, lactic acid, phosphoric acid or salts and combinations thereof. In some aspects, the pH modifier is sodium hydroxide, calcium hydroxide, or hydrochloric acid.

[0019] A composition can comprise particles made from one or more degradable polymers and hyaluronic acid, a hyaluronic acid salt or a hyaluronic acid derivative. In some aspects, a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative comprises between about 0.5% and about 95% of a composition. In some aspects, a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative comprises between about 50% and about 90% of a composition. In some aspects, a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative comprises between about 40% and about 60% of a composition. In some aspects, a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative comprises between about 0.5% and about 50% of a composition. In some aspects, a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative comprises between about 0.5% and about 25% of a composition. In some aspects, a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative comprises between about 0.5% and about 10% of a composition. In some aspects, a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative comprises between about 1% and about 7% of a composition.

[0020] A composition can comprise particles made from one or more degradable polymers, water and hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative. In some aspects, a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative comprises between about 0.5% and about 5% of an aqueous composition. In some aspects, a hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivative comprises between about 0.5% and about 2% of an aqueous composition.

[0021] In some aspects, the composition can comprise polydioxanone particles, poly glycolide particles, and hyaluronic acid or a sodium salt thereof. In some aspects, the composition can comprise polydioxanone particles, polyglycolide particles, and a thioether containing aliphatic derivative of hyaluronic acid. In some aspects, the composition can comprise polydioxanone particles, polyglycolide particles, and an ester-containing aliphatic derivative of hyaluronic acid. In some aspects, the composition can comprise hyaluronic acid or a sodium salt thereof, and particles comprising a copolymer of glycolide, caprolactone and trimethylene carbonate. In some aspects, the composition can comprise a thioether containing aliphatic derivative of hyaluronic acid, and particles comprising a copolymer of glycolide, caprolactone and trimethylene carbonate. In some aspects, the composition can comprise an ester-containing aliphatic derivative of hyaluronic acid, and particles comprising a copolymer of glycolide, caprolactone and trimethylene carbonate. In some aspects, the composition can comprise hyaluronic acid or a sodium salt thereof, particles comprising polyglycolic acid, and particles comprising a copolymer of glycolide, caprolactone and trimethylene carbonate. In some aspects, the composition can comprise a thioether containing aliphatic derivative of hyaluronic acid, particles comprising polyglycolic acid, and particles comprising a copolymer of glycolide, caprolactone and trimethylene carbonate. In some aspects, the composition can comprise an ester-containing aliphatic derivative of hyaluronic acid, particles comprising polyglycolic acid, and particles comprising a copolymer of glycolide, caprolactone and trimethylene carbonate. In some aspects, the composition can comprise hyaluronic acid or a sodium salt thereof, and particles comprising polyglycolic acid. In some aspects, the composition can comprise a thioether containing aliphatic derivative of hyaluronic acid, and particles comprising polyglycolic acid. In some aspects, the composition can comprise an ester-containing aliphatic derivative of hyaluronic acid, and particles comprising polyglycolic acid.

[0022] A composition can further comprise a biologically active agent. A biologically active agent can include but is not limited to antiandrogens, antibacterial, antioestrogens, androgens and anabolic agents, antibiotics, antimigraine drugs, antihistamines, antianxiety drugs, antidiuretics, antihistamines, antirheumatic agents, antigens, analgesics, antidepressants, anti-inflammatories, anesthetics, aminoglycosides antibodies, antiviral, adrenergic stimulants, anticonvulsants, antianginal agents, antiarrhythmics, antimalarials, anti-mitotic, anthelmintics, anorectic agents, antitussives, antipruritics, antipyretics, anti-Alzheimer’s agents, anti-Parkinson's agents, antiemetics and antinauseants, antihypertensives, anticoagulants, antifungals, antimicrobials, allergens, antidiarrheals, antihyperuricemic agents, adrenergic stimulants, antiparasitic agents, antiproliferative agents, antipsychotic drugs, antithyroid agents, beta-adrenergic blocking agents, bronchodilators; bronchospasm relaxants, blood clotting factors, blood coagulation factors, cytotoxic agents, cytostatic agents, chemotherapeutics, clot inhibitors, clot dissolving agents, cells, CNS stimulants, Corticosteroids, calcium channel blockers, cofactors, ceramides, cardiotonic glycosides, cytokines (e.g., lymphokines, monokines, chemokines); colony stimulating factors (e.g., GCSF, GM-CSF, MCSF); dermatological agents, decongestants, diuretics, expectorants, endectocide agents, growth factors, hemostatic agents, hypoglycemic agents, hormones and hormone analogs, hypercalcemia, Hypnotics, interleukins (IL-2, IL-3, IL-4, IL-6); interferons (.beta.-IFN, ,alpha.-IFN and . gamma. -IFN); immunosuppressants, muscle relaxants, microorganisms, non-steroidal anti-inflammatory agents, nucleic acids, nutritional agents, neuromuscular blocking agents, neuroleptics. Neurotoxins, nutraceuticals, oligonucleotides, oestrogens, obstetric drugs, ovulation inducers, opioids, progestogens, pituitary hormones, Pituitary inhibitors proteins, peptides, polysaccharides, protease inhibitors, prostaglandins, quinolones, reductase inhibitors, sulfa drugs, sclerosant, sedatives, sodium channel blockers, steroids, steroidal anti-inflammatory agents, smoking cessation agents, toxins, thrombolytic agents, thyroid hormones, tumor necrosis factor; vesicles, vitamins, viruses, vasodilators, vaccines, chlorhexidine, or combinations thereof.

[0023] Antibiotics can include but are not limited to bacitracin, polysporin, neosporin, neomycin, polymyxin B, mupirocin, nitrofurazone, fusidic acid, amoxicillin-clavulanate, cephalexin, clindamycin, dicloxacillin, doxycycline, trimethoprim-sulfamethoxazole, cephalosporins, penicillin, fluoroquinolones, moxifloxacin, ciprofloxacin, fleroxacin, levofloxacin, moxifloxacin, nitroimidazoles, glycopeptides, oxazolidinone, carbapenems, minocycline, rifampicin, vancomycin, silver sulfadiazine and combinations thereof. Antimicrobials can include but are not limited to povidone-iodine, cadexomer iodine, silver, silver salts and silver complexes, polyhexamethylene biguanide, chlorhexidine, octenidine, honey, gramicidin, oritavancin, dalbavancin, daptomycin, zinc oxide, and titanium dioxide.

[0024] A biologically active agent can be physically mixed with a particulate material, coated onto a particulate material or incorporated into a particulate material. In some aspects, a biologically active agent can be physically mixed with hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid. In some aspects, a biologically active agent can be dissolved in a hyaluronic acid solution, a solution of a salt of hyaluronic acid or a solution of derivative of hyaluronic acid. In some aspects, a biologically active agent can be part of a hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid component, as well as a particulate component. In some aspects, a hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid component, can comprise a biologically active agent that is different to that which is part of a particulate component.

[0025] A composition of the present disclosure can be in the form of a kit. A kit can comprise a composition of the present disclosure. In some aspects, a kit can comprise particles that are in a dry sterile form. In some aspects, particles can be in a syringe. In some aspects, particles can be in a syringe that comprises a plunger and a cap. In some aspects, particles can be in a glass container. In some aspects, particles can be in a plastic container. A kit can further comprise hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid. In some aspects, a hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid can be in a dry sterile powder form. In some aspects, degradable polymer particles and hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid are in different containers. In some aspects, degradable polymer particles and hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid are in the same container. In some aspects, a container is a syringe, a glass vial, a plastic vial, a plastic bellows-type container, or a combination thereof. A kit can further comprise a syringe connector. In some aspects, a syringe connector is a Luer lock syringe connector. In some aspects, a syringe connector is sterile. A kit can further comprise a dispensing component that can be attached to a syringe. In some aspects, a dispensing component is a needle. In some aspects, a dispensing component is a cannula. In some aspects, a cannula is a flexible cannula. In some aspects, a cannula is a vial access cannula. In some aspects, a kit comprises hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid in a solution. In some aspects, a solution further comprises sodium chloride. In some aspects, a solution comprises about 0.9% sodium chloride. In some aspects, a hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid solution is sterile. In some aspects, a kit can further comprise a biologically active agent. In some aspects, a kit can further comprise an antibacterial, an antibiotic, a growth factor, a hormone, a protein, an anti-fungal, a hemostat, or a combination thereof. In some aspects, a biologically active agent is separate from the particles and the hyaluronic acid, the salt of hyaluronic acid or a derivative of hyaluronic acid. In some aspects, a biologically active agent is in the same container as the hyaluronic acid, the salt of hyaluronic acid or a derivative of hyaluronic acid. In some aspects, a biologically active agent is in the same container as the particles.

[0026] A composition of the present disclosure can be used to enhance the healing rate of a wound. A wound can include but is not limited to an acute or a chronic wound. A wound can be the result of a laceration, trauma, a bum, a bed sore, a diabetic ulcer, a venous ulcer, an ulcer, a surgical procedure, an abrasion, a partial thickness wound, a full thickness wound or a combination thereof. A composition can be applied to a portion of a wound or the entire wound. In some aspects, a composition can be applied to a wound directly. In some aspects, a composition can be applied to a wound in a dry form. In some aspects, a composition can be applied to a wound in a dry form and then water or saline can be added to the applied composition. In some aspects, a composition can be applied to a wound as a powder. In some aspects, a composition can be applied to a wound as a paste or a gel. In some aspects, a composition can be applied as a film. In some aspects, a composition can be applied as a fenestrated film. In some aspects, a composition can be applied as a foam. In some aspects, a composition can be applied to a wound and then a secondary covering can be applied over the composition. A secondary covering can include but is not limited to gauze, a polymeric film or a silicone film or a foam. In some aspects, a composition can be applied in conjunction or adjunct to a second wound healing material. A second wound healing material can include but is not limited to a collagen-based material, a gelatin-based material, an electrospun material, an animal derived material, an acellular dermal matrix material, a hyaluronic acid-based product or a combination thereof. An electrospun material can comprise a sheet, a fenestrated sheet or particles of an electrospun material. In some aspects, a composition can be applied followed by a second wound healing material. In some aspects, a second wound healing material can be applied first followed by a composition. In some aspects, a composition can be applied to a wound for a single application. In some aspects, a composition can be applied to a wound and then reapplied one or more times following the initial application. [0027] A composition can be applied into or onto tissue. Tissue can include but is not limited to skin, ocular tissue, bone, buccal tissue, vaginal tissue, muscular tissue, soft tissue, tendons, hard tissue, cartilage, epithelial tissue, dermal tissue, brain tissue, nerves, abdominal tissue, the stomach, veins, arteries, cancer tissue, tumor tissue, cardiovascular tissue, lung tissue, esophageal tissue, connective tissue, or a combination thereof. A tissue can be animal tissue or human tissue. In some aspects, a composition can be used as a drug delivery system for application onto or into tissue.

[0028] A preparation of a composition for use can comprise adding water or saline to particles of degradable polymer to prepare a slurry or paste and then applying this to a wound. In some aspects, a solution of a hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid is mixed with particles of degradable polymer to prepare a slurry or paste that is then applied to a wound. In some aspects, a preparation of a composition solution comprises 1) taking a syringe that comprises a hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid solution (e.g., an aqueous solution), 2) connecting a Luer lock syringe connector to the syringe, 3) connecting the other end of the Luer lock connector to a syringe that comprises particles of one or more biodegradable polymers, 4) transferring the hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid solution into the syringe comprising the particles of one or more biodegradable polymers, 5) passing the resultant mixture back and forth for at least 4 passes, 6) disconnecting the syringe that comprises the resultant composition and 7) applying the composition to the wound. In some aspects, the viscosity of the composition prepared by mixing the aqueous solution of hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid with the degradable polymer particles, results in a composition that has a viscosity that is greater than that of the aqueous solution of hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid. In some aspects, the viscosity' is of the composition is at least 10% greater than the viscosity of the aqueous solution of hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid. In some aspects, the viscosity’ is of the composition is at least 20% greater than the viscosity of the aqueous solution of hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid. In some aspects, the viscosity is of the composition is more that 50% greater than the viscosity⁷ of the aqueous solution of hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid.

[0029] A composition that comprises water or saline can have a pH of less than about 7. In some aspects, a pH of a composition that comprises water or saline is less than about 6. In some aspects, a pH of a composition that comprises water or saline is less than about 5.5. In some aspects, a pH of a composition that comprises water or saline is less than about 5. In some aspects, a pH of a composition that comprises water or saline is less than about 4.5. In some aspects, a pH of a composition that comprises water or saline is less than about 4. In some aspects, a pH of a composition that comprises water or saline is less than about 3.6. In some aspects, a pH of a composition that comprises water or saline is between about 2.5 and 6. In some aspects, a pH of a composition that comprises water or saline is between about 2.5 and 5. In some aspects, a pH of a composition that comprises water or saline is between about 2.5 and 4.5. In some aspects, a pH of a composition that comprises water or saline is between about 2.5 and 4. In some aspects, a pH of a solution which comprises 2 g of a composition and 50 mL of deionized water (DI) is less than about 5, 24 hours after the composition is added to the deionized water. In some aspects, a pH of a solution which comprises 2 g of a composition and 50 mL of deionized water less than about 4.5, 24 hours after the composition is added to the deionized water. In some aspects, a pH of a solution which comprises 2 g of a composition and 50 mL of deionized water less than about 4, 24 hours after the composition is added to deionized water. In some aspects, a pH of a solution which comprises 2 g of a composition and 50 mL of deionized water less than about 3.5, 24 hours after the composition is added to the deionized water. In some aspects, a pH of a solution which comprises 2 g of a composition and 50 mL of deionized water is less than about 5, 1 hour after the composition is added to the deionized water. In some aspects, a pH of a solution which comprises 2 g of a composition and 50 mL of deionized water less than about 4.5, 1 hour after the composition is added to the deionized water. In some aspects, a pH of a solution which comprises 2 g of a composition and 50 mL of deionized water less than about 4, 1 hour after the composition is added to deionized water. In some aspects, a pH of a solution which comprises 2 g of a composition and 50 mL of deionized waterless than about 3.5. 1 hour after the composition is added to the deionized water.

[0030] A method of using a composition can comprise applying dry particles to a desired tissue. In some aspects, a method of using a composition can comprise applying dry particles and dry hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid to a desired tissue. In some aspects, a method of using a composition can comprise applying particles that have been mixed with a solution of hyaluronic acid, a solution of a salt of hyaluronic acid or solution of a derivative of hyaluronic acid to a desired tissue. In some aspects, a method of using a composition can comprise applying the composition to a desired tissue and then applying a secondary covering over the applied composition. In some aspects, a method of using a composition can comprise applying the composition to a desired tissue and then applying a second wound healing material to the desired tissue. In some aspects, a method of using a composition can comprise applying a wound healing material to a desired tissue and then applying the composition to the desired tissue. In some aspects, a method of using a composition can comprise applying the composition and a secondary wound healing material to a desired tissue and then applying a secondary' covering over the applied composition and second wound healing material.

[0031] The following Examples are offered by way of illustration and not by way of limitation. In the Examples, DI stands for deionized water, PBS stands for phosphate buffered saline, PEG stands for polyethylene glycol, HA-C18 stands for a octadecane derivatized hyaluronic acid (thioether derivative), HA-MBA stands for a mercaptobenzoic acid derivatized hyaluronic acid (thioether derivative), PDO stands for poly(dioxanone), PG stands for poly (glycolide) and PGCT stands for a degradable triaxial poly(glycolide-co-caprolactone-co-trimethylene carbonate).

EXAMPLES Example 1 Composition - Particles and Hyaluronic acid [0032] About 0.5g Polyglycolide particles (Mw between 3500-7000 g/mol, average particle size between 2-10pm) were weighed into a 3 mL plastic Luer lock syringe (closure cap attached, plunger removed). The plunger was inserted into the syringe. The syringe was inverted and the cap was removed. The plunger was pushed until there was virtually no air gap. The cap was replaced. A 2% hyaluronic acid [HA] (sodium salt, -800 000 g/mol) / 0.9% NaCl solution was prepared. About 1g of this HA solution was transferred to a plastic 3 mL Luer lock syringe (closure cap attached, plunger removed). The plunger was inserted into the syringe. The syringe was inverted and the cap was removed. The plunger was pushed until there was virtually no air gap. The cap was replaced. The cap of the HA solution was removed and a Luer lock syringe connector was connected. The cap of the syringe that contained the particles was removed and the syringe was attached to the open end of the syringe connector. The plunger of the HA solution was depressed to pass the HA solution into the syringe containing the particles. The plungers of the syringes were depressed sequentially such that the HA solution and the polyglycolide particles were well mixed. The composition has a paste like consistency but could be extruded from the syringe.

Example 2 Composition - Particles and Hyaluronic acid - 2

[0033] Polyglycolide particles (Mw between 3500-7000 g/mol, average particle size between 2- 10pm) and polydioxanone particles (average particle size between 60-90pm) were weighed into a container at a ratio of 40:60. The two populations of particles were physically mixed. About 1 .25g of the particle mixture were weighed into a 5 mL plastic Luer lock syringe (closure cap attached, plunger removed). The plunger was inserted into the syringe. The syringe was inverted and the cap was removed. The plunger was pushed until there was virtually no air gap. The cap was replaced. A 2% hyaluronic acid [HA] (sodium salt, -800 000 g/mol) / phosphate buffered saline solution was prepared. About 2.5g of this HA solution was transferred to a plastic 5 mL Luer lock syringe (closure cap attached, plunger removed). The plunger was inserted into the syringe. The syringe was inverted and the cap was removed. The plunger was pushed until there was virtually no air gap. The cap was replaced. The cap of the HA solution was removed and a Luer lock syringe connector was connected. The cap of the syringe that contained the particles was removed and the syringe was attached to the open end of the syringe connector. The plunger of the HA solution was depressed to pass the HA solution into the syringe containing the particles. The plungers of the syringes were depressed sequentially such that the HA solution and the polyglycolide particles were well mixed. The composition has a paste like consistency but could be extruded from the syringe.

Example 3 Composition - Particles and Hyaluronic acid derivative

[0034] A mixture of poly(dioxanone) and poly(glycolide) particles at a mass ratio of 60:40 were placed in a syringe. A 2% solution of a mercaptobenzoic acid derivative of HA (HA-MBA) in deionized water was placed in a second syringe. The materials were mixed as described in Example 2 to produce a wound healing matrix. The compositions were prepared at different levels of substitution for the HA-MBA and at different HA-MBA solution : particle ratios as described below:

[0035] The composition preparation was repeated using a 90: 10 HA: HA-C18 (3-6% substitution) solution in DI water and a HA solution: particles (60:40 poly(dioxanone) : poly(glycolide) ) of 2:1. The compositions have a paste-like consistency.

Example 4

Composition - Particles and Hyaluronic acid - 3

[0036] Several compositions were prepared in a similar manner as to that described in Example 2. A 2% hyaluronic acid [HA] (sodium salt, -800 000 g/mol) / saline (0.9% NaCl in deionized water) solution was prepared. Particles of the degradable linear polymers poly(dioxanone) [PDO], poly(glycolide) [PG] and a degradable triaxial poly(glycolide-co-caprolactone-co-trimethylene carbonate) [PGCT] (> 90% glycolide, average particle size about 28 pm) were used. The compositions prepared as detailed below:

[0037] The compositions have a paste-like consistency. The pH of the compositions were measured at about 10 minutes after preparation and were found to be in the about pH 2.5 to about pH 4 range.

Example 5

Composition - Particles and Hyaluronic acid - film

[0038] A 2% hyaluronic acid [HA] (sodium salt, -800 000 g/mol) solution was prepared in DI water. 40 mg Polyglycolide particles (Mw between 3500-7000 g/mol, average particle size between 2- 10pm) were added to 2g of the HA solution. The composition was mixed using a spatula. The composition was then poured out onto a glass plate. The composition was allowed to dry under a flow of air. A solid flexible film was obtained. When applied to moist skin and once hydrated, the film adhered to the skin. The film remained adhered to the skin under a gentle flow of water.

Example 6

Composition - Particles and Hyaluronic acid - 4

[0039] A 2% hyaluronic acid [HA] (sodium salt, -800 000 g/mol) solution was prepared in DI water, saline and PBS respectively. Particles of triaxial poly(glycolide-co-caprolactone-co- trimethylene carbonate) [PGCT] (> 90% glycolide, average particle size about 72 pm) were formulated with the HA solutions in a similar manner as to that described in Example 2. The pH of the compositions were measured about 10 minutes after preparation. Compositions prepared are detailed below:

[0040] The compositions have a paste-like consistency.

Example 7

Composition - Particles and Hyaluronic acid - 5

[0041] 50 mg hyaluronic acid [HA] (sodium salt, -800 000 g/mol) particles were weighed into a 20 mL glass scintillation vial. 50 mg particles of triaxial poly(glycolide-co-caprolactone-co- trimethylene carbonate) [PGCT] (> 90% glycolide, average particle size about 74 pm) were weighed into the same glass vial. The vial was capped and the mixture was shaken until the HA and polymer particles were mixed. The process was repeated in separate vials using 1) 50 mg polyglycolide particles (Mw between 3500-7000 g/mol, average particle size between 2-10pm) and 2) 20 mg polyglycolide particles (Mw between 3500-7000 g/mol, average particle size between 2-10pm) and 30 mg polydioxanone particles (average particle size between 75-80 pm). The samples were sterilized using e-beam radiation. Example 8

Composition - Particles and Hyaluronic acid derivative - 8

[0042] 200 mg thioether containing octadecane derivative of hyaluronic acid (sodium salt, -200 000 g/mol, substitution of approximately 3% [prepared per US 11440976) particles are weighed into a 20 mL glass scintillation vial. 200 mg particles of triaxial poly(glycolide-co-caprolactone- co-trimethylene carbonate) [PGCT] (> 90% glycolide, average particle size about 74 pm) are weighed into the same glass vial. The vial is capped and the mixture is shaken until the HA derivative and polymer particles are mixed. The process is repeated in separate vials using 1) 200 mg polyglycolide particles (Mw between 3500-7000 g/mol, average particle size between 2-10pm) and 2) 80 mg polyglycolide particles (Mw between 3500-7000 g/mol, average particle size between 2-10pm) and 120 mg polydioxanone particles (average particle size between 75-80 pm). The samples are sterilized using e-beam radiation.

Example 9

Composition - Particles, HA and Hyaluronic acid derivative - 9

[0043] 100 mg thioether containing octadecane derivative of hyaluronic acid (sodium salt, -200 000 g/mol, substitution of approximately 3% [prepared per US 11440976) particles are weighed into a 20 mL glass scintillation vial. 100 mg hyaluronic acid [HA] (sodium salt, -800 000 g/mol) particles are weighed into the same 20 mL glass scintillation vial. 200 mg particles of triaxial poly(glycolide-co-caprolactone-co-trimethylene carbonate) [PGCT] (> 90% glycolide, average particle size about 74 pm) are weighed into the same glass vial. The vial is capped and the mixture is shaken until the HA. HA derivative and polymer particles are mixed. The process is repeated in separate vials using 1) 200 mg polyglycolide particles (Mw between 3500-7000 g/mol, average particle size between 2-10pm) and 2) 80 mg polyglycolide particles (Mw between 3500-7000 g/mol, average particle size between 2-10pm) and 120 mg polydioxanone particles (average particle size between 75-80 pm). The samples are sterilized using e-beam radiation.

EXAMPLE ASPECTS

[0044] Example 1 : A composition comprising hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid and particles of a degradable polymer, wherein the degradable polymer comprises greater than about 70% repeat units derived from glycolide.

[0045] Example 2: The composition of any examples herein, particularly Examples 1. wherein the composition comprises athioether-containing derivative of hyaluronic acid.

[0046] Example 3: The composition of any examples herein, particularly Example 2, wherein the thioether-containing derivative of hyaluronic acid is a thioether-containing aliphatic derivative of hyaluronic acid.

[0047] Example 4: The composition of any examples herein, particularly Examples 2-3, wherein the thioether-containing derivative of hyaluronic acid is a thioether-containing octadecane derivative of hyaluronic acid.

[0048] Example 5: The composition of any examples herein, particularly Examples 1-4, wherein the composition comprises an ester-containing derivative of hyaluronic acid.

[0049] Example 6: The composition of any examples herein, particularly Examples 1-5, wherein the hyaluronic acid, salt of hyaluronic acid, or derivative of hyaluronic acid is in the form of particles or a powder.

[0050] Example 7: The composition of any examples herein, particularly Examples 1-5, wherein the hyaluronic acid, salt of hyaluronic acid, or derivative of hyaluronic acid is in the form of an aqueous solution.

[0051] Example 8: The composition of any examples herein, particularly Examples 1-7. wherein the composition further comprises polydioxanone particles.

[0052] Example 9: The composition of any examples herein, particularly Examples 1-8, wherein the pH of the composition is between about pH 2.5 and about pH 5.

[0053] Example 10: The composition of any examples herein, particularly Examples 1-9, wherein the composition further comprises a biologically active agent.

[0054] Example 11: The composition of any examples herein, particularly Example 10, wherein the biologically active agent comprises an antibiotic.

[0055] Example 12: The composition of any examples herein, particularly Examples 10-11, wherein the biologically active agent comprises an antimicrobial.

[0056] Example 13: The composition of any examples herein, particularly Examples 1 -12, wherein the degradable polymer comprises greater than about 80% repeat units derived from glycolide.

[0057] Example 14: The composition of any examples herein, particularly Examples 1-13, wherein the degradable polymer comprises polygly colic acid.

[0058] Example 15: The composition of any examples herein, particularly Examples 1-14, wherein the particles of the degradable polymer have an average diameter of less than 100 pm.

[0059] Example 16: The composition of any examples herein, particularly Examples 1-15, wherein the particles of the degradable polymer comprise at least two different populations of particles that differ in composition and/or particle size.

[0060] Example 17: The composition of any examples herein, particularly Examples 1-16, wherein the composition is sterile. [0061 ] Example 18: A method of treating a wound, the method comprising administering the composition of any examples herein, particularly Examples 1-17, to said wound.

[0062] Example 19: The method of any examples herein, particularly Example 18, wherein the method enhances a healing rate of the wound.

[0063] Example 20: The method of any examples herein, particularly Examples 18-19, wherein the composition further comprises an antibiotic and/or an antimicrobial.

DEFINITIONS

[0064] As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a functional group," "an alkyl," or "a residue" includes mixtures of two or more such functional groups, alkyds, or residues, and the like.

[0065] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0066] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. A mole percent (mole % or %(molar)) of a component, unless specifically stated to the contrary', is based on the total moles of all monomers used to manufacture the composition in which the component is included.

[0067] As used herein, when a compound is referred to as a monomer or a compound, it is understood that this is not interpreted as one molecule or one compound. For example, two monomers generally refers to two different monomers, and not two molecules.

[0068] As used herein, the terms "optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0069] As used herein, the terms "about," "approximate," and "at or about" mean that the amount or value in question can be the exact value designated or a value that provides equivalent results or effects as recited in the claims or taught herein. That is. it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off. measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In general an amount, size, formulation, parameter or other quantity or characteristic is "about," "approximate," or "at or about" whether or not expressly stated to be such. It is understood that where "about," "approximate," or "at or about" is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0070] As used herein, the terms "comprises," "comprising," "includes," "including," "containing," "characterized by," "has," "having" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

[0071] The transitional phrase "consisting of excludes any element, step, or ingredient not specified in the claim, closing the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase "consists of appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.

[0072] The transitional phrase "consisting essentially of limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. A 'consisting essentially of claim occupies a middle ground between closed claims that are written in a 'consisting of format and fully open claims that are drafted in a 'comprising' format. Optional additives as defined herein, at a level that is appropriate for such additives, and minor impurities are not excluded from a composition by the term "consisting essentially of.

[0073] When a composition, a process, a structure, or a portion of a composition, a process, or a structure, is described herein using an open-ended term such as "comprising," unless otherwise stated the description also includes an embodiment that "consists essentially of or "consists of the elements of the composition, the process, the structure, or the portion of the composition, the process, or the structure.

[0074] The articles "a" and "an" may be employed in connection with various elements and components of compositions, processes or structures described herein. This is merely for convenience and to give a general sense of the compositions, processes or structures. Such a description includes "one or at least one" of the elements or components. Moreover, as used herein, the singular articles also include a description of a plurality of elements or components, unless it is apparent from a specific context that the plural is excluded.

[0075] The term "about" means that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is "about" or "approximate" whether or not expressly- stated to be such.

[0076] The term "or", as used herein, is inclusive; that is, the phrase "A or B" means "A, B, or both A and B". More specifically, a condition "A or B" is satisfied by any one of the following: A is true (or present) and B is false (or not present); A is false (or not present) and B is true (or present); or both A and B are true (or present). Exclusive "or" is designated herein by terms such as "either A or B" and "one of A or B", for example.

[0077] In addition, the ranges set forth herein include their endpoints unless expressly stated otherwise. Further, when an amount, concentration, or other value or parameter is given as a range, one or more preferred ranges or a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether such pairs are separately disclosed. The scope of the invention is not limited to the specific values recited when defining a range.

[0078] When materials, methods, or machinery are described herein with the term "known to those of skill in the art", "conventional" or a synonymous word or phrase, the term signifies that materials, methods, and machinery- that are conventional at the time of filing the present application are encompassed by this description. Also encompassed are materials, methods, and machinery that are not presently conventional, but that will have become recognized in the art as suitable for a similar purpose.

[0079] Unless stated otherwise, all percentages, parts, ratios, and like amounts, are defined by weight.

[0080] All patents, patent applications and references included herein are specifically incorporated by reference in their entireties.

[0081] It should be understood, of course, that the foregoing relates only- to preferred embodiments of the present disclosure and that numerous modifications or alterations may be made therein without departing from the spirit and the scope of the disclosure as set forth in this disclosure.

[0082] The present disclosure is further illustrated by the examples contained herein, which are not to be construed in any way as imposing limitations upon the scope thereof. On the contrary-, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or the scope of the appended claims.

Claims

What is claimed:

1. A composition comprising hyaluronic acid, a salt of hyaluronic acid, or a derivative of hyaluronic acid and particles of a degradable polymer, wherein the degradable polymer comprises greater than about 70% repeat units derived from glycolide.

2. The composition of claim 1, wherein the composition comprises a thioether-containing derivative of hyaluronic acid.

3. The composition of claim 2, wherein the thioether-containing derivative of hyaluronic acid is a thioether-containing aliphatic derivative of hyaluronic acid.

4. The composition of claim 2, wherein the thioether-containing derivative of hyaluronic acid is a thioether-containing octadecane derivative of hyaluronic acid.

5. The composition of claim 1, wherein the composition comprises an ester-containing derivative of hyaluronic acid.

6. The composition of claim 1, wherein the hyaluronic acid, salt of hyaluronic acid, or derivative of hyaluronic acid is in the form of particles or a powder.

7. The composition of claim 1, wherein the hyaluronic acid, salt of hyaluronic acid, or derivative of hyaluronic acid is in the form of an aqueous solution.

8. The composition of claim 1, wherein the composition further comprises polydioxanone particles.

9. The composition of claim 1, wherein the pH of the composition is between about pH 2.5 and about pH 5.

10. The composition of claim 1, wherein the composition further comprises a biologically active agent.

1 1. The composition of claim 10, wherein the biologically active agent comprises an antibiotic.

12. The composition of claim 10, wherein the biologically active agent comprises an antimicrobial.

13. The composition of claim 1, wherein the degradable polymer comprises greater than about 80% repeat units derived from glycolide.

14. The composition of claim 1, wherein the degradable polymer comprises poly glycolic acid.

15. The composition of claim 1, wherein the particles of the degradable polymer have an average diameter of less than 100 pm.

16. The composition of claim 1, wherein the particles of the degradable polymer comprise at least two different populations of particles that differ in composition and/or particle size.

17. The composition of claim 1, wherein the composition is sterile.

18. A method of treating a wound, the method comprising administering the composition of any one of claims 1-17 to said wound.

19. The method of claim 18, wherein the method enhances a healing rate of the wound.

20. The method of claim 18, wherein the composition further comprises an antibiotic and/or an antimicrobial.