Hyaluronic acid-based drug delivery system

Abstract

The present disclosure provides a hyaluronic acid-based drug delivery system comprising a compound of formula (I): (I) or a pharmaceutically acceptable salt or solvate thereof, where X, R1 and R2 are as defined herein. The present disclosure also provides compositions comprising the hyaluronic acid-based drug delivery system described herein and one or more active pharmaceutical ingredients. The disclosure also provides methods of delivering one or more active pharmaceutical ingredients to the eye of a subject in need thereof and methods of treating an ocular disease, disorder, or condition in a subject in need thereof, comprising administering to the subject the compositions disclosed herein.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to hyaluronic acid modified by crosslinking hydrophobic groups, covalent addition of hydrophobic groups, and / or covalent addition of one or more active pharmaceutical ingredients. The present disclosure also relates to compositions comprising the hyaluronic acid described herein and one or more active pharmaceutical ingredients. The present disclosure also relates to methods of delivering one or more active pharmaceutical ingredients to one or both eyes of a subject in need thereof and methods of treating an ocular disease, disorder, or condition in a subject in need thereof comprising administering to the subject a composition disclosed herein. BACKGROUND

[0002] Active pharmaceutical ingredients must achieve therapeutic concentrations at the target tissue for an appropriate duration of time to have a beneficial effect. This presents an extreme challenge for ocular drugs, as not every active pharmaceutical ingredient can be formulated for topical use. For those active pharmaceutical ingredients that can be formulated for topical use, the bioavailability of those active pharmaceutical ingredients in the aqueous humor is typically only 1-5%.

[0003] Injectable formulations can potentially be provided by in situ gelling depots and hydrogels or sustained delivery microparticles sequestered by in situ gelling depots or hydrogels. Injectable depots are attractive for delivery to the posterior segment of the eye as they can potentially deliver high payloads through small gauge needles. The materials are typically hydrophilic and hydrated, conferring a degree of biocompatibility.

[0004] Hyaluronic acid (HA) and collagen (Col) are attractive polymers for intraocular drug delivery system design as both are naturally present in the vitreous. HA has a history of clinical use as a mucous supplement therapy or as a surgical adjunct with a broad positive safety profile. Non-crosslinked HA is known to clear rapidly from the posterior segment relative to the desired 3 month or 12 month or longer delivery profile.

[0005] Accordingly, there remains a need to develop drug delivery systems and compositions thereof capable of sustained release of one or more active pharmaceutical ingredients over a controlled period of time. SUMMARY

[0006] The present disclosure provides a hyaluronic acid comprising a compound of Formula (I): (I) or a salt thereof or solvate thereof, wherein: n is an integer from 500 to 25,000; X is, at each occurrence, selected from the group consisting of -NH- and -O-; R 1 and R 2 is, at each occurrence, independently selected from the group consisting of hydrogen, a hydrophobic group, -L1 -L 2 -A and -A; Each L 1 It may be an amino acid or it may not be present. Each L 2 It is a connector; and Each A is independently a covalently bonded active pharmaceutical ingredient, wherein each instance of -A can be the same or different.

[0007] In some respects, n is between 1,200 and 5,000.

[0008] In some respects, X is -NH-.

[0009] In some respects, X is -O-.

[0010] In some respects, the hydrophobic group is selected from optionally substituted C1-C. 18 A group composed of alkyl groups and amino acids.

[0011] In some respects, the hydrophobic group is a C1-C group substituted with a phenyl group. 18 alkyl.

[0012] In some respects, the hydrophobic group is selected from the C1-C group consisting of the following groups: 18 alkyl: , , and .

[0013] In some respects, the hydrophobic group is an amino acid selected from the group consisting of: , and .

[0014] In some respects, L 1 Choose from the following groups: and ; In some respects, L 2 Choose from the following groups: , and .

[0015] In some respects, each A is independently selected from the group consisting of: intraocular pressure (IOP) lowering agents, CNTF analogs, FAS inhibitors or FAS ligand inhibitors, HIF-1α inhibitors, HIF-2α inhibitors, VEGF inhibitors, VIP analogs, histone-rich analogs, α-lens protein aggregation inhibitors, reducing agents, mitochondrial stabilizers, and TNF-α inhibitors.

[0016] In some respects, IOP reducers are prostaglandins, beta blockers, alpha agonists, carbonic anhydrase inhibitors, cholinergic agents, rho kinase inhibitors, or cannabinoid receptor agonists.

[0017] In some respects, prostaglandins are prostaglandin compounds, prostaglandin EP2 agonists, prostaglandin EP3 agonists, nitric oxide donor prostaglandin compounds, or combinations thereof.

[0018] In some respects, prostaglandin compounds are bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprostene, tafluprost, or tafluprost acid.

[0019] In some respects, prostaglandin EP2 agonists are taprenepagisopropyl or omidenepag isopropyl.

[0020] In some respects, prostaglandin EP3 agonists are dinoprostone, misoprostol, limaprost, gemeprost, alprostadil, or rivenprost.

[0021] In some respects, the nitric oxide donor prostaglandin compound is latanoprostene bunod.

[0022] In some respects, beta-blockers are timolol, betaxolol, levobunolol, or metipranolol.

[0023] In some respects, alpha agonists are brimonidine or araclonidine.

[0024] In some respects, carbonic anhydrase inhibitors are brinzolamide, acetazolamide, dorzolamide, or methazolamide.

[0025] In some respects, cholinergic agents are pilocarpine or carbachol.

[0026] In some respects, the rho kinase inhibitor is netarsudil.

[0027] In some respects, CNTF analogs are SEQ ID NO: 18, SEQ ID NO: 1, SEQ ID NO: 2, or recombinant CNTF.

[0028] In some respects, FAS inhibitors are bicyclic alcohols, FLIP, MET12 (SEQ ID NO: 3), compound 1 (SEQ ID NO: 5), compound 2 (SEQ ID NO: 6), compound 3 (SEQ ID NO: 7), compound 4 (SEQ ID NO: 8), compound 5 (SEQ ID NO: 9), compound 6 (SEQ ID NO: 10), compound 7 (SEQ ID NO: 11), compound 8 (SEQ ID NO: 12), compound 9 (SEQ ID NO: 13), compound 10 (SEQ ID NO: 14), compound 11 (SEQ ID NO: 15), ONL1204, SEQ ID NO: 4, FAIM, NOL3, human decoy receptor 1 (DcR1), human decoy receptor 2 (DcR2), or human decoy receptor 3 (DcR3).

[0029] In some respects, TNF-α inhibitors are etanercept, infliximab, golimumab, certolizumab, adalimumab, TNFR1-selective antagonistic mutant TNF (RlantTNF), DMS5540, TNF receptor-silenced (TROS), or ATROS.

[0030] In some respects, cannabinoid receptor agonists are Δ 9 -Tetrahydrocannabinol (Δ9 -THC), arachidonic acid ethanolamine, 2-arachidonic glycerol, 1,1-dimethylheptyl-11-hydroxytetrahydrocannabinol (HU-210), ( cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthyl ketone (R-(+)-WIN55212), (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthyl ketone (JWH-015), 3-(1,1-dimethylbutyl)-6,6,9-trimethyl-6α,7,10,10α-tetrahydro-6H-benzo[c]chromene (JWH-133) Onternabez (HU-308), 1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole (AM1241), 1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole (GW405833), 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro-2H-pyronin-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide (GW842166X) or 1-(4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl)-3-methylcyclohexanol (O-1966).

[0031] In some respects, approximately 1% to approximately 50% of the R groups are hydrophobic groups.

[0032] In some respects, approximately 1% to approximately 50% of the R groups are -L. 1 -L 2 -A or -A.

[0033] In some respects, each -A in formula (I) is selected from an active pharmaceutical ingredient.

[0034] In some respects, each -A in formula (I) is selected from two active pharmaceutical ingredients.

[0035] In some respects, each -A in formula (I) is selected from three active pharmaceutical ingredients.

[0036] In some respects, compounds of formula (I) are prepared by the following means: (i) reacting unsubstituted hyaluronic acid with the first active pharmaceutical ingredient; and (ii) React the product of step (i) with the second active pharmaceutical ingredient; To provide the hyaluronic acid.

[0037] In some respects, compounds of formula (I) are prepared by the following means: (i) Reacting unsubstituted hyaluronic acid with the first active pharmaceutical ingredient; (ii) Reacting the product of step (i) with the second active pharmaceutical ingredient; and (iii) React the product of step (ii) with the third active pharmaceutical ingredient; To provide the hyaluronic acid.

[0038] In some aspects, the hyaluronic acid comprises a first formula (I) compound crosslinked with a second formula (I) compound, wherein the first compound comprises a first active pharmaceutical ingredient and the second compound comprises a second active pharmaceutical ingredient.

[0039] In some aspects, the hyaluronic acid comprises a first formula (I) compound crosslinked with a second formula (I) compound and a third formula (I) compound, wherein the first compound comprises a first active pharmaceutical ingredient, the second compound comprises a second active pharmaceutical ingredient, and the third compound comprises a third active pharmaceutical ingredient.

[0040] This disclosure also provides a composition comprising the hyaluronic acid and free active pharmaceutical ingredient disclosed herein.

[0041] In some respects, the free active pharmaceutical ingredient is selected from the group consisting of: IOP depressants, CNTF analogs, FAS inhibitors, HIF-1α inhibitors, HIF-2α inhibitors, VEGF inhibitors, VIP analogs, histone-rich analogs, α-lens protein aggregation inhibitors, reducing agents, and TNF-α inhibitors.

[0042] In some respects, IOP reducers are prostaglandins, beta blockers, alpha agonists, carbonic anhydrase inhibitors, cholinergic agents, rho kinase inhibitors, or cannabinoid receptor agonists.

[0043] In some respects, prostaglandins are prostaglandin compounds, prostaglandin EP2 agonists, prostaglandin EP3 agonists, nitric oxide donor prostaglandin compounds, or combinations thereof.

[0044] In some respects, prostaglandin compounds are bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprostene, tafluprost, or tafluprost acid.

[0045] In some respects, prostaglandin EP2 agonists are taprenepagisopropyl or omidenepag isopropyl.

[0046] In some respects, prostaglandin EP3 agonists are dinoprostone, misoprostol, limaprost, gemeprost, alprostadil, or rivenprost.

[0047] In some respects, the nitric oxide donor prostaglandin compound is latanoprostene bunod.

[0048] In some respects, beta-blockers are timolol, betaxolol, levobunolol, or metipranolol.

[0049] In some respects, alpha agonists are brimonidine or araclonidine.

[0050] In some respects, carbonic anhydrase inhibitors are brinzolamide, acetazolamide, dorzolamide, or methazolamide.

[0051] In some respects, cholinergic agents are pilocarpine or carbachol.

[0052] In some respects, the rho kinase inhibitor is netarsudil.

[0053] In some respects, CNTF analogs are SEQ ID NO: 18, SEQ ID NO: 1, SEQ ID NO: 2, or recombinant CNTF.

[0054] In some respects, FAS inhibitors are bicyclic alcohols, FLIP, MET12 (SEQ ID NO: 3), compound 1 (SEQ ID NO: 5), compound 2 (SEQ ID NO: 6), compound 3 (SEQ ID NO: 7), compound 4 (SEQ ID NO: 8), compound 5 (SEQ ID NO: 9), compound 6 (SEQ ID NO: 10), compound 7 (SEQ ID NO: 11), compound 8 (SEQ ID NO: 12), compound 9 (SEQ ID NO: 13), compound 10 (SEQ ID NO: 14), compound 11 (SEQ ID NO: 15), ONL1204, SEQ ID NO: 4, FAIM, NOL3, human decoy receptor 1 (DcR1), human decoy receptor 2 (DcR2), or human decoy receptor 3 (DcR3).

[0055] In some respects, TNF-α inhibitors are etanercept, infliximab, golimumab, certolizumab, adalimumab, TNFR1-selective antagonistic mutant TNF (RlantTNF), DMS5540, TNF receptor-silenced (TROS), or ATROS.

[0056] In some respects, cannabinoid receptor agonists are Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), arachidonic acid ethanolamine, 2-arachidonic glycerol, 1,1-dimethylheptyl-11-hydroxytetrahydrocannabinol (HU-210), ( cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthyl ketone (R-(+)-WIN55212), (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthyl ketone (JWH-015), 3-(1,1-dimethylbutyl)-6,6,9-trimethyl-6α,7,10,10α-tetrahydro-6H-benzo[c]chromene (JWH-133) Onternabez (HU-308), 1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole (AM1241), 1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole (GW405833), 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro-2H-pyronin-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide (GW842166X) or 1-(4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl)-3-methylcyclohexanol (O-1966).

[0057] In some respects, the concentration of the free active pharmaceutical ingredient is from about 1% by weight to about 20% by weight.

[0058] In some respects, the concentration of the hyaluronic acid is from about 0.1% by weight to about 5% by weight.

[0059] In some respects, the composition further comprises a second polymer.

[0060] In some respects, the second polymer is collagen or poloxamer.

[0061] In some respects, the poloxamer is Pluronic® L64, Pluronic® P65, Pluronic® P84, Pluronic® P85, Pluronic® F88, Pluronic® P103, Pluronic® P104, Pluronic® P105, Pluronic® F108, Pluronic® F123, or Pluronic® F127.

[0062] In some respects, the concentration of the hyaluronic acid is from about 1 mg / mL to about 10 mg / mL.

[0063] In some respects, the concentration of the second polymer is from about 1 mg / mL to about 250 mg / mL.

[0064] In some respects, the concentration of the second polymer is from about 1 mg / mL to about 5 mg / mL.

[0065] In some respects, the combined active pharmaceutical ingredient is released over a period of approximately 6 to approximately 24 months.

[0066] In some respects, the free active pharmaceutical ingredient is released over a period of approximately 6 to approximately 24 months.

[0067] In some respects, the hyaluronic acid is a hydrogel.

[0068] In some respects, the composition is a solid implant.

[0069] This disclosure also provides a method for delivering an active pharmaceutical ingredient to the anterior chamber, posterior chamber, suprachoroidal space, or vitreous body of one or both eyes of a subject in need, the method comprising injecting the hyaluronic acid disclosed herein or the composition disclosed herein into one or both eyes of the subject or implanting the composition disclosed herein into one or both eyes of the subject.

[0070] This disclosure also provides a method for treating glaucoma, age-related macular degeneration (AMD), macular degeneration (MD), uveitis, retinal vein occlusion, macular edema, macular capillary dilation, endophthalmitis, retinitis, lens dysfunction syndrome (DLS), Fuch's dystrophy, Sjögren's syndrome, Stargardt disease, cataract, diabetic retinopathy, ocular hypertension, optic neuritis, corneal dystrophy, keratitis, scleritis, amblyopia, strabismus, blepharitis, blepharospasm, central retinal vein occlusion, defects, ocular histoplasmosis syndrome, conjunctivitis, presbyopia, or dry eye in a subject of need, the method comprising applying the hyaluronic acid disclosed herein or the compositions disclosed herein to one or both eyes of the subject or implanting the compositions disclosed herein into one or both eyes of the subject.

[0071] In some respects, the composition is applied to or implanted into the anterior chamber, posterior chamber, suprachoroidal space, or vitreous body of one or both eyes of a subject.

[0072] In some respects, the glaucoma referred to is open-angle glaucoma, closed-angle glaucoma, congenital glaucoma, or secondary glaucoma. Attached Figure Description

[0073] Figure 1 It is a line graph depicting the maximum pupil diameter of a beagle dog as a result of intravitreal injection of bimatoprost acid reservoirs or mediators over time.

[0074] Figure 2 It is a line graph depicting the change of intraocular pressure relative to baseline over time in beagle dogs that have received intravitreal bimatoprostate reservoirs or mediators.

[0075] Figure 3 It is a line graph depicting the change in intraocular pressure over time in beagle dogs that have received intravitreal injections of bimatoprostate reservoirs or mediators.

[0076] Figure 4 It is a line graph depicting the change of intraocular pressure relative to baseline in beagle dogs over time as a result of the injection of bimatoprost acid reservoirs or mediators into the choroid.

[0077] Figure 5 It is a line graph depicting the maximum pupil diameter of a beagle over time as a result of injecting bimatoprost acid reservoirs or mediators into the choroid.

[0078] Figure 6 It is a line graph depicting the Hackett McDonald tolerance score of beagle dogs over time, showing the changes in the bimatoprost acid reservoir or medium injected into the choroid. Detailed Implementation

[0079] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of conflict, the application including the definitions shall prevail. Unless the context otherwise requires, singular terms shall include the plural form and plural terms shall include the singular form. All publications, patents and other references mentioned herein are incorporated herein by reference in their entirety for all purposes, as if each individual publication or patent application were specifically and separately instructed to be incorporated by reference.

[0080] While methods and materials similar to or equivalent to those described herein may be used to practice or test this disclosure, suitable methods and materials are described below. The materials, methods, and examples described are illustrative only and are not intended to be limiting. Other features and advantages of this disclosure will become apparent from the detailed description and the claims.

[0081] To further define this disclosure, the following terms and definitions are provided.

[0082] As used herein, the term "active pharmaceutical ingredient" means any substance intended to be incorporated into a final pharmaceutical product and intended to provide pharmacological activity or other direct effects that diagnose, cure, alleviate, treat, or prevent disease or affect the structure or any function of the body. Substances include, but are not limited to, small molecules, peptides, and biologics such as antibodies.

[0083] As used herein, the term “final pharmaceutical product” refers to a final dosage form (e.g., tablet, capsule, or solution) containing at least one active pharmaceutical ingredient (usually but not necessarily) along with other ingredients in a final packaging form suitable for distribution to patients or consumers by pharmacies, pharmaceutical companies, or other marketers or distributors.

[0084] As used herein, the term "drug delivery system" refers to a composition capable of releasing one or more active pharmaceutical ingredients at a known and / or controlled rate.

[0085] As used herein, the terms “pharmaceutical formulation,” “composition,” and “pharmaceutical composition” are used interchangeably and refer to a formulation which is in a form that allows for the effective bioactivity of one or more active pharmaceutical ingredients and does not contain any additional components that would have unacceptable toxicity to a subject to be administered the formulation. Pharmaceutical formulations may be sterile.

[0086] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, formulations, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio. It should be noted that something can be pharmaceutically acceptable even if there is a very rare allergic reaction to any compound, material, composition, formulation, and / or dosage form.

[0087] The term "excipient" refers to any substance that is not itself an active pharmaceutical ingredient, but can be used in a composition to deliver the active pharmaceutical ingredient to a subject, or combined with the active pharmaceutical ingredient (e.g., to form a pharmaceutical composition) to improve its handling or storage properties or to allow or facilitate the formation of a dosage unit of said composition. Excipients include, but are not limited to, solvents, penetration enhancers, wetting agents, antioxidants, lubricants, emollients, substances added to improve the appearance or texture of the composition, and substances for forming hydrogels. Any such excipient can be used in any dosage form according to this disclosure. The foregoing category of excipients is not intended to be exhaustive but is merely illustrative, as those skilled in the art will recognize that additional types and combinations of excipients can be used to achieve the desired goal of delivering one or more active pharmaceutical ingredients. Excipients can be inert, inactive, and / or non-medically active substances. Excipients can be used for a variety of purposes. Those skilled in the art can select one or more excipients with respect to a particular desired property through routine experimentation without any overloading. The amount of each excipient used can vary within the conventional range in the art. The technologies and excipients that can be used in formulations are described in Handbook of Pharmaceutical Excipients, 6th edition, edited by Rowe et al., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2009); and Remington: the Science and Practice of Pharmacy, 21st edition, edited by Gennaro, Lippincott Williams & Wilkins (2005).

[0088] As used herein, the term "dosage unit of a composition" refers to a drug delivery system containing an amount of one or more active pharmaceutical ingredients such that one or more predetermined units can be provided as a single therapeutic dose.

[0089] As used herein, the terms "administer / dministering / administration," etc., refer to methods that can be used to deliver one or more active pharmaceutical ingredients (e.g., bimatoprostolic acid) to a desired biological site of action (e.g., the eye). Administration techniques that can be used with the active pharmaceutical ingredients and methods described herein can be found in […]. For example Goodman and Gilman The Pharmacological Basis of TherapeuticsCurrent version, Pergamon; and Remington's. Pharmaceutical Sciences Current version, Mack Publishing Co., Easton, Pa.

[0090] As used herein, the terms "subject" and "patient" are used interchangeably. A subject can be an animal. In some respects, a subject is an animal, such as a non-human animal (…). For example (Cattle, pigs, horses, cats, dogs, rats, mice, monkeys, or other primates, etc.). In some respects, the subjects are humans.

[0091] The term "therapeutic effective amount" refers to the amount of an active pharmaceutical ingredient that is effective in treating a subject's disease or condition. "Prophylactic effective amount" refers to the amount that is effective in achieving the desired preventative outcome.

[0092] Terms such as “treating” and “alleviating” refer to therapeutic measures that cure a pathological condition or symptom, alleviate a pathological condition or symptom, reduce one or more of its symptoms, and / or stop its progression. Therefore, those subjects requiring treatment include those who have been diagnosed with or are suspected of having the aforementioned conditions.

[0093] As used herein, the terms "bound active pharmaceutical ingredient" and "covalently bonded active pharmaceutical ingredient" refer to an active pharmaceutical ingredient that is attached to a drug delivery system, such as hyaluronic acid. In some respects, the active pharmaceutical ingredient is attached to the drug delivery system via a covalent bond.

[0094] As used herein, the term "free active pharmaceutical ingredient" refers to an active pharmaceutical ingredient that is not connected to a drug delivery system. For example, an active pharmaceutical ingredient dissolved in a solution without any additional components would be considered a free active pharmaceutical ingredient.

[0095] As used herein, the term "hydrophobic group" refers to a chemical fragment that is substantially nonpolar and imparts reduced water solubility to the larger compound and / or polymer to which the fragment is attached. Non-limiting examples of hydrophobic groups include alkyl groups, cycloalkyl groups, and phenyl groups.

[0096] As used herein, the term "alkyl" itself, or as part of another group, refers to a group containing one to twelve carbon atoms (i.e., C1-C1). 12Alkyl groups (or straight-chain or branched aliphatic hydrocarbons with a specified number of carbon atoms), such as C1-C3 alkyl groups, such as methyl, ethyl, propyl, or isopropyl; C1-C4 alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; and so on. In one embodiment, the alkyl group is a straight-chain alkyl group. In another embodiment, the alkyl group is a branched alkyl group. In one embodiment, the alkyl group is a C1-C8 alkyl group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1-C3 alkyl group. Non-limiting exemplary C1-C 12 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, Secondary -Butyl, Tertiary -Butyl, Iso -Butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0097] As used herein, the term "optionally substituted alkyl" itself or as part of another group refers to an unsubstituted or substituted alkyl group, wherein each of the substituents is independently a halogen, nitro, cyano, hydroxy, amino, alkoxy, alkylthio, or cycloalkyl.

[0098] As used herein, the term “halogen” or “halogen” itself or as part of another group refers to -Cl, -F, -Br, or -I.

[0099] As used in this article, the term "nitro" itself, or as part of another group, refers to -NO2.

[0100] As used herein, the term "cyano" itself, or as part of another group, refers to -CN.

[0101] As used herein, the term "hydroxyl group" itself, or as part of another group, refers to -OH.

[0102] The term "amino" as used on its own or as part of another group refers to the formula -NR 3 R 4 The group, wherein R 3 and R 4 Independently, it is either hydrogen or alkyl. In some respects, the amino group is -NH2. In other respects, the amino group is "alkylamino", i.e., where R is hydrogen or alkyl. 3 It is C 1-6 Alkyl and R 4 It is an amino group of hydrogen. In some respects, the amino group is a "dialkylamino", that is, where R is a hydrogen-containing amino group. 3 and R 4 C is independent 1-6 The amino group of an alkyl group.

[0103] As used herein, the term "alkoxy" itself, or as part of another group, refers to an optionally substituted alkyl group attached to a terminal oxygen atom. In some aspects, the optionally substituted alkyl group is a C1-C6 alkyl group and the resulting alkoxy group is referred to as "C1-C6 alkoxy". In some aspects, the optionally substituted alkyl group is a C1-C4 alkyl group and the resulting alkoxy group is referred to as "C1-C4 alkoxy". Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and Tertiary Butoxy group.

[0104] As used herein, the term "alkathio" itself, or as part of another group, refers to an optionally substituted alkyl group attached to a terminal sulfur atom. In some aspects, the optionally substituted alkyl group is a C1-C6 alkyl group and the resulting alkathio group is referred to as "C1-C6 alkathio". In some aspects, the optionally substituted alkyl group is a C1-C4 alkyl group and the resulting alkathio group is referred to as "C1-C4 alkathio". Non-limiting exemplary alkathio groups include -SCH3 and -SCH2CH3.

[0105] As used herein, the term "cycloalkyl" itself, or as part of another group, refers to saturated and partially unsaturated compounds, such as those containing one or two double bonds and containing three to twelve carbon atoms (i.e., C3-C2). 12 A cycloalkyl group is a monocyclic, bicyclic, or tricyclic aliphatic hydrocarbon with a specified number of carbon atoms (e.g., C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In one embodiment, the cycloalkyl group is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl group is monocyclic, i.e., it has one ring. In another embodiment, the cycloalkyl group is C3-C8 cycloalkyl. In yet another embodiment, the cycloalkyl group is C6-C8 cycloalkyl. 3- C6 cycloalkyl. In another embodiment, the cycloalkyl group is a C5 cycloalkyl group, namely cyclopentyl. In another embodiment, the cycloalkyl group is a C6 cycloalkyl group, namely cyclohexyl. Non-limiting exemplary C3-C 12 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norcamphenyl, naphthane, adamantyl, cyclohexenyl and spiroheptane[3.3].

[0106] As used herein, the term "optionally substituted cycloalkyl" itself or as part of another group refers to an unsubstituted or substituted cycloalkyl group, wherein each of the substituents is independently a halogen, nitro, cyano, hydroxy, alkyl, amino, alkoxy, or alkylthio group.

[0107] As used in this disclosure and claims, the singular forms “a / an” and “the” include the plural forms unless the context clearly indicates otherwise.

[0108] As used herein, the term “comprising” is inclusive or open-ended and does not exclude additional unstated elements or method steps, and is synonymous with “including,” “containing,” or “characterized in.”

[0109] As used herein, the term "consistently of..." limits the scope of claims that specify the materials and steps and those that do not substantially affect the essential and novel features of the claimed invention.

[0110] As used herein, the term "composed of" excludes any element, step, or component not specified in the claims.

[0111] It should be understood that regardless of which aspects are described in this text by the language "contains", other similar aspects described by "consisting of" and / or "substantially consisting of" are also provided.

[0112] Unless the context specifically indicates or is clear from the context, the term "or" as used herein should be understood as inclusive. The term "and / or" as used in phrases such as "A and / or B" is intended to include "A and B", "A or B", and "A and B". Similarly, the term "and / or" as used in phrases such as "A, B and / or C" is intended to cover each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0113] As used herein, the terms “about” and “approximately” when used to modify numerical values ​​or ranges indicate that deviations of 10% above or below the value or range remain within the intended meaning of the value or range.

[0114] describe This disclosure provides physical blends of hyaluronic acid forming drug delivery systems in the form of injectable reservoirs capable of retaining small molecules and / or peptides for delivery to the eye and isolating microparticles within the vitreous humor. Different degrees of functionalization and / or crosslinking with hydrophobic groups can be used to control reservoir erosion. In some embodiments, the HA drug delivery system also includes collagen.

[0115] Hyaluronic acid has three readily conjugated functional groups: amide, carboxylic acid, and alcohol. The carboxylic acid group can be used to synthesize amide- and ester-based conjugates. In this disclosure, hyaluronic acid that is not functionalized or conjugated with hydrophobic groups and / or active pharmaceutical ingredients is referred to as "unsubstituted hyaluronic acid."

[0116] This disclosure provides hyaluronic acid comprising compounds of formula (I): (I) Or a pharmaceutically acceptable salt or a solvate thereof, wherein: n is an integer between 500 and 25,000; X is either -NH- or -O- each time it appears; R 1 and R 2 Each time it appears, it is independently selected from the following groups: hydrogen, hydrophobic groups, -L 1 -L 2 -A and -A; Each L 1 It may be an amino acid or it may not be present. Each L 2 It is a connector; and Each A is an independent combination of active pharmaceutical ingredients, wherein each instance of A may be the same or different.

[0117] In some respects, n is between 1,200 and 5,000.

[0118] In some respects, X is -NH-. In other respects, X is -O-.

[0119] In some respects, the hydrophobic group is selected from optionally substituted C1-C. 18 A group composed of alkyl groups and amino acids.

[0120] In some respects, the hydrophobic group is a C1-C group substituted with a phenyl group. 18 Alkyl group. In some respects, the hydrophobic group is a C1-C group selected from the group consisting of... 18 alkyl: , , and .

[0121] In some respects, the hydrophobic group is an amino acid selected from the group consisting of: , and .

[0122] In some respects, L 1 Choose from the following groups: and .

[0123] In some respects, L 2 Choose from the following groups: , and .

[0124] In some respects, each –A of formula (I) is independently selected from the group consisting of: intraocular pressure (IOP) lowering agents, ciliary neurotrophic factor (“CNTF”) analogs, FAS inhibitors (also known as FAS ligand inhibitors), HIF-1α inhibitors, HIF-2α inhibitors, vascular endothelial growth factor (“VEGF”) inhibitors, vasoactive intestinal peptide (“VIP”) analogs, histone-rich analogs, α-lens protein aggregation inhibitors, reducing agents, mitochondrial stabilizers, and tumor necrosis factor-α (“TNF-α”) inhibitors.

[0125] IOP reducers include, but are not limited to, prostaglandins, beta blockers, alpha agonists, carbonic anhydrase inhibitors, cholinergics, rho kinase inhibitors, and cannabinoid receptor agonists.

[0126] Non-limiting examples of prostaglandins include prostaglandin compounds, prostaglandin EP2 agonists, prostaglandin EP3 agonists, and nitric oxide donor prostaglandin compounds. Non-limiting examples of prostaglandin compounds include bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprostone, tafluprost, and tafluprost acid. Non-limiting examples of prostaglandin EP2 agonists include taprenapag isopropyl ester and omeprazole isopropyl ester. Non-limiting examples of prostaglandin EP3 agonists include dinoprostone, misoprostol, limaprost, gemcitabine, prostaglandin E1, and livanprost. Non-limiting examples of nitric oxide donor prostaglandin compounds include latanoprostone bromoprost.

[0127] Non-limiting examples of beta-blockers include timolol, betalol, zobuprofenolol, and metenolol.

[0128] Non-limiting examples of alpha agonists include brimonidine and clonidine.

[0129] Non-limiting examples of carbonic anhydrase inhibitors include brinzolamide, acetazolamide, dzodamide, and acetazolamide.

[0130] Non-limiting examples of cholinergic agents include pilocarpine and carbachol.

[0131] Non-limiting examples of rho kinase inhibitors include nettadil and rosudil.

[0132] Non-limiting examples of CNTF analogues include SEQ ID NO: 18, SEQ ID NO: 1, SEQ ID NO: 2, recombinant CNTF, compounds having a structure or activity similar to ciliary neurotrophic factor (CNTF), or neurotrophic peptides identified in U.S. Patent No. 8,592,374, which is incorporated herein by reference.

[0133] Non-limiting examples of FAS inhibitors include bicyclol, FLIP, MET12 (SEQ ID NO: 3), compound 1 (SEQ ID NO: 5), compound 2 (SEQ ID NO: 6), compound 3 (SEQ ID NO: 7), compound 4 (SEQ ID NO: 8), compound 5 (SEQ ID NO: 9), compound 6 (SEQ ID NO: 10), compound 7 (SEQ ID NO: 11), compound 8 (SEQ ID NO: 12), compound 9 (SEQ ID NO: 13), compound 10 (SEQ ID NO: 14), compound 11 (SEQ ID NO: 15), ONL1204, SEQ ID NO: 4, FAIM, NOL3, human decoy receptor 1 (DcR1), human decoy receptor 2 (DcR2), and human decoy receptor 3 (DcR3).

[0134] Non-limiting examples of TNF-α inhibitors include etanercept, infliximab, golimumab, sertozumab, adalimumab, TNFR1-selective antagonistic mutant TNF (RlantTNF), DMS5540, TNF receptor-silencer (TROS), and ATROSAB.

[0135] Non-limiting examples of mitochondrial stabilizers include elamipretide and risuteganib.

[0136] Non-limiting examples of cannabinoid receptor agonists include Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), arachidonic acid ethanolamine, 2-arachidonic glycerol, 1,1-dimethylheptyl-11-hydroxytetrahydrocannabinol (HU-210), ( cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthyl ketone (R-(+)-WIN55212), (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthyl ketone (JWH-015), 3-(1,1-dimethylbutyl)-6,6,9-trimethyl-6α,7,10,10α-tetrahydro-6H-benzo[c]chromene (JWH-133) Onternabez (HU-308), 1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole (AM1241), 1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole (GW405833), 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro-2H-pyronin-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide (GW842166X) and 1-(4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl)-3-methylcyclohexanol (O-1966).

[0137] In some respects, each –A of formula (I) is independently bimatoprost, bimatoprost acid, brimonidine, nettadil, latanoprost, tafluprost, travoprost, latanoprostone bromoprost, dazolamide, brinzolamide, echotiophate iodide, unoprostone, dipivefrin, pilocarpine, metivolol, omeprazole isopropyl ester, carteolol, carbachol, acetylcholine, benzodiazepine, betalol, timolol, levobunolol, difluprednisolone, cloprednisolone, methylprednisolone acetate, triamcinolone acetate, betamethasone, triamcinolone hexacetonide, dexamethasone, fluocinolone, fluocinolone, triamcinolone, rimexolone, prednisolone, lifitegrast, cyclosporine, bromofenac, nepafenac, ketorolac, diclofenac, sulprofen, flurbiprofen, moxifloxacin, gatifloxacin, ganciclovir, azithromycin, besifloxacin, tobramycin, trifluralin, vidarabine, erythromycin, levofloxacin, ofloxacin, gentamicin, chloramphenicol, bacitracin, tropicamide, phenylephrine, homatropine, cyclopentolate, or atropine.

[0138] In some respects, each –A of formula (I) is independently a compound or peptide disclosed in WO 2019 / 246130 A1, WO 2021 / 127124 A1, WO 2019 / 246141 A1 and / or WO 2021 / 127052 A1, the contents of which are incorporated herein by reference.

[0139] In some respects, approximately 1% to approximately 50% of the R of formula (I) 1 and R 2 The group is a hydrophobic group. In some respects, about 1% to about 50% of the R of formula (I) 1 and R 2 The group is -L 1 -L 2-A or -A. In any of these respects, each instance of the group "-A" in formula (I) may be the same or different. In some respects, there is only one active pharmaceutical ingredient represented by -A in formula (I). In some respects, there are two active pharmaceutical ingredients represented by -A in formula (I). In some respects, there are three active pharmaceutical ingredients represented by -A in formula (I). When there is more than one active pharmaceutical ingredient represented by -A in formula (I), the ratio of the active pharmaceutical ingredients may be any stoichiometric ratio suitable for treating the disease.

[0140] In some respects, there are two or more active pharmaceutical ingredients represented by –A in formula (I). In some respects, multiple different active pharmaceutical ingredients (represented by –A) can be added to hyaluronic acid by reacting hyaluronic acid with appropriate amounts of each active pharmaceutical ingredient in sequence. For example, hyaluronic acid can be reacted with 0.5 molar equivalent of a first active pharmaceutical ingredient to prepare a first hyaluronic acid-pharmaceutical active ingredient complex. The first hyaluronic acid-pharmaceutical active ingredient complex can then be reacted with 0.5 molar equivalent of a second active pharmaceutical ingredient to produce a compound of formula (I), wherein approximately 50% of the –A groups are the first active pharmaceutical ingredient and approximately 50% of the –A groups are the second active pharmaceutical ingredient.

[0141] In some aspects, the first formula (I) compound and one or more additional formula (I) compounds are crosslinked to form crosslinked hyaluronic acid. In some aspects, the first formula (I) compound and one or more additional formula (I) compounds are crosslinked via covalent bonds, such as bonds formed by a free hydroxyl group of the formula (I) compound and a free acid of the additional formula (I) compound. In some aspects, the first formula (I) compound and one or more additional formula (I) compounds are crosslinked via non-covalent interactions, including but not limited to hydrophobic interactions, hydrogen bonding, charge interactions, or stereocomplexation. In some aspects, the first formula (I) compound and one or more additional formula (I) compounds comprise different active pharmaceutical ingredients.

[0142] Amide-based conjugates In some respects, compounds of formula (I) are covalently bonded to one or more active pharmaceutical ingredients and / or hydrophobic groups via amide bonds. Amide bonds can be formed by various methods. In some respects, hyaluronic acid salts (e.g., sodium hyaluronate) are converted to more hydrophobic salts (e.g.,... Tertiary 1-Butylammonium (TBA) salt), which further reacts with the active pharmaceutical ingredient or hydrophobic group and appropriate peptide coupling agent to form amide bonds.

[0143] In some aspects, sodium hyaluronate is first converted into Tertiary-Butylammonium (TBA) salts. Sodium HA with a molecular weight (MW) of 500 kDa to 2 MDa can be converted to TBA salts by passing it through an ion exchange resin (e.g., Amberlite IR-120) in TBA form. The eluent can then be vacuum-dried or lyophilized for future use. To synthesize the amide-based hydrophobic conjugate, HA TBA is dissolved in a solvent (e.g., an organic solvent, such as DMSO). A catalytic amount of methanesulfonic acid and 1,1'-carbonyldiimidazole can then be added and activated by stirring at room temperature. After 60 minutes, an alkylamine or amino acid can be added and stirred overnight at 42°C to produce the final product. The amount of alkylamine or amino acid can vary from a 1:2 ratio of alkylamine or amino acid mEq to HA disaccharide unit mEq to a 1:1 ratio and ultimately a 2:1 ratio. Various ratios will produce different degrees of substitution (see Scheme 1).

[0144] Option 1 Compounds of formula (I) containing hydrophobic amino acids can be synthesized using leucine, phenylalanine, and / or other hydrophobic non-natural amino acids. HA TBA can be dissolved in a solvent (e.g., an organic solvent, such as DMSO), to which a carboxyl activator EDC (1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride) is added, along with NHS (N-hydroxysuccinimide), to form an amine-reactive NHS ester of HA. The reactive NHS HA ester can then be added to a solution of the hydrophobic amino acids to prepare compounds of formula (I).

[0145] Ester-based conjugates In some respects, compounds of formula (I) can be covalently bonded to the active pharmaceutical ingredient and / or hydrophobic groups via ester linkage. Ester linkage can be formed by various methods. In some respects, hyaluronic acid salts (e.g., sodium hyaluronate) are converted into more hydrophobic salts (e.g.,... Tertiary -Butylammonium (TBA) salt), which further reacts with the active pharmaceutical ingredient or hydrophobic group (e.g., an active pharmaceutical ingredient or hydrophobic group containing an alkyl halide) to form an ester bond.

[0146] Sodium hyaluronate can be converted first. Tertiary-Butylammonium (TBA) salts are used to increase the solubility of the conjugate in solvents (e.g., organic solvents). To synthesize the ester-based hydrophobic conjugate, HA TBA can be dissolved in a suitable amount of solvent (e.g., organic solvent, such as DMSO). An appropriate amount of alkyl halide can be added while stirring at 30°C for 12 hours to form the ester. The amount of alkyl halide used in the reaction will vary from a 1:2 ratio of alkyl halide mEq to HA disaccharide units mEq to a 1:1 ratio and ultimately a 2:1 ratio. Various ratios will produce different degrees of substitution (see Scheme 2).

[0147] Option 2 Hydrophobic substituents can be derived from the homologous series of methyl halides (e.g., methyl bromide) with octadecyl halides and benzyl halides, ethyl phenyl halides and propyl phenyl halides.

[0148] In-situ gelling hydrophobic HA storage The hydrophobic HA synthesized in this disclosure (e.g., a compound of formula (I)) can be dissolved in an aqueous solution of 0.1% w / w to 5% w / w of the active pharmaceutical ingredient. The concentration of the active pharmaceutical ingredient in the aqueous solution can range from 1% w / w to 20% w / w. The final formulation will be a shear-diluted hydrogel, which can be injected through a small-hole needle (22 gauge or smaller). After injection into the eye or other biological system, the hydrophobic HA will self-assemble into micelles according to the substituents and retain one or more active pharmaceutical ingredients in the solution.

[0149] One or more active pharmaceutical ingredients retained in the reservoir will be released into the vitreous body over a period of 1 week to 12 months or longer. The hydrophobic HA reservoir is expected to degrade over a period of 1 week to 12 months or longer, simultaneously releasing the active pharmaceutical ingredient.

[0150] In-situ reservoirs from physical blends of polymers and hydrophobic HA In some respects, collagen and poloxamers such as Pluronics can be used to enhance the gel formation of HA. In some respects, by adding these to hydrophobic HA, in-situ reservoirs can be formed that retain the release of one or more active pharmaceutical ingredients. Collagen or poloxamer can be added to hydrophobic HA according to Table 1 below. Solutions of one or more active pharmaceutical ingredients in collagen or poloxamer can be prepared. In the collagen or poloxamer solution, the active pharmaceutical ingredient ranges from about 0.1% w / w to about 50% w / w. Hydrogel aqueous solutions of hydrophobic HA can be prepared at HA concentrations of about 0.2% w / w to about 10% w / w. Equal volumes of the active pharmaceutical ingredient solution and the HA solution can then be mixed to form the final formulation.

[0151] Table 1 In some aspects, the concentrations of collagen or poloxamer are approximately 0.1 mg / mL to approximately 10 mg / mL, approximately 0.1 mg / mL to approximately 50 mg / mL, approximately 0.1 mg / mL to approximately 100 mg / mL, approximately 0.1 mg / mL to approximately 200 mg / mL, approximately 0.1 mg / mL to approximately 300 mg / mL, approximately 0.1 mg / mL to approximately 400 mg / mL, approximately 0.1 mg / mL to approximately 500 mg / mL, approximately 10 mg / mL to approximately 50 mg / mL, approximately 10 mg / mL to approximately 100 mg / mL, approximately 10 mg / mL to approximately 200 mg / mL, approximately 10 mg / mL to approximately 300 mg / mL, approximately 10 mg / mL to approximately 400 mg / mL, approximately 10 mg / mL to approximately 500 mg / mL, approximately 100 mg / mL to approximately 200 mg / mL, approximately 100 mg / mL to approximately 300 mg / mL, approximately 100 mg / mL to approximately 400 mg / mL. mg / mL, about 100 mg / mL to about 500 mg / mL, about 200 mg / mL to about 300 mg / mL, about 200 mg / mL to about 400 mg / mL, about 200 mg / mL to about 500 mg / mL, about 300 mg / mL to about 400 mg / mL, about 300 mg / mL to about 500 mg / mL, or about 400 mg / mL to about 500 mg / mL.

[0152] In some cases, the concentrations of collagen or poloxamer are 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 50 mg / mL, about 100 mg / mL, about 150 mg / mL, about 200 mg / mL, about 250 mg / mL, about 300 mg / mL, about 350 mg / mL, about 400 mg / mL, about 450 mg / mL, or about 500 mg / mL.

[0153] HA with a pyrolytic connector In some aspects, compounds of formula (I) are covalently linked to one or more active pharmaceutical ingredients via cleavable linkers. The release of one or more active pharmaceutical ingredients can be further tuned, and the active pharmaceutical ingredient loading can be increased by linking the desired active pharmaceutical ingredient to the HA backbone. Since the effect of HA on the disposal or efficacy of the attached active pharmaceutical ingredient is unknown, cleavable linkers may be necessary in some aspects. Utilizing cleavable linkers to covalently bond hydrophobic or native HA backbones allows for further optimization of the release of the active pharmaceutical ingredient from the reservoir. In one aspect, the release of the active pharmaceutical ingredient becomes a function of the diffusion properties of the reservoir and the kinetics of linker cleavage. Several linkers that can cleave in the vitreous body to release the linked one or more active pharmaceutical ingredients have been considered.

[0154] Various cleavable linkers can be used to link small molecules, peptides, and / or proteins to the HA backbone. Hydrophobic HA can be used, wherein the hydrophobic substituents on the HA backbone are substituted to a degree ranging from 0% to 50% molar equivalent with the disaccharide unit. Cleavable linkers that can be used include, but are not limited to, ester linkers, disulfide linkers, or mixtures thereof.

[0155] Lysine-based cleavable HA linker In some respects, compounds of formula (I) are covalently linked to one or more active pharmaceutical ingredients and / or hydrophobic groups via lysine linkers. Lysine linkers can be attached to hyaluronic acid by various methods, such as peptide coupling.

[0156] In some aspects, compounds of formula (I) are conjugated to one or more active pharmaceutical ingredients and / or hydrophobic groups via different types of linkers. Non-limiting examples of linkers include esters, amides, and disulfides. Linkers may contain optionally substituted alkyl groups or optionally substituted cycloalkyl groups. In some aspects, linkers are derived from amino acids, such as lysine.

[0157] In some respects, the compound of formula (I) is prepared by the following process. First, sodium hyaluronate is converted to tert-butylammonium salt (HA TBA). HA can be conjugated with lysine by EDC / NHS activation, for example, with HA carboxylic acid. HA TBA is dissolved in a solvent (e.g., DMSO), a carboxyl activator, such as EDC, is added thereto, and NHS is added thereto to form an amine-reactive NHS ester of HA. The reactive NHS HA ester can then be added to a lysine solution to form a lysine amide of HA. HA-lysine amide can be reacted with a diol (e.g., 1,4-butanediol), which can then be used to esterify the C-terminus of a peptide or carboxylic acid residue of a small molecule active pharmaceutical ingredient (e.g., bimatoprost). HA-lysine amide can also be reacted with a compound comprising an alkyl halide and a carboxylic acid ester (e.g., bromobutyrate), which can then be used to esterify the C-terminus of a peptide or hydroxyl residue of a small molecule active pharmaceutical ingredient. Compound of formula (I) prepared using 1,4-butanediol is shown in Formula I, while compound of formula (I) prepared using bromobutyric acid is shown in Formula II.

[0158] Formula I Formula II Direct ester-based conjugates In some respects, the compound of formula (I) is prepared by the following process. First, sodium hyaluronate is converted into... Tertiary - Butylammonium salt (HA TBA). Dissolve 1 gram of HA TBA in an organic solvent (e.g., DMSO). Add an appropriate amount of alkyl halide, such as an alkyl halide linked to the active pharmaceutical ingredient, to form an ester. The amount of alkyl halide will vary between an alkyl halide mEq to HA disaccharide unit mEq ratio of about 1:2 to about 1:1 and ultimately about 2:1. In some respects, the ratio of alkyl halide mEq to HA disaccharide unit mEq is about 1:3, about 2:5, about 1:2, about 4:7, about 2:3, about 4:5, about 1:1, about 5:4, about 3:2, about 7:4, about 2:1, about 5:2, or about 3:1. Various ratios will produce different degrees of substitution. Compounds of formula (I) linked to alkyl halides are shown in Scheme 3.

[0159] Option 3 Disulfide-based pyrolytic joints In some respects, compounds of formula (I) contain a pyrolytic disulfide junction, namely L 2It contains a disulfide, which links the active pharmaceutical ingredient (i.e., -A) to the compound. The disulfide bond can undergo oxidative cleavage, resulting in high concentrations of reduced glutathione in the eye. This forms a prodrug uniquely suited to the intraocular environment.

[0160] In some respects, the compound of formula (I) can be synthesized as shown in Scheme 4 below. Briefly, the HA-TBA salt is dissolved in an organic solvent (e.g., N,N-dimethylformamide (DMF)) optionally containing a salt (e.g., LiCl), and heated until dissolved, then cooled to room temperature. A base (e.g., pyridine) can be added to and reacted with a halogenated acyl halide (e.g., chloroacetyl chloride) to form a haloacetyl-modified HA. The haloacetyl HA can then be reacted with an excess of a dithiol (e.g., dithiothreitol) in solution (e.g., an aqueous buffer). The thiolated HA thus formed can be used to form a disulfide prodrug containing a thiol group, such as a peptide containing cysteine. Substituents can be added to the dithiothreitol to control the oxidative cleavage rate.

[0161] Option 4 Composition This disclosure also provides compositions comprising a compound of formula (I) disclosed herein and one or more free active pharmaceutical ingredients.

[0162] In some respects, each of one or more free active pharmaceutical ingredients is independently selected from the group consisting of: intraocular pressure (IOP) lowerers, ciliary neurotrophic factor (“CNTF”) analogs, FAS inhibitors (also known as FAS ligand inhibitors), HIF-1α inhibitors, HIF-2α inhibitors, vascular endothelial growth factor (“VEGF”) inhibitors, vasoactive intestinal peptide (“VIP”) analogs, histone-rich analogs, α-lens protein aggregation inhibitors, reducing agents, mitochondrial stabilizers, and tumor necrosis factor-α (“TNF-α”) inhibitors. Non-limiting examples of these formulations are provided above.

[0163] In some respects, one or more free active pharmaceutical ingredients are selected from the group consisting of: bimatoprost, bimatoprost acid, brimonidine, netardil, latanoprost, tafluprost, travoprost, latanoprostone bromoprost, dazolamide, brinzolamide, teicoplanin, unoprostone, dipiformin, pilocarpine, metevolol, omeprazole isopropyl ester, cartevolol, carbachol, acetylcholine, aclonidine, betalol, timolol, levobunolol, difluprednisolone, clotiprednisolone acetate, methylprednisolone acetate. Triamcinolone acetonide, betamethasone, hexamethasone, dexamethasone, fluocinolone acetonide, flumethonolone, triamcinolone acetonide, rimesolone, prednisolone, riferidine, cyclosporine, bromofenac, napafenamide, ketorolac, diclofenac, sulprofen, flurbiprofen, moxifloxacin, gatifloxacin, ganciclovir, azithromycin, bexifloxacin, tobramycin, trifluralin, vidarabine, erythromycin, levofloxacin, ofloxacin, gentamicin, chloramphenicol, bacitracin, tropicamide, phenylephrine, homatropine, cyclopentolate, and atropine.

[0164] In some aspects, the respective concentrations of one or more free active pharmaceutical ingredients are from about 1% to about 20% by weight. In some aspects, the respective concentrations of one or more free active pharmaceutical ingredients are from about 1% to about 2% by weight, from about 1% to about 4% by weight, from about 1% to about 6% by weight, from about 1% to about 8% by weight, from about 1% to about 10% by weight, from about 1% to about 12% by weight, from about 1% to about 14% by weight, from about 1% to about 16% by weight, from about 1% to about 18% by weight, from about 2% to about 4% by weight, from about 2% to about 6% by weight, from about 2% to about 8% by weight, from about 2% to about 10% by weight. % by weight, about 2% by weight to about 12% by weight, about 2% by weight to about 14% by weight, about 2% by weight to about 16% by weight, about 2% by weight to about 18% by weight, about 2% by weight to about 20% by weight, about 4% by weight to about 6% by weight, about 4% by weight to about 8% by weight, about 4% by weight to about 10% by weight, about 4% by weight to about 12% by weight, about 4% by weight to about 14% by weight, about 4% by weight to about 16% by weight, about 4% by weight to about 18% by weight, about 4% by weight to about 20% by weight, about 6% by weight to about 8% by weight About 6% by weight to about 10% by weight, about 6% by weight to about 12% by weight, about 6% by weight to about 14% by weight, about 6% by weight to about 16% by weight, about 6% by weight to about 18% by weight, about 6% by weight to about 20% by weight, about 8% by weight to about 10% by weight, about 8% by weight to about 12% by weight, about 8% by weight to about 14% by weight, about 8% by weight to about 16% by weight, about 8% by weight to about 18% by weight, about 8% by weight to about 20% by weight, about 10% by weight to about 12% by weight, about 10% by weight to about 14% by weight The concentrations are approximately 10% to approximately 16% by weight, approximately 10% to approximately 18% by weight, approximately 10% to approximately 20% by weight, approximately 12% to approximately 14% by weight, approximately 12% to approximately 16% by weight, approximately 12% to approximately 18% by weight, approximately 12% to approximately 20% by weight, approximately 14% to approximately 16% by weight, approximately 14% to approximately 18% by weight, approximately 14% to approximately 20% by weight, approximately 16% to approximately 18% by weight, approximately 16% to approximately 20% by weight, or approximately 18% to approximately 20% by weight. In any of the foregoing aspects, the total concentration of all respective free active pharmaceutical ingredients is approximately 1% by weight to approximately 50% by weight.

[0165] In some aspects, the concentration of each individual free active pharmaceutical ingredient is about 5% by weight. In other aspects, the concentration of each individual free active pharmaceutical ingredient is about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 20% by weight.

[0166] In some respects, the concentration of hydrophobic groups on hyaluronic acid is about 0.1% by weight to about 50% by weight relative to the total weight of hyaluronic acid excluding the active pharmaceutical ingredient (–A) in formula (I). In some respects, relative to the total weight of hyaluronic acid excluding the active pharmaceutical ingredient (–A) in formula (I), the concentration of hydrophobic groups on hyaluronic acid is about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 2 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 4 wt%, about 0.5 wt% to about 1 wt%, about 0.5 wt% to about 2 wt%, about 0.5 wt% to about 3 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 5 wt%, about 1 wt% to about 2 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 5 wt%, about 2 wt% to about 3 wt%, about 2 wt% to about 4 wt%, about 2 wt% to about 5 wt%, about 3 wt% to about 4 wt%, about 3 wt% to about 5 wt%, or about 4 wt% to about 5 wt%. In some respects, relative to the total weight of hyaluronic acid excluding the active pharmaceutical ingredient (–A) in formula (I), the concentration of hydrophobic groups on hyaluronic acid is about 1% to about 10% by weight, about 1% to about 20% by weight, about 1% to about 30% by weight, about 1% to about 40% by weight, about 1% to about 50% by weight, about 10% to about 20% by weight, about 10% to about 30% by weight, about 10% to about 40% by weight, about 10% to about 50% by weight, about 20% to about 30% by weight, about 20% to about 40% by weight, about 20% to about 50% by weight, about 30% to about 40% by weight, about 30% to about 50% by weight, or about 40% to about 50% by weight.

[0167] In some aspects, the concentration of hydrophobic groups on hyaluronic acid is about 2% by weight relative to the total weight of hyaluronic acid excluding the active pharmaceutical ingredient (–A) of formula (I). In some aspects, the concentration of hydrophobic groups on hyaluronic acid is about 0.5% by weight, about 1% by weight, about 1.5% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, about 4.5% by weight, or about 5% by weight relative to the total weight of hyaluronic acid excluding the active pharmaceutical ingredient (–A) of formula (I). In some aspects, the concentration of hydrophobic groups on hyaluronic acid is about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight relative to the total weight of hyaluronic acid excluding the active pharmaceutical ingredient (–A) of formula (I).

[0168] In some aspects, the composition further comprises a solvent, such as water. In other aspects, hyaluronic acid is dissolved in the solvent.

[0169] In some aspects, the concentration of hyaluronic acid comprising the compound of formula (I) in the composition is from about 1 mg / mL to about 10 mg / mL. In some aspects, the concentration of hyaluronic acid in the composition is from about 1 mg / mL to about 2.5 mg / mL, from about 1 mg / mL to about 5 mg / mL, from about 1 mg / mL to about 7.5 mg / mL, from about 2.5 mg / mL to about 5 mg / mL, from about 2.5 mg / mL to about 7.5 mg / mL, from about 2.5 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 7.5 mg / mL, from about 5 mg / mL to about 10 mg / mL, or from about 7.5 mg / mL to about 10 mg / mL.

[0170] In some aspects, the concentration of hyaluronic acid comprising the compound of formula (I) in the composition is about 5 mg / mL. In some aspects, the concentration of hyaluronic acid in the composition is about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, or about 10 mg / mL.

[0171] In some respects, hyaluronic acid forms hydrogels in the composition.

[0172] In some respects, the composition contains hyaluronic acid in the form of a solid implant.

[0173] In some aspects, the composition further comprises a second polymer. In some aspects, the second polymer is collagen or poloxamer. In some aspects, the poloxamer is Pluronic® L64, Pluronic® P65, Pluronic® P84, Pluronic® P85, Pluronic® F88, Pluronic® P103, Pluronic® P104, Pluronic® P105, Pluronic® F108, Pluronic® F123, or Pluronic® F127. In some aspects, the collagen is VitriCol®.

[0174] In some aspects, the concentration of the second polymer is from about 1 mg / mL to about 250 mg / mL. In other aspects, the concentration of the second polymer is from about 1 mg / mL to about 5 mg / mL. In some aspects, the concentration of the second polymer is about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 150 mg / mL, about 1 mg / mL to about 200 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 50 mg / mL, about 5 mg / mL to about 100 mg / mL, about 5 mg / mL to about 150 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 250 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 150 mg / mL, about 10 mg / mL to about 200 mg / mL, about 10 mg / mL to about 250 mg / mL, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 150 mg / mL. mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 250 mg / mL, about 100 mg / mL to about 150 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 250 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 250 mg / mL, or about 200 mg / mL to about 250 mg / mL.

[0175] In some aspects, the concentration of the second polymer is about 5 mg / mL. In other aspects, the concentration of the second polymer is about 1 mg / mL, about 10 mg / mL, about 25 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, about 125 mg / mL, about 150 mg / mL, about 175 mg / mL, about 200 mg / mL, about 225 mg / mL, or about 250 mg / mL.

[0176] In some aspects, the concentration of the second polymer is from about 0.1 wt% to about 25 wt%. In some aspects, the concentration of the second polymer is from about 0.1 wt% to about 0.5 wt%. In some aspects, the concentration of the second polymer is from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 5 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 15 wt%, from about 0.1 wt% to about 20 wt%, from about 0.5 wt% to about 1 wt%, from about 0.5 wt% to about 5 wt%, from about 0.5 wt% to about 10 wt%, from about 0.5 wt% to about 15 wt%, from about 0.5 wt% to about 20 wt%, from about 0.5 wt% to about 25 wt%, from about 1 wt% to about 5 wt%. About 1% to about 10% by weight, about 1% to about 15% by weight, about 1% to about 20% by weight, about 1% to about 25% by weight, about 5% to about 10% by weight, about 5% to about 15% by weight, about 5% to about 20% by weight, about 5% to about 25% by weight, about 10% to about 15% by weight, about 10% to about 20% by weight, about 10% to about 25% by weight, about 15% to about 20% by weight, about 15% to about 25% by weight, or about 20% to about 25% by weight.

[0177] In some aspects, the concentration of the second polymer is about 0.5% by weight. In other aspects, the concentration of the second polymer is about 0.1% by weight, about 1% by weight, about 2.5% by weight, about 5% by weight, about 7.5% by weight, about 10% by weight, about 12.5% ​​by weight, about 15% by weight, about 17.5% by weight, about 20% by weight, about 22.5% by weight, or about 25% by weight.

[0178] In some aspects, one or more covalently bonded active pharmaceutical ingredients are released over a period of approximately 6 months to approximately 24 months. In some aspects, one or more covalently bonded active pharmaceutical ingredients are released over the following periods: approximately 6 months to approximately 8 months, approximately 6 months to approximately 10 months, approximately 6 months to approximately 12 months, approximately 6 months to approximately 14 months, approximately 6 months to approximately 16 months, approximately 6 months to approximately 18 months, approximately 6 months to approximately 20 months, approximately 6 months to approximately 22 months, approximately 8 months to approximately 24 months, approximately 10 months to approximately 12 months, approximately 10 months to approximately 14 months, approximately 10 months to approximately 16 months, approximately 10 months to approximately 18 months, approximately 10 months to approximately 20 ...4 months, approximately 10 months to approximately 24 months, approximately 10 months to approximately 16 months, approximately 10 months to approximately 18 months, approximately 10 months to approximately 20 months, approximately 10 months to approximately 24 months, approximately 10 months to approximately 24 months, approximately 10 months to approximately 24 months, approximately 10 months to approximately 24 months, approximately 10 months to approximately 24 months, approximately 10 months to approximately 24 Approximately 12 months to 22 months, approximately 10 months to 24 months, approximately 12 months to 14 months, approximately 12 months to 16 months, approximately 12 months to 18 months, approximately 12 months to 20 months, approximately 12 months to 22 months, approximately 12 months to 24 months, approximately 14 months to 16 months, approximately 14 months to 18 months, approximately 14 months to 20 months, approximately 14 months to 22 months, approximately 14 months to 24 months, approximately 16 months to 18 months, approximately 16 months to 20 months, approximately 16 months to 22 months, approximately 16 months to 24 months, approximately 18 months to 20 months, approximately 18 months to 22 months, approximately 18 months to 24 months, approximately 20 months to 22 months, approximately 20 months to 24 months, or approximately 22 months to 24 months.

[0179] In some aspects, one or more covalently bonded active pharmaceutical ingredients are released over the following time periods: approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 13 months, approximately 14 months, approximately 15 months, approximately 16 months, approximately 17 months, approximately 18 months, approximately 19 months, approximately 20 months, approximately 21 months, approximately 22 months, approximately 23 months, or approximately 24 months. In some aspects, one or more covalently bonded active pharmaceutical ingredients are released over a time period of approximately 6 months. In some aspects, one or more covalently bonded active pharmaceutical ingredients are released over a time period of approximately 12 months. In some aspects, one or more covalently bonded active pharmaceutical ingredients are released over a time period of approximately 18 months. In some aspects, one or more covalently bonded active pharmaceutical ingredients are released over a time period of approximately 24 months.

[0180] In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 6 months to approximately 24 months. In some aspects, one or more covalently bonded active pharmaceutical ingredients are released over the following periods: approximately 6 months to approximately 8 months, approximately 6 months to approximately 10 months, approximately 6 months to approximately 12 months, approximately 6 months to approximately 14 months, approximately 6 months to approximately 16 months, approximately 6 months to approximately 18 months, approximately 6 months to approximately 20 months, approximately 6 months to approximately 22 months, approximately 8 months to approximately 10 months, approximately 8 months to approximately 12 months, approximately 10 months to approximately 14 months, approximately 10 months to approximately 16 months, approximately 10 months to approximately 18 months, approximately 10 months to approximately 20 months, approximately 10 months to approximately 20 months, approximately 10 months to approximately 24 months, approximately 10 ...4 months, approximately 10 months to approximately 24 months, approximately 10 months to approximately 24 months, approximately 10 months to approximately 24 months, approximately 1 Approximately 12 months to 22 months, approximately 10 months to 24 months, approximately 12 months to 14 months, approximately 12 months to 16 months, approximately 12 months to 18 months, approximately 12 months to 20 months, approximately 12 months to 22 months, approximately 12 months to 24 months, approximately 14 months to 16 months, approximately 14 months to 18 months, approximately 14 months to 20 months, approximately 14 months to 22 months, approximately 14 months to 24 months, approximately 16 months to 18 months, approximately 16 months to 20 months, approximately 16 months to 22 months, approximately 16 months to 24 months, approximately 18 months to 20 months, approximately 18 months to 22 months, approximately 18 months to 24 months, approximately 20 months to 22 months, approximately 20 months to 24 months, or approximately 22 months to 24 months.

[0181] In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately one month. In some aspects, one or more free active pharmaceutical ingredients are released over the following periods: approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 13 months, approximately 14 months, approximately 15 months, approximately 16 months, approximately 17 months, approximately 18 months, approximately 19 months, approximately 20 months, approximately 21 months, approximately 22 months, approximately 23 months, or approximately 24 months. In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 6 months. In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 12 months. In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 18 months. In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 24 months.

[0182] This disclosure also provides compositions comprising cross-linked hyaluronic acid and one or more free active pharmaceutical ingredients.

[0183] Certain cross-linked hyaluronic acids are known in the art, such as Juvederm® Ultra, Juvederm® UltraPlus, Healaflow®, Restylane®, Puragen®, Hylaform®, and Captique®.

[0184] In some respects, each of one or more free active pharmaceutical ingredients is independently selected from the group consisting of: intraocular pressure (IOP) lowering agents, ciliary neurotrophic factor (“CNTF”) analogs, FAS inhibitors (also known as FAS ligand inhibitors), HIF-1α inhibitors, HIF-2α inhibitors, vascular endothelial growth factor (“VEGF”) inhibitors, vasoactive intestinal peptide (“VIP”) analogs, histone-rich analogs, α-lens protein aggregation inhibitors, reducing agents, mitochondrial stabilizers, and tumor necrosis factor-α (“TNF-α”) inhibitors. Non-limiting examples of these agents are provided above.

[0185] In some respects, one or more free active pharmaceutical ingredients are selected from the group consisting of: bimatoprost, bimatoprost acid, brimonidine, netardil, latanoprost, tafluprost, travoprost, latanoprostone bromoprost, dazolamide, brinzolamide, teicoplanin, unoprostone, dipiformin, pilocarpine, metevolol, omeprazole isopropyl ester, cartevolol, carbachol, acetylcholine, aclonidine, betalol, timolol, levobunolol, difluprednisolone, clotiprednisolone acetate, methylprednisolone acetate. Triamcinolone acetonide, betamethasone, hexamethasone, dexamethasone, fluocinolone acetonide, flumethonolone, triamcinolone acetonide, rimesolone, prednisolone, riferidine, cyclosporine, bromofenac, napafenamide, ketorolac, diclofenac, sulprofen, flurbiprofen, moxifloxacin, gatifloxacin, ganciclovir, azithromycin, bexifloxacin, tobramycin, trifluralin, vidarabine, erythromycin, levofloxacin, ofloxacin, gentamicin, chloramphenicol, bacitracin, tropicamide, phenylephrine, homatropine, cyclopentolate, and atropine.

[0186] In some aspects, the respective concentrations of one or more free active pharmaceutical ingredients are from about 1% to about 20% by weight. In some aspects, the respective concentrations of one or more free active pharmaceutical ingredients are from about 1% to about 2% by weight, from about 1% to about 4% by weight, from about 1% to about 6% by weight, from about 1% to about 8% by weight, from about 1% to about 10% by weight, from about 1% to about 12% by weight, from about 1% to about 14% by weight, from about 1% to about 16% by weight, from about 1% to about 18% by weight, from about 2% to about 4% by weight, from about 2% to about 6% by weight, from about 2% to about 8% by weight, from about 2% to about 10% by weight. % by weight, about 2% by weight to about 12% by weight, about 2% by weight to about 14% by weight, about 2% by weight to about 16% by weight, about 2% by weight to about 18% by weight, about 2% by weight to about 20% by weight, about 4% by weight to about 6% by weight, about 4% by weight to about 8% by weight, about 4% by weight to about 10% by weight, about 4% by weight to about 12% by weight, about 4% by weight to about 14% by weight, about 4% by weight to about 16% by weight, about 4% by weight to about 18% by weight, about 4% by weight to about 20% by weight, about 6% by weight to about 8% by weight About 6% by weight to about 10% by weight, about 6% by weight to about 12% by weight, about 6% by weight to about 14% by weight, about 6% by weight to about 16% by weight, about 6% by weight to about 18% by weight, about 6% by weight to about 20% by weight, about 8% by weight to about 10% by weight, about 8% by weight to about 12% by weight, about 8% by weight to about 14% by weight, about 8% by weight to about 16% by weight, about 8% by weight to about 18% by weight, about 8% by weight to about 20% by weight, about 10% by weight to about 12% by weight, about 10% by weight to about 14% by weight The concentrations are approximately 10% to approximately 16% by weight, approximately 10% to approximately 18% by weight, approximately 10% to approximately 20% by weight, approximately 12% to approximately 14% by weight, approximately 12% to approximately 16% by weight, approximately 12% to approximately 18% by weight, approximately 12% to approximately 20% by weight, approximately 14% to approximately 16% by weight, approximately 14% to approximately 18% by weight, approximately 14% to approximately 20% by weight, approximately 16% to approximately 18% by weight, approximately 16% to approximately 20% by weight, or approximately 18% to approximately 20% by weight. In any of the foregoing aspects, the total concentration of all respective free active pharmaceutical ingredients is approximately 1% by weight to approximately 50% by weight.

[0187] In some aspects, the concentration of each individual free active pharmaceutical ingredient is about 5% by weight. In other aspects, the concentration of each individual free active pharmaceutical ingredient is about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 20% by weight.

[0188] In some respects, the free active pharmaceutical ingredient is encapsulated, for example, in microspheres.

[0189] In some aspects, the composition further comprises a second polymer. In some aspects, the second polymer is collagen or poloxamer. In some aspects, the poloxamer is Pluronic® L64, Pluronic® P65, Pluronic® P84, Pluronic® P85, Pluronic® F88, Pluronic® P103, Pluronic® P104, Pluronic® P105, Pluronic® F108, Pluronic® F123, or Pluronic® F127. In some aspects, the collagen is VitriCol®.

[0190] In some aspects, the concentration of the second polymer is from about 1 mg / mL to about 250 mg / mL. In other aspects, the concentration of the second polymer is from about 1 mg / mL to about 5 mg / mL. In some aspects, the concentration of the second polymer is about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 150 mg / mL, about 1 mg / mL to about 200 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 50 mg / mL, about 5 mg / mL to about 100 mg / mL, about 5 mg / mL to about 150 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 250 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 150 mg / mL, about 10 mg / mL to about 200 mg / mL, about 10 mg / mL to about 250 mg / mL, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 150 mg / mL. mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 250 mg / mL, about 100 mg / mL to about 150 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 250 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 250 mg / mL, or about 200 mg / mL to about 250 mg / mL.

[0191] In some aspects, the concentration of the second polymer is about 5 mg / mL. In other aspects, the concentration of the second polymer is about 1 mg / mL, about 10 mg / mL, about 25 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, about 125 mg / mL, about 150 mg / mL, about 175 mg / mL, about 200 mg / mL, about 225 mg / mL, or about 250 mg / mL.

[0192] In some aspects, the concentration of the second polymer is from about 0.1 wt% to about 25 wt%. In some aspects, the concentration of the second polymer is from about 0.1 wt% to about 0.5 wt%. In some aspects, the concentration of the second polymer is from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 5 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 15 wt%, from about 0.1 wt% to about 20 wt%, from about 0.5 wt% to about 1 wt%, from about 0.5 wt% to about 5 wt%, from about 0.5 wt% to about 10 wt%, from about 0.5 wt% to about 15 wt%, from about 0.5 wt% to about 20 wt%, from about 0.5 wt% to about 25 wt%, from about 1 wt% to about 5 wt%. About 1% to about 10% by weight, about 1% to about 15% by weight, about 1% to about 20% by weight, about 1% to about 25% by weight, about 5% to about 10% by weight, about 5% to about 15% by weight, about 5% to about 20% by weight, about 5% to about 25% by weight, about 10% to about 15% by weight, about 10% to about 20% by weight, about 10% to about 25% by weight, about 15% to about 20% by weight, about 15% to about 25% by weight, or about 20% to about 25% by weight.

[0193] In some aspects, the concentration of the second polymer is about 0.5% by weight. In other aspects, the concentration of the second polymer is about 0.1% by weight, about 1% by weight, about 2.5% by weight, about 5% by weight, about 7.5% by weight, about 10% by weight, about 12.5% ​​by weight, about 15% by weight, about 17.5% by weight, about 20% by weight, about 22.5% by weight, or about 25% by weight.

[0194] In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 6 months to approximately 24 months. In some aspects, one or more free active pharmaceutical ingredients are released over the following periods: approximately 6 months to approximately 8 months, approximately 6 months to approximately 10 months, approximately 6 months to approximately 12 months, approximately 6 months to approximately 14 months, approximately 6 months to approximately 16 months, approximately 6 months to approximately 18 months, approximately 6 months to approximately 20 months, approximately 6 months to approximately 22 months, approximately 8 months to approximately 10 months, approximately 8 months to approximately 12 months, approximately 10 months to approximately 14 months, approximately 10 months to approximately 16 months, approximately 10 months to approximately 18 months, approximately 10 months to approximately 20 months, approximately 10 months to approximately 20 months, approximately 10 months to approximately 24 months, approximately 10 months to approximately 12 months, approximately 10 months to approximately 14 months, approximately 10 months to approximately 16 months, approximately 10 months to approximately 18 months, approximately 10 months to approximately 20 months, approximately 10 months to approximately 20 months, approximately 10 months to approximately 24 months. About 22 months, about 10 months to about 24 months, about 12 months to about 14 months, about 12 months to about 16 months, about 12 months to about 18 months, about 12 months to about 20 months, about 12 months to about 22 months, about 12 months to about 24 months, about 14 months to about 16 months, about 14 months to about 18 months, about 14 months to about 20 months, about 14 months to about 22 months, about 14 months to about 24 months, about 16 months to about 18 months, about 16 months to about 20 months, about 16 months to about 22 months, about 16 months to about 24 months, about 18 months to about 20 months, about 18 months to about 22 months, about 18 months to about 24 months, about 20 months to about 22 months, about 20 months to about 24 months, or about 22 months to about 24 months.

[0195] In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately one month. In some aspects, one or more free active pharmaceutical ingredients are released over the following periods: approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 13 months, approximately 14 months, approximately 15 months, approximately 16 months, approximately 17 months, approximately 18 months, approximately 19 months, approximately 20 months, approximately 21 months, approximately 22 months, approximately 23 months, or approximately 24 months. In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 6 months. In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 12 months. In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 18 months. In some aspects, one or more free active pharmaceutical ingredients are released over a period of approximately 24 months.

[0196] In some respects, the composition comprises cross-linked hyaluronic acid, collagen, and at least one free active pharmaceutical ingredient.

[0197] In some respects, the composition comprises cross-linked hyaluronic acid, collagen, and bimatoprostolic acid.

[0198] In some aspects, the composition comprises about 4 mg / mL to about 12 mg / mL of cross-linked hyaluronic acid, about 0.5 mg / mL to about 4 mg / mL of collagen, and about 1 mg / mL to about 10 mg / mL of at least one free active pharmaceutical ingredient.

[0199] In some aspects, the composition comprises about 4 mg / mL to about 12 mg / mL of cross-linked hyaluronic acid, about 0.5 mg / mL to about 4 mg / mL of collagen, and about 1 mg / mL to about 10 mg / mL of bimatoprost acid.

[0200] In some respects, the composition comprises cross-linked hyaluronic acid, histone-rich analogs, CNTF analogs, and optionally VIP analogs.

[0201] In some respects, the composition comprises cross-linked hyaluronic acid and CNTF analogs and / or FAS inhibitors and / or prostaglandin analogs.

[0202] In some aspects, the composition comprises cross-linked hyaluronic acid and CNTF analogs and / or FAS inhibitors and optionally VEGF inhibitors.

[0203] In some respects, the composition comprises cross-linked hyaluronic acid and CNTF analogs and / or FAS inhibitors.

[0204] How to use This disclosure also provides a method for delivering one or more active pharmaceutical ingredients to the anterior chamber, posterior chamber, suprachoroidal space, or vitreous body of the eye of a subject in need, the method comprising injecting the composition disclosed herein into the eye of the subject.

[0205] This disclosure also provides methods for treating glaucoma, age-related macular degeneration (AMD), macular degeneration (MD), uveitis, retinal vein occlusion, macular edema, macular capillary dilation, endophthalmitis, retinitis, lens dysfunction syndrome (DLS), Fuchs' dystrophy, Schogren's syndrome, Staghorn's disease, cataracts, diabetic retinopathy, ocular hypertension, optic neuritis, corneal dystrophy, keratitis, scleritis, amblyopia, strabismus, blepharitis, blepharospasm, central retinal vein occlusion, defects, ocular histoplasmosis syndrome, conjunctivitis, presbyopia, or dry eye in subjects of need, said methods comprising administering the hyaluronic acid disclosed herein or a composition disclosed herein to the eye of the subject.

[0206] In some respects, the composition is applied to the anterior chamber, posterior chamber, suprachoroidal space, or vitreous body of the subject's eye.

[0207] In some respects, the glaucoma referred to is open-angle glaucoma, closed-angle glaucoma, congenital glaucoma, or secondary glaucoma.

[0208] This disclosure also provides a method for delivering one or more active pharmaceutical ingredients to the joints of a subject in need, the method comprising injecting the hyaluronic acid disclosed herein or a composition disclosed herein into the joints of the subject.

[0209] This disclosure also provides a method for treating osteoarthritis in a subject in need, the method comprising administering the disclosed hyaluronic acid or a composition disclosed herein to the joint of the subject.

[0210] This disclosure also provides a method of delivering one or more active pharmaceutical ingredients to the teeth, roots, or gums of a subject in need, the method comprising injecting the hyaluronic acid disclosed herein or a composition disclosed herein into the teeth, roots, or gums of the subject.

[0211] This disclosure also provides methods for treating dental or periodontal diseases, conditions, or disorders in a subject in need, the methods comprising applying the hyaluronic acid disclosed herein or a composition disclosed herein to the subject's teeth, roots, or gums.

[0212] This disclosure also provides the sequences listed in Table 2.

[0213] Table 2 The following examples are illustrative and do not limit the scope of the claimed aspects.

[0214] Example Example 1 HA conjugates based on amides Convert sodium hyaluronate into Tertiary -Butylammonium (TBA) salts. Sodium HA with a molecular weight (MW) from 500 kDa to 2 MDa was converted to TBA salts by passing it through an Amberlite IR-120 ion exchange resin in TBA form. The eluent was then vacuum-dried or lyophilized for future use. To synthesize the amide-based hydrophobic conjugate, 1 g of HA TBA was dissolved in 100 mL of DMSO. A catalytic amount of methanesulfonic acid and 1,1'-carbonyldiimidazole were added and activated by stirring at room temperature for 60 min. After 60 min, an alkylamine was added and stirred overnight at 42 °C to produce the final product.

[0215] Example 2 HA conjugates based on esters Convert sodium hyaluronate into Tertiary-Butylammonium (TBA) salt. To synthesize the ester-based hydrophobic conjugate, 1 g of HA TBA was dissolved in 100 mL of DMSO. An appropriate amount of alkyl halide was added, and the mixture was stirred at 30 °C for 12 hours to form the ester.

[0216] Example 3 HA conjugates based on lysine Sodium hyaluronate was converted to tert-butylammonium (TBA) salt. HA was then conjugated to lysine using EDC / NHS activation with HA carboxylic acid. HA TBA was dissolved in DMSO, and EDC (1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride) and NHS (N-hydroxysuccinimide) were added to form an amine-reactive NHS ester of HA. The reactive NHS HA ester was then added to a lysine solution to form a lysine amide of HA.

[0217] HA-lysine amide is reacted with 1,4-butanediol, which can then be used to esterify the C-terminus of peptide or carboxylic acid residues of small molecule active pharmaceutical ingredients such as bimatoprost.

[0218] Alternatively, HA-lysine amide is reacted with bromobutyrate, which can then be used to esterify the C-terminus of peptide or carboxylic acid residues of small molecule active pharmaceutical ingredients such as bimatoprost.

[0219] Example 4 Direct ester HA conjugate Convert sodium hyaluronate into Tertiary -Butylammonium (TBA) salt. To synthesize the ester-based hydrophobic conjugate, 1 g of HA TBA was dissolved in 100 mL of DMSO. An appropriate amount of alkyl halide, such as an alkyl halide linked to the active pharmaceutical ingredient, was added while stirring at 30 °C for 12 hours to form the ester.

[0220] Example 5 Disulfide-based cleavable HA conjugates HA-TBA salt was dissolved in N,N-dimethylformamide (DMF) containing 2% LiCl at 90 °C until a solution was obtained, which was then cooled to room temperature. Pyridine and chloroacetyl chloride were added and reacted for 4 hours to form chloroacetyl-modified HA. The chloroacetyl HA was then reacted with excess dithiothreitol in an aqueous buffer at pH 7.4. The thiolated HA thus formed can be used to form disulfide prodrugs containing thiol groups, such as peptides containing cysteine. Substituents can be added to dithiothreitol to control the oxidative cleavage rate.

[0221] Example 6 Intravitreal injection of bimatoprost reservoir in beagle dogs The efficacy and tolerability of intravitreal injection of bimatoprostolic acid (BA) microspheres in the form of cross-linked hyaluronic acid (HA) and collagen reservoirs were evaluated in beagle dogs. A sustained-release formulation containing 5.5 mg / mL bimatoprostolic acid and 0.8% hyaluronic acid and 0.2% collagen, as well as a placebo formulation, were administered. Test items are shown in Table 3.

[0222] Table 3 Prepare test items in a biosafety cabinet to ensure sterility. Prepare a 4 mg / mL human collagen solution (VitriCol®) with water for injection (WIFI) at pH 2.0. Adjust the pH of the WIFI to 2.0 with HCl. Use cross-linked HA (Juvederm® Ultra, 24 mg / mL HA) accepted as is. Add 0.5 mL of the collagen solution and 0.333 mL of the HA gel to a 1-mL syringe. Add 100 µL of 10X PBS solution to the same syringe. Connect the 1-mL syringe to a 3-mL syringe via the quick-fill connector. Homogenize the mixture by pushing the material through the quick-fill connector into the 3-mL syringe and back into the 1-mL syringe 50 times. Push the final gel back into the 1-mL syringe.

[0223] The microspheres containing bimatoprost acid were then incorporated into the gel. 220 mg of BA microspheres were added to a separate 3-mL syringe. This syringe was then connected to a 1-mL gel syringe via a quick-fill connector. The microspheres and gel were then mixed by passing the connector 50 times, leaving the final product in the 1-mL syringe.

[0224] Using the same process and formulation media as the active formulation, only BA microspheres were left as a control.

[0225] The efficacy and tolerability of BA-HA gel were evaluated using beagle dogs. Following the initial intraocular pressure measurement adaptation phase, animals received a single intravitreal injection of both the placebo (OS) and test item (OD) on day 1. Eye examination, intraocular pressure measurement, pupillary measurement, fundus imaging, fluorescein angiography, slit-lamp imaging, and OCT imaging were performed over 84 days. Histological examination was performed on day 84.

[0226] Following a single injection of the sustained-release BA formulation in the first few months, a 50% reduction in IOP relative to the initial baseline was observed, followed by a 25% reduction over the next 84 days. Figure 2 and Figure 3 As shown. Significant pupillary constriction was observed in the treated eyes within 84 days, demonstrating efficacy, as...Figure 1 As shown. Prostaglandins such as bimatoprostolic acid caused significant pupillary constriction in dogs. All measures of the formulation were well tolerated in all three dogs during the study. One animal showed inflammation of the treated eye on day 21.

[0227] Compared to the expected delivery characteristics of 3 to 6 months, uncrosslinked HA is known to be rapidly cleared from the vitreous. The vitreous half-life of HA depends on its molecular weight and degree of crosslinking. Uncrosslinked HA has a vitreous half-life of several weeks, although some estimates are as short as 2 days (Nakagawa M, Tanaka M, Miyata T. Evaluation of collagen gel and hyaluronic acid as vitreous substitutes. Ophthalmic Res. 1997;29(6):409-20. doi: 10.1159 / 000268042. PMID: 9380343). HA is cleared from the vitreous by dissolution and elimination from the anterior chamber or by metabolism via hyaluronidase. Crosslinking and crosslinking density can modify the clearance rate and prolong the duration of clearance.

[0228] This embodiment demonstrates the practicality of cross-linked HA reservoirs. The duration of the cross-linked HA reservoir in the vitreous exceeds 84 days. Mydriasis and reduced IOP induced by bimatoprost were observed within 84 days, indicating the presence of a reservoir. Furthermore, the microparticles isolated in the reservoir do not migrate across the eye and into the anterior chamber. In three eyes that received the cross-linked-HA bimatoprost reservoir, no anterior chamber material was observed at 56 days post-injection, and in two eyes, no material was observed for the full 84 days. One eye began showing some material in the anterior chamber on day 70. However, this was observed with a microsphere-free medium, indicating that it was not due to microparticle migration in that eye.

[0229] Example 7 Injecting bimatoprost reservoir into the choroid of a Beagle Bimatoprostol (BA) microspheres suspended in hyaluronic acid were administered via intrachoroidal injection in beagle dogs, and intraocular pressure reduction (IOP) and tolerability were assessed. Each of three dogs received 100 µL of BA formulation at an intrachoroidal dose (OD) and 100 µL of mediator article (OS). The activity test article contained 6.12 mg / mL of BA delivered as a microsphere formulation suspended in HA (Healon® Pro). The test article was prepared by placing 241.2 mg of BA microspheres into a 1-mL syringe. 0.85 mL of HA was added to the same syringe via a quick-fill connector. The 1-mL syringe was then connected to a 3-mL syringe via the quick-fill connector. The mixture was homogenized by pushing the material through the quick-fill connector into the 3-mL syringe and back into the 1-mL syringe 50 times. The final gel was then pushed back into the 1 mL syringe.

[0230] The BA formulation was administered to beagle dogs by injecting 100 µL from a 1-mL syringe through a 27-gauge needle into the suprachoroidal space. Eye examinations, IOP / pupil measurements, and fundus imaging were performed on days 2, 5, and 7. Rear-segment OCT was performed on day 7. In the active BA group, IOP decreased by 60% on day 2 and by 29% on days 5 and 7. The formulation was also well tolerated during the 7-day study. Changes in IOP and pupil diameter relative to baseline (CFB) are shown in the figures. Figure 4 and Figure 5 The Hackett-McDonald Tolerance Score shows that... Figure 6 middle.

Claims

1. Hyaluronic acid, compound of formula (I): (I) or its salt or its solvate, wherein: n is an integer between 500 and 25,000; X is selected from the group consisting of -NH- and -O- each time it appears; R 1 and R 2 Each time it appears, it is independently selected from the following groups: hydrogen, hydrophobic groups, -L 1 -L 2 -A and -A; Each L 1 It may be an amino acid or it may not be present. Each L 2 It is a connector; and Each A is independently a covalently bonded active pharmaceutical ingredient, wherein each instance of -A can be the same or different.

2. The hyaluronic acid of claim 1, wherein n is from 1,200 to 5,000.

3. The hyaluronic acid as described in claim 1 or 2, wherein X is -NH-.

4. The hyaluronic acid as described in claim 1 or 2, wherein X is -O-.

5. The hyaluronic acid according to any one of claims 1-4, wherein the hydrophobic group is selected from the group consisting of: optionally substituted C1-C 18 Alkyl groups and amino acids.

6. The hyaluronic acid of claim 5, wherein the hydrophobic group is a C1-C group substituted with a phenyl group. 18 alkyl.

7. The hyaluronic acid of claim 5 or 6, wherein the hydrophobic group is selected from the C1-C group of the group consisting of... 18 alkyl: , , and .

8. The hyaluronic acid of claim 5, wherein the hydrophobic group is an amino acid selected from the group consisting of: , and .

9. The hyaluronic acid according to any one of claims 1-8, wherein L 1 Choose from the following groups: and .

10. The hyaluronic acid according to any one of claims 1-9, wherein L 2 Choose from the following groups: , and .

11. The hyaluronic acid according to any one of claims 1-10, wherein each A is independently selected from the group consisting of: intraocular pressure (IOP) reducers, CNTF analogs, FAS inhibitors or FAS ligand inhibitors, HIF-1α inhibitors, HIF-2α inhibitors, VEGF inhibitors, VIP analogs, histone-rich analogs, α-lens protein aggregation inhibitors, reducing agents, mitochondrial stabilizers, and TNF-α inhibitors.

12. The hyaluronic acid of claim 11, wherein the IOP reducer is a prostaglandin, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, a cholinergic agent, a rho kinase inhibitor, or a cannabinoid receptor agonist.

13. The hyaluronic acid of claim 12, wherein the prostaglandin is a prostaglandin compound, a prostaglandin EP2 agonist, a prostaglandin EP3 agonist, a nitric oxide donor prostaglandin compound, or a combination thereof.

14. The hyaluronic acid of claim 13, wherein the prostaglandin compound is bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprostone, tafluprost, or tafluprost acid.

15. The hyaluronic acid of claim 13, wherein the prostaglandin EP2 agonist is taprenapag isopropyl ester or omepag isopropyl ester.

16. The hyaluronic acid of claim 13, wherein the prostaglandin EP3 agonist is dinoprostone, misoprostol, limaprost, gemcitabine, alprostadil, or livanprost.

17. The hyaluronic acid of claim 13, wherein the nitric oxide donor prostaglandin compound is latanoprostonebutide.

18. The hyaluronic acid of claim 12, wherein the β-blocker is timolol, betalol, levobunolol, or metemolol.

19. The hyaluronic acid of claim 12, wherein the α-agonist is brimonidine or aclomid.

20. The hyaluronic acid of claim 12, wherein the carbonic anhydrase inhibitor is brinzolamide, acetazolamide, dzodamine, or acetazolamide.

21. The hyaluronic acid of claim 12, wherein the cholinergic agent is pilocarpine or carbacholine.

22. The hyaluronic acid of claim 12, wherein the rho kinase inhibitor is nertadil.

23. The hyaluronic acid of claim 11, wherein the CNTF analog is SEQ ID NO: 18, SEQ ID NO: 1, SEQ ID NO: 2 or recombinant CNTF.

24. The hyaluronic acid of claim 11, wherein the FAS inhibitor is a bicyclic alcohol, FLIP, MET12 (SEQ ID NO: 3), compound 1 (SEQ ID NO: 5), compound 2 (SEQ ID NO: 6), compound 3 (SEQ ID NO: 7), compound 4 (SEQ ID NO: 8), compound 5 (SEQ ID NO: 9), compound 6 (SEQ ID NO: 10), compound 7 (SEQ ID NO: 11), compound 8 (SEQ ID NO: 12), compound 9 (SEQ ID NO: 13), compound 10 (SEQ ID NO: 14), compound 11 (SEQ ID NO: 15), ONL1204, SEQ ID NO: 4, FAIM, NOL3, human decoy receptor 1 (DcR1), human decoy receptor 2 (DcR2), or human decoy receptor 3 (DcR3).

25. The hyaluronic acid of claim 11, wherein the TNF-α inhibitor is etanercept, infliximab, golimumab, sertozumab, adalimumab, TNFR1-selective antagonistic mutant TNF (RlantTNF), DMS5540, TNF receptor-silencer (TROS), or ATROSAB.

26. The hyaluronic acid of claim 12, wherein the cannabinoid receptor agonist is Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), arachidonic acid ethanolamine, 2-arachidonic glycerol, 1,1-dimethylheptyl-11-hydroxytetrahydrocannabinol (HU-210), ( )-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthyl ketone (R-(+)-WIN55212), (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthyl ketone (JWH-015), 3-(1,1-dimethylbutyl)-6,6,9-trimethyl-6α,7,10,10α-tetrahydro-6H-benzo[c]chromene (JW H-133), Ontnabe (HU-308), 1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole (AM1241), 1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole (GW405833), 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro-2H-pyronin-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide (GW842166X) or 1-(4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl)-3-methylcyclohexanol (O-1966).

27. The hyaluronic acid according to any one of claims 1-26, wherein about 1% to about 50% of the R group is a hydrophobic group.

28. The hyaluronic acid according to any one of claims 1-27, wherein about 1% to about 50% of the R group is -L. 1 -L 2 -A or -A.

29. The hyaluronic acid according to any one of claims 1-28, wherein each -A of formula (I) is selected from an active pharmaceutical ingredient.

30. The hyaluronic acid according to any one of claims 1-28, wherein each -A of formula (I) is selected from two active pharmaceutical ingredients.

31. The hyaluronic acid according to any one of claims 1-28, wherein each -A of formula (I) is selected from three active pharmaceutical ingredients.

32. The hyaluronic acid of claim 30, wherein the compound of formula (I) is prepared by: (i) reacting unsubstituted hyaluronic acid with the first active pharmaceutical ingredient; and (ii) React the product of step (i) with the second active pharmaceutical ingredient; To provide the hyaluronic acid.

33. The hyaluronic acid of claim 31, wherein the compound of formula (I) is prepared by: (i) Reacting unsubstituted hyaluronic acid with the first active pharmaceutical ingredient; (ii) Reacting the product of step (i) with the second active pharmaceutical ingredient; and (iii) React the product of step (ii) with the third active pharmaceutical ingredient; To provide the hyaluronic acid.

34. The hyaluronic acid of claim 1, comprising a first compound (I) crosslinked with a second compound (I), wherein the first compound comprises a first active pharmaceutical ingredient and the second compound comprises a second active pharmaceutical ingredient.

35. The hyaluronic acid of claim 1, comprising a first compound (I) crosslinked with a second compound (I) and a third compound (I), wherein the first compound comprises a first active pharmaceutical ingredient, the second compound comprises a second active pharmaceutical ingredient, and the third compound comprises a third active pharmaceutical ingredient.

36. A composition comprising hyaluronic acid as described in any one of claims 1-35 and a free active pharmaceutical ingredient.

37. The composition of claim 36, wherein the free active pharmaceutical ingredient is selected from the group consisting of: IOP reducers, CNTF analogs, FAS inhibitors, HIF-1α inhibitors, HIF-2α inhibitors, VEGF inhibitors, VIP analogs, histone-rich analogs, α-lens protein aggregation inhibitors, reducing agents, and TNF-α inhibitors.

38. The composition of claim 37, wherein the IOP reducer is a prostaglandin, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, a cholinergic agent, a rho kinase inhibitor, or a cannabinoid receptor agonist.

39. The composition of claim 38, wherein the prostaglandin is a prostaglandin compound, a prostaglandin EP2 agonist, a prostaglandin EP3 agonist, a nitric oxide donor prostaglandin compound, or a combination thereof.

40. The composition of claim 39, wherein the prostaglandin compound is bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprostone, tafluprost, or tafluprost acid.

41. The composition of claim 39, wherein the prostaglandin EP2 agonist is taprenapag isopropyl ester or omepag isopropyl ester.

42. The composition of claim 39, wherein the prostaglandin EP3 agonist is dinoprostone, misoprostol, limaprost, gemcitabine, alprostadil, or livanprost.

43. The composition of claim 39, wherein the nitric oxide donor prostaglandin compound is latanoprostone bromoprost.

44. The composition of claim 38, wherein the β-blocker is timolol, betalol, levobunolol, or metenolol.

45. The composition of claim 38, wherein the α-agonist is bromonidine or aclomid.

46. ​​The composition of claim 38, wherein the carbonic anhydrase inhibitor is brinzolamide, acetazolamide, dzodamine, or acetazolamide.

47. The composition of claim 38, wherein the cholinergic agent is pilocarpine or carbachol.

48. The composition of claim 38, wherein the rho kinase inhibitor is nertadil.

49. The composition of claim 37, wherein the CNTF analog is SEQ ID NO: 18, SEQ ID NO: 1, SEQ ID NO: 2 or recombinant CNTF.

50. The composition of claim 37, wherein the FAS inhibitor is a bicyclic alcohol, FLIP, MET12 (SEQ ID NO: 3), compound 1 (SEQ ID NO: 5), compound 2 (SEQ ID NO: 6), compound 3 (SEQ ID NO: 7), compound 4 (SEQ ID NO: 8), compound 5 (SEQ ID NO: 9), compound 6 (SEQ ID NO: 10), compound 7 (SEQ ID NO: 11), compound 8 (SEQ ID NO: 12), compound 9 (SEQ ID NO: 13), compound 10 (SEQ ID NO: 14), compound 11 (SEQ ID NO: 15), ONL1204, SEQ ID NO: 4, FAIM, NOL3, human decoy receptor 1 (DcR1), human decoy receptor 2 (DcR2), or human decoy receptor 3 (DcR3).

51. The composition of claim 37, wherein the TNF-α inhibitor is etanercept, infliximab, golimumab, sertozumab, adalimumab, TNFR1-selective antagonistic mutant TNF (RlantTNF), DMS5540, TNF receptor-silencer (TROS), or ATROSAB.

52. The composition of claim 38, wherein the cannabinoid receptor agonist is Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), arachidonic acid ethanolamine, 2-arachidonic glycerol, 1,1-dimethylheptyl-11-hydroxytetrahydrocannabinol (HU-210), ( cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthyl ketone (R-(+)-WIN55212), (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthyl ketone (JWH-015), 3-(1,1-dimethylbutyl)-6,6,9-trimethyl-6α,7,10,10α-tetrahydro-6H-benzo[c]chromene (JWH-133) Onternabez (HU-308), 1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole (AM1241), 1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole (GW405833), 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro-2H-pyronin-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide (GW842166X) or 1-(4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl)-3-methylcyclohexanol (O-1966).

53. The composition of any one of claims 36-52, wherein the concentration of the free active pharmaceutical ingredient is from about 1% by weight to about 20% by weight.

54. The composition of any one of claims 36-53, wherein the concentration of said hyaluronic acid is from about 0.1% by weight to about 5% by weight.

55. The composition of any one of claims 36-54, wherein the composition further comprises a second polymer.

56. The composition of claim 55, wherein the second polymer is collagen or poloxamer.

57. The composition of claim 56, wherein the poloxamer is Pluronic® L64, Pluronic® P65, Pluronic® P84, Pluronic® P85, Pluronic® F88, Pluronic® P103, Pluronic® P104, Pluronic® P105, Pluronic® F108, Pluronic® F123, or Pluronic® F127.

58. The composition of any one of claims 36-57, wherein the concentration of said hyaluronic acid is from about 1 mg / mL to about 10 mg / mL.

59. The composition of any one of claims 36-58, wherein the concentration of the second polymer is from about 1 mg / mL to about 250 mg / mL.

60. The composition of claim 59, wherein the concentration of the second polymer is from about 1 mg / mL to about 5 mg / mL.

61. The composition of any one of claims 36-60, wherein the combined active pharmaceutical ingredient is released over a period of about 6 months to about 24 months.

62. The composition of any one of claims 36-60, wherein the free active pharmaceutical ingredient is released over a period of about 6 months to about 24 months.

63. The composition of any one of claims 36-62, wherein the hyaluronic acid is a hydrogel.

64. The composition of any one of claims 36-62, wherein the composition is a solid implant.

65. A method of delivering an active pharmaceutical ingredient to the anterior chamber, posterior chamber, suprachoroidal space, or vitreous body of one or both eyes of a subject in need, the method comprising injecting hyaluronic acid as claimed in any one of claims 1-35 or a composition as claimed in any one of claims 36-63 into one or both eyes of the subject or implanting a composition as claimed in claim 64 into one or both eyes of the subject.

66. A method for treating glaucoma, age-related macular degeneration (AMD), macular degeneration (MD), uveitis, retinal vein occlusion, macular edema, macular capillary dilation, endophthalmitis, retinitis, lens dysfunction syndrome (DLS), Fuchs' dystrophy, Shoegren's syndrome, Staggett's disease, cataract, diabetic retinopathy, ocular hypertension, optic neuritis, corneal dystrophy, keratitis, scleritis, amblyopia, strabismus, blepharitis, blepharospasm, central retinal vein occlusion, defect, ocular histoplasmosis syndrome, conjunctivitis, presbyopia, or dry eye in a subject, the method comprising applying hyaluronic acid as described in any one of claims 1-35 or a composition as described in any one of claims 36-63 to one or both eyes of the subject or implanting a composition as described in claim 64 into one or both eyes of the subject.

67. The method of claim 66, wherein the composition is applied to or implanted into the anterior chamber, posterior chamber, suprachoroidal space, or vitreous body of one or both eyes of the subject.

68. The method of claim 66 or 67, wherein the glaucoma is open-angle glaucoma, closed-angle glaucoma, congenital glaucoma, or secondary glaucoma.

Images