Ocular sealant formulations and systems and methods of preparation and use thereof

The system of any preceding claim, wherein the container comprises less than about 0.50 wt. % water, less than about 0.25 wt. % water, less than about 0.20 wt. % water, or less than about 0.15 wt. % water based on the total weight of the container.

The system of any preceding claim, wherein the container comprises a water absorbance value of less than about 0.50% water, less than about 0.25% water, less than about 0.20% water, or less than about 0.15% water.

The system of any preceding claim, wherein the container comprises a basin configured to store the nucleophilic group-containing crosslinker component.

The system of any preceding claim, wherein the container comprises a recess comprising the electrophilic group-containing multi-arm-polymer precursor component in a patterned configuration.

The system of any preceding claim, wherein the patterned configuration provides a dissolution of the electrophilic group-containing multi-arm-polymer precursor component into a solution in less than about 5 minutes, less than about 2 minutes, less than about 1 minute, less than about 30 seconds, or less than about 5 seconds.

The system of any preceding claim, wherein the nucleophilic group-containing crosslinker component comprises a crosslinking agent having one or more of amine functional groups, thiol functional groups, carboxyl functional groups or carbonyl functional groups.

The system of any preceding claim, wherein the nucleophilic group-containing crosslinker component comprises a crosslinking agent having a small molecule amine with a molecular weight below about 100,000 Da, below about 50,000 Da, below about 25,000 Da, below about 10,000 Da, or below about 1,000 Da, comprising two or more primary aliphatic amine groups.

The system of any preceding claim, wherein the nucleophilic group-containing crosslinker component comprises one or more of dilysine, trilysine, tetralysine, ethylenediamine, 1,3-diaminopropane, 1,3-diaminopropane, diethylenetriamine, trimethylhexamethylenediamine, amine terminated polyethylene glycol, thiol terminated polyethylene glycol, pharmaceutically acceptable salts, hydrates, derivatives and conjugates thereof.

The system of any preceding claim, wherein the electrophilic group-containing multi-arm-polymer precursor component comprises polyethylene glycol.

The system of any preceding claim, wherein the electrophilic group-containing multi-arm-polymer precursor component comprises one or more of polyethylene glycol units, amine functional groups, thiol functional groups, N-hydroxysuccinimides functional groups or sulfosuccinimides functional groups.

The system of any preceding claim, wherein the electrophilic group-containing multi-arm-polymer precursor component comprises one or more of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, or random or block copolymers.

The system of any preceding claim, wherein the electrophilic group-containing multi-arm-polymer precursor component is not a lyophilized solid.

The system of any preceding claim, wherein the electrophilic group-containing multi-arm-polymer precursor component is derived from a printed melt of polyethylene glycol.

The system of any preceding claim, wherein the solvent is configured to dissolve the nucleophilic group-containing crosslinker component and the electrophilic group-containing multi-arm-polymer precursor component to form a solution, and

• wherein at least one salt comprises a phosphate salt and a borate salt,
• optionally, wherein salt comprises sodium phosphate dibasic, sodium phosphate monobasic and sodium borate decahydrate.

The system of any preceding claim, wherein the container comprises a recess comprising a basin configured to store the nucleophilic group-containing crosslinker component.

The system of any preceding claim, wherein the nucleophilic group-containing crosslinker component comprises about 1.0 wt. % to about 10 wt. % trilysine acetate based on the total weight of the formulation.

The system of any preceding claim, wherein the electrophilic group-containing multi-arm-polymer precursor component comprises about 80 wt. % to about 99 wt. % polyethylene glycol based on the total weight of the formulation, optionally, wherein the electrophilic group-containing multi-arm-polymer precursor component comprises a mass of about 5.0 mg to about 20.0 mg or about 8.5 mg to about 15 mg.

The system of any preceding claim, wherein the electrophilic group-containing multi-arm-polymer precursor component comprises polyethylene glycol having a molecular weight of about 1000 Da to about 50,000 Da.

The system of any preceding claim, wherein the ocular sealant formulation further comprises a solubility enhancer.

The system of any one of claims 28 to 30, wherein the solubility enhancer comprises one or more of a carrier, an effervescent, a sorbitol isomer, a buffer, a co-solvent, or a surfactant.

The system of any preceding claim, wherein at least one of the nucleophilic group-containing crosslinker component or the electrophilic group-containing multi-arm-polymer precursor component further comprises an active agent,

• optionally wherein the active agent comprises one or more of a cyclodextrin, an antibiotic or a combination thereof,
• optionally, wherein the cyclodextrin comprises one or more of acetazolamide, anandamide, a cannabinoid, cyclosporin, a dehydroepiandrosterone, dexamethasone, diclofenac, dipivefrine, fluorometholone, hydrocortisone, loteprednol etabonate or pilocarpine, and
• optionally, wherein the antibiotic comprises one or more of azithromycin, bacitracin, neomycin, polymyxin B, mupirocin, nitrofurazone and fusidic acid.

The system of any preceding claim, wherein the formulation has a shelf-life of about 9 months to about 4 years.

The system of any preceding claim, further comprising an applicator.

The ocular sealant dosage form of any one of claims 98 to 111, comprising a shelf-life of about 9 months to about 4 years.

The ocular sealant dosage form of any one of claims 98 to 112, comprising about 30 wt. % to about 70 wt. %, about 40 wt. % to about 60 wt. %, or about 41 wt. % to about 52 wt. % of the polyethylene glycol amine component.

The ocular sealant dosage form of any one of claims 98 to 113, wherein dosage form is a compressed tablet, a powder, a granulation, pellets, extruded units or milled particles.

The ocular sealant dosage form of any one of claims 98 to 114, wherein the dosage form is a compressed tablet of milled particles having a particle size distribution of less than about 1,000 μm.

The ocular sealant dosage form of any one of claims 98 to 115, wherein the dosage form does not comprise trilysine acetate.

The ocular sealant dosage form of any one of claims 98 to 116, wherein the dosage form is configured to dissolve in a solvent in less than about 45 seconds, less than about 40 seconds, less than about 35 seconds, or from about 10 seconds to about 60 seconds.

The ocular sealant dosage form of any one of claims 98 to 117, wherein the at least one excipient comprises one or more of a solubility enhancer, an effervescent, a binder, a disintegrant or a lubricant.

The ocular sealant dosage form of any one of claims 98 to 118, comprising citric acid in an amount of about 15 wt. % to about 30 wt. %, or about 20 wt. % to about 25 wt. % of the total weight of the dosage form.

The ocular sealant dosage form of any one of claims 98 to 119, comprising sodium bicarbonate in an amount of about 15 wt. % to about 30 wt. %, or about 20 wt. % to about 27 wt. % of the total weight of the dosage form.

The system of claim 121, wherein the solvent comprises a phosphate salt and a borate salt.

The system of claim 121 or 122, wherein the solvent comprises sodium phosphate dibasic, sodium phosphate monobasic and sodium borate decahydrate.

The system of any one of claims 121 to 123, wherein the electrophilic group-containing multi-arm-polymer precursor component is non-lyophilized.

The system of any one of claims 121 to 124, comprising about 20 wt. % to about 75 wt. %, about 25 wt. % to about 60 wt. %, or about 37 wt. % to about 55 wt. % of polyethylene glycol based on the total weight of the formulation.

The system of any one of claims 121 to 125, wherein the electrophilic group-containing multi-arm-polymer precursor component comprises polyethylene glycol having a molecular weight of about 1000 Da to about 50,000 Da.

The method of claim 137, wherein at least one of:

• milling is performed in the presence of dry ice or the method is completed within an inert environment.