Intracanalicular hydrogel inserts for delivery of anesthetics

Abstract

To provide safe and effective pharmaceutical compositions which allow for the sustained release of ophthalmic anesthetics.SOLUTION: A biodegradable ophthalmic hydrogel composition comprises an anesthetic and a polymer network, wherein the anesthetic is delivered to the eye in a sustained manner for about 12 hours or longer. Preferably, the polymer network comprises a plurality of polyethylene glycol (PEG) units, and more preferably, the polymer network comprises a plurality of multi-arm PEG units having from 4 to 8 arms.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 838,789, filed Apr. 25, 2019, the contents of which are hereby incorporated by reference in their entirety.

Background Art

[0002] Eye trauma, specifically corneal abrasion or corneal detachment, is a common injury that can be extremely painful. In clinical practice, ophthalmic anesthetics (such as bupivacaine (BPI), proparacaine, and tetracaine) are commonly used. However, these drugs are typically administered as eye drops, and their onset of action is rapid (0.25 - 10 minutes), and their duration of action is limited (up to 30 minutes). Furthermore, the concentration of these drugs required to achieve corneal anesthesia is 0.2 - 5% - 4%. At these concentrations, ophthalmic anesthetics can temporarily damage the superficial corneal epithelium. If used frequently or at overlapping times, these injuries can progress to extensive corneal epithelial erosion and grayish corneal stromal infiltration. This can lead to permanent scarring and blindness. Long - term application of ophthalmic anesthetics is also further associated with delayed corneal re - epithelialization after injury, tear changes, corneal swelling, and disruption of epithelial cell mitosis and migration. Due to concerns about the short duration of action and the potential for toxicity of current ophthalmic anesthetics, it is not possible to widely use such ophthalmic anesthetics in chronic pain conditions and time - consuming ophthalmic clinical procedures. Furthermore, there are concerns about potential toxicity associated with overuse.

[0003] Therefore, physicians are reluctant to offer patients the option of self-administering ophthalmic anesthetics. hesitate.

[0004] In ophthalmology, there is a clinical need for formulations that contain one or more ophthalmic anesthetics and have improved safety and efficacy to extend the duration of pain management. Safety and effectiveness have been improved, and the formulation is clinically required. SUMMARY OF THE INVENTION

[0005] This specification provides a safe and effective hydrogel composition that enables sustained release of one or more ophthalmic anesthetics. The use of such a hydrogel composition in the treatment or prevention of ocular discomfort (such as eye pain) is also provided. gel composition is provided. The use of such a hydrogel composition in the treatment or prevention of ocular discomfort (such as eye pain) is also provided. gel composition is also provided.

[0006] The disclosed composition effectively delivered a therapeutic dose of the anesthetic bupivacaine to male beagle dogs with corneal wounds over a period of about 5 days, substantially reducing corneal sensation. For example, see Table 4. This table shows that the concentration of bupivacaine present in the tear fluid increased for 4 days and then began a steady decline on the 5th day. No substantial difference in the corneal wound healing rate was observed between the treated and untreated dogs. of the anesthetic bupivacaine was effectively delivered, and corneal sensation was substantially reduced. For example, see Table 4. This table shows that the concentration of bupivacaine present in the tear fluid increased for 4 days and then began a steady decline on the 5th day. No substantial difference in the corneal wound healing rate was observed between the treated and untreated dogs. Refer to this table. This table shows that after the concentration of bupivacaine present in the tear fluid increased for 4 days, a steady decline began on the 5th day. showed that a steady decline began on the 5th day. There was no substantial difference in the corneal wound healing rate between the treated dogs and the untreated dogs. No substantial difference in the corneal wound healing rate was observed between the treated and untreated dogs.

[0007] In a comparison between the eyes treated with the inventive composition containing bupivacaine and the untreated control, the disclosed composition had no negative effect on the corneal wound healing rate. See Figure 6. Furthermore, composition had no negative effect on the corneal wound healing rate. See Figure 6. Furthermore, even when the disclosed composition containing bupivacaine was administered intratubularly, no negative effect on the overall health of the animals was observed. No negative effect on the overall health of the animals was observed. BRIEF DESCRIPTION OF THE DRAWINGS

[0008]

Figure 1A

Figure 1B

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

DETAILED DESCRIPTION OF THE INVENTION

[0009] Provided herein is an ophthalmic hydrogel composition comprising an anesthetic and a polymer network, and the anesthetic is delivered over a long period of time (e.g., 12 hours or more).

[0010] Also provided herein are methods, uses, and pharmaceutical formulations for treating or preventing ocular discomfort in a subject, which comprise administering the ophthalmic hydrogel composition to the subject's eye in a therapeutically effective amount.

[0011] Further provided is a process for preparing the disclosed ophthalmic hydrogel composition.

[0012] 1. Definitions The term "biodegradable" refers to a substance (such as the disclosed ophthalmic hydrogel composition) that degrades in vivo. The degradation of the substance occurs over time, and this degradation is simultaneous with the release of the anesthetic or can occur after the release of the anesthetic. In one aspect, "biodegradability" means complete dissolution of the ophthalmic composition, i.e., no residual composition remains, e.g., in the subject's eye. In an alternative aspect, degradation can occur independently of the release of the anesthetic, such that, for example, a residual composition remains after degradation.

[0013] The term "polymer network" refers to a group of polymers that include multiple branched structures ( arms) crosslinked with other polymer chains. Such polymer chains can be of the same or different chemical structures (e.g., as found in complementary or non-complementary repeating units). They can be.

[0014] The naming of the synthetic precursors used to generate the disclosed polymer networks is done using the number of arms, next the MW of the PEG, and then the reactive group (e.g., an electrophilic or nucleophilic group). For example, 4a20K PEG SAZ refers to a 20,000 Da PEG having 4 arms with azelaic acid succinimidyl end groups, 4a20K PEG S AP refers to a 20,000 Da PEG having 4 arms with adipic acid succinimidyl end groups, 4a20K PEG SG refers to a 20,000 Da PEG having 4 arms with glutaric acid succinimidyl end groups, 4a20K PEG SS refers to a 20,000 Da PEG having 4 arms with succinic acid succinimidyl end groups, etc. Similarly, 4a20K PEG NH2 means a 20,000 Da PEG having 4 arms with amine end groups, 8a20K PEG NH2 means a 20,000 Da PEG having 8 arms with amine end groups. Examples of such measures include:

[0015] The term "clearance zone" refers to the area of ​​the hydrogel prior to or after the release of the anesthetic agent. The term "clearance zone" and "zone" refer to the area where no undissolved anesthetic particles are present after injection. The terms "clearance" and "clearance zone" are used interchangeably. Figure 1 shows an example of a clearance zone. As shown, the clearance zone is formed by the undissolved cellulose contained in the hydrogel composition. Provides a protective barrier between the dissolved anesthetic (e.g., undissolved anesthetic) and adjacent tissues in the eye. Without wishing to be bound by theory, the reason for this is that the surface concentration is proportional to the solubility of the anesthetic in water. As the properties of the polymer network change, For example, as the polymer network gradually degrades, the anesthetic is released By first passing through a clearance zone before coming into direct contact with the eyes. The anesthetic continues to be released from the hydrogel composition. In one aspect, the release of the anesthetic is driven by its solubility. The force acting on the polymer network is the force acting on the polymer network, except for the dimensional changes that accompany the polymer transformation. In some embodiments, the overall size of the clearance zone is not affected by changes in The clearance increases with the progression of release of the anesthetic from the hydrogel composition. It is desirable to balance the size of the zone with the degradation rate of the hydrogel composition. The polymer is then added so that the hydrogel degrades with increasing clearance zone size. The rate of water decomposition is matched to the solubility of the anesthetic, so that the hydrolysis occurs almost simultaneously with the disappearance of the anesthetic. This results in the loss of the signal.

[0016] The term "amorphous" refers to the appearance of a polymer or polymers in X-ray or electron scattering experiments. - A network does not exhibit a crystalline structure.

[0017] The term "semicrystalline" refers to a polymer or polymer network having some crystalline characteristics, i.e., exhibiting crystalline properties in a thermal analysis experiment, an X-ray scattering experiment, or an electron scattering experiment. In some embodiments, a "semicrystalline" polymer or a "semicrystalline" polymer network has a highly ordered molecular structure with a sharp melting point. In some embodiments, a "semicrystalline" polymer or a "semicrystalline" polymer network does not soften gradually as the temperature increases, but instead retains its solid state until a given amount of heat is absorbed, after which it rapidly changes to a rubber or liquid state with a sharp decrease.

[0018] As used herein, "uniformly dispersed" means that the component (such as an anesthetic) is uniformly dispersed throughout the entire hydrogel or polymer network, except for the portion containing the clearance zone.

[0019] The terms "treat", "treating", or "treatment" are used interchangeably and refer to causing one or more of the following with respect to the ocular discomfort or its symptoms described herein: improvement, alleviation, delay in onset, or inhibition of progression.

[0020] The terms "prevent", "preventing", or "prevention" are used interchangeably and include preventing recurrence, spread, or occurrence of the disclosed ocular discomfort. Prevention also includes administering the provided composition to eliminate the sensation of pain before the onset of ocular discomfort (e.g., to eliminate the sensation before a surgical or non-invasive procedure on the eye).

[0021] The terms "subject" and "patient" can be used interchangeably and refer to a mammal in need of treatment and such mammals include, for example, companion animals (e.g., dogs, cats, and the like), livestock (e.g., cows, pigs, horses, sheep, goats, and the like) , as well as laboratory animals (e.g., rats, mice, guinea pigs, and the like). Typically, the subject is a human in need of treatment.

[0022] The term "effective amount" or "therapeutically effective amount" refers to the amount of the disclosed composition that will induce a biological or medical response in a subject. It will be understood that the specific dosage regimen and treatment regimen for any particular patient will depend on a variety of factors. Such factors include the activity of the specific protein used, age, weight, general health, sex, diet, time of administration, rate of excretion, the judgment of the treating physician, and the severity of the specific condition being treated or prevented.

[0023] 2. Compositions As part of a first embodiment, provided herein is a biodegradable hydrogel composition comprising an anesthetic and a polymer network, wherein the anesthetic is delivered to the eye in a sustained-like

[0024] manner over about 12 hours or more. As part of a second embodiment, the polymer network of the disclosed hydrogel composition (e.g., as described for the first embodiment) comprises a plurality of polyethylene glycol (PEG) units. Alternatively, as part of a second embodiment, the polymer network of the disclosed hydrogel composition (e.g., as described for the first embodiment) comprises a plurality of multi-arm PEG units.

[0025] ​​​​ As part of the third embodiment, the plurality of polyethylene glycol (PEG) units contained in the disclosed composition are crosslinked to form a polymer network containing a plurality of multi-arm PEG units having at least two arms, and the remaining features of the composition are those described herein (e.g., those described for the first embodiment or the second embodiment). Alternatively, as part of the third embodiment, the polymer network of the disclosed composition contains a plurality of multi-arm PEG units having 2 to 10 arms, and the remaining features of the composition are those described herein (e.g., those described for the first embodiment or the second embodiment). Another option is that, as part of the third embodiment, the polymer network of the disclosed composition contains a plurality of multi-arm PEG units having 4 to 8 arms, and the remaining features of the composition are those described herein (e.g., those described for the first embodiment or the second embodiment). Another option is that, as part of the third embodiment, the polymer network of the disclosed composition contains a plurality of 4-arm PEG units, and the remaining features of the composition are those described herein (e.g., those described for the first embodiment or the second embodiment). Another option is that, as part of the third embodiment, the polymer network of the disclosed composition contains a plurality of 8-arm PEG units, and the remaining features of the composition are those described herein (e.g., those described for the first embodiment or the second embodiment). As part of the fourth embodiment, the polymer network of the disclosed composition contains a plurality of PEG units having a number average molecular weight (Mn) of about 5 kDa to about 50 kDa, and the remaining features of the composition are those described herein.

[0026] ​​​​​​​​​​​​The features are those described herein (e.g., those described for the first to third embodiments). Alternatively, as part of the fourth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having a number average molecular weight (Mn) of about 5 kDa to about 40 kDa, and the remaining features of the composition are those described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the po lymer network of the disclosed composition has a number average molecular weight (Mn) of about 5 kDa to about 30 kDa and comprises a plurality of PEG units, and the remaining features of the composition are those described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having a number average molecular weight (Mn) of about 10 kDa to about 50 kDa, and the remaining features of the composition are those described herein (e.g., those described for the first to third embodiments). In another option, the polymer network of the disclosed composition, as part of the fourth embodiment, has a number average molecular weight (Mn) of about 10 kDa to about 40 kDa and comprises a plurality of PEG units, and the remaining features of the composition are those described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition has a number average molecular weight (Mn) of about 10 kDa to about 30 kDa and comprises a plurality of PEG units, and the remaining features of the composition are those described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition has a number average molecular weight (Mn) of about 10 kDa to about 20 kDa and comprises a plurality of PEG units, and the remaining features of the composition are those described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition has a number average molecular weight (Mn) of about 10 kDa to about comprising a plurality of PEG units, and the remaining features of the composition are those described herein (e.g., as described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having a number average molecular weight (Mn) of about 30 kDa to about 50 kDa, and the remaining features of the composition are those described herein (e.g., as described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having a number average molecular weight (Mn) of about 35 kDa to about 45 kDa, and the remaining features of the composition are those described herein (e.g., as described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having a number average molecular weight (Mn) of about 15 kDa to about 30 kDa, and the remaining features of the composition are those described herein (e.g., as described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having a number average molecular weight (Mn) of about 15 kDa to about 25 kDa, and the remaining features of the composition are those described herein (e.g., as described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having a number average molecular weight (Mn) of at least about 5 kDa, and the remaining features of the composition are those described herein (e.g., as described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having a number average molecular weight (M n) of about 15 kDa to about 25 kDa, and the remaining features of the composition are those described herein (e.g., as described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having a number average molecular weight of at least about 5 kDa, and the remaining features of the composition are those described herein (e.g., as described for the first to third embodiments). In another option, the remaining features of the composition are those described herein (e.g., as described for the first to third embodiments). In another option, In the limbs, as part of the fourth embodiment, the polymer network of the disclosed composition contains a plurality of PEG units having a number average molecular weight (Mn) of at least about 10 KDa, and the remaining features of the composition are as described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition contains a plurality of PEG units having a number average molecular weight (Mn) of at least about 15 KDa, and the remaining features of the composition are as described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition contains a plurality of PEG units having a number average molecular weight (Mn) of at least about 20 KDa, and the remaining features of the composition are as described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition contains a plurality of PEG units having a number average molecular weight (Mn) of at least about 30 KDa, and the remaining features of the composition are as described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition contains a plurality of PEG units having a number average molecular weight (Mn) of at least about 40 KDa, and the remaining features of the composition are as described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the polymer network of the disclosed composition contains a plurality of PEG units having a number average molecular weight (Mn) of about 10 KDa, and the remaining features of the composition are as described herein (e.g., those described for the first to third embodiments). ​ ) It is. In another option, as part of the fourth embodiment, the polymer network of the disclosed composition work contains a plurality of PEG units having a number average molecular weight (Mn) of about 15 KDa, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the poly mer network of the disclosed composition contains a plurality of PEG units having a number average molecular weight (Mn) of about 20 KDa, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to third embodiments). In another option, as part of the fourth embodiment, the disclosed composition polymer network contains a plurality of PE G units having a number average molecular weight (Mn) of about 40 KDa, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to third embodiments).

[0027] In the fifth embodiment, the polymer network of the disclosed composition contains a plurality of PEG units crosslinked by a hydrolyzable linker, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to fourth embodiments). Alternatively, as part of the fifth embodiment, the polymer network of the disclosed composition contains a plurality of PEG units crosslinked by a hydrolyzable linker having the formula

Chemical formula

[0028] In the sixth embodiment, the polymer network of the disclosed composition is formed by reacting a plurality of polyethylene glycol (PEG) units containing nucleophilic attack-susceptible groups with one or more nucleophilic groups such that the polymer network is formed , and the remainder of the composition is as described herein (e.g., as described for the first to fifth embodiments). . Examples of suitable groups susceptible to nucleophilic attack include, but are not limited to, activated esters (e.g thioesters, succinimidyl esters, benzotriazolyl esters, acrylic esters of acids, and the like). Examples of suitable nucleophilic groups include, but are not limited to, amines and thiols.

[0029] In a seventh embodiment, the polymer network of the disclosed composition has the molecular weights described above for the fourth embodiment and includes a plurality of polyethylene glycol (PEG) units having groups susceptible to nucleophilic attack, and one or more of the PEG units are reacted with a nucleophilic group so as to form the polymer network, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to sixth embodiments). Alternatively, as part of the seventh embodiment, the polymer network of the disclosed hydrogel implant has the molecular weights described above for the fourth embodiment and includes a plurality of polyethylene glycol (PEG) units having succinimidyl ester groups, and one or more of the PEG units are reacted with a nucleophilic group so as to form the polymer network, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to fourth embodiments). In another option, as part of the seventh embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units selected from 4a20K PEG SAZ, 4a20K PEG SAP 4a20K PEG SG, 4a20K PEG SS, 8a20K PEG SAZ 8a20K PEG SAP, 8a20K PEG SG, 8a20K PEG SS and the remaining characteristics of the composition are those described herein (e.g., those described for the first to sixth embodiments). ​​​​​​​​​

[0030] In the eighth embodiment, the polymer network of the disclosed composition is susceptible to nucleophilic attack by reacting a plurality of polyethylene glycol (PEG) units containing groups susceptible to nucleophilic attack with one or more amine groups such that the polymer network is formed and the remaining characteristics of the composition are those described herein (e.g., those described for the first to seventh embodiments). Alternatively, as part of the eighth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG ) units containing groups susceptible to nucleophilic attack with one or more PEG-based or lysine-based amine groups such that the polymer network is formed, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to seventh embodiments). Another option is that, as part of the eighth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units containing groups susceptible to nucleophilic attack with one or more PEG-based or lysine-based amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2, and trilysin, and its salts such that the polymer network is formed, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to seventh embodiments). is that, as part of the eighth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units containing groups susceptible to nucleophilic attack with one or more PEG-based or lysine-based amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2, and trilysin, and its salts such that the polymer network is formed, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to seventh embodiments). such that the polymer network is formed, and the remaining characteristics of the composition are those described herein (e.g., those described for the first to seventh embodiments).

[0031] As part of the ninth embodiment, the polymer network of the disclosed composition is amorphous (e.g., under aqueous conditions (such as in vivo)), and the remaining characteristics of the composition are those described herein (e.g., those described for the first to eighth embodiments). Alternatively, for the ninth ​​​​​​​​As part of an embodiment, the polymer network of the disclosed composition is semi-crystalline (e.g., in the absence of water below), and the remaining features of the composition are those described herein (e.g., those described for the first through eighth embodiments).

[0032] As part of a tenth embodiment, the anesthetic inhibitor of the disclosed composition is uniformly dispersed (e.g., as microparticles) within the polymer network, and the remaining features of the composition are those described herein (e.g., those described for the first through ninth embodiments).

[0033] As part of an eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 6 hours to about 20 days, and the remaining features of the composition are those described herein (e.g., those described for the first through tenth embodiments). Alternatively, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 20 days, and the remaining features of the composition are those described herein (e.g., those described for the first through tenth embodiments). Another option is that, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 15 days, and the remaining features of the composition are those described herein (e.g., those described for the first through tenth embodiments). Another option is that, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 10 days, and the remaining features of the composition are those described herein (e.g., those described for the first through tenth embodiments). Another option is that, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about ​​​​​​​​Delivered to the eye in a sustained manner over 12 hours to about 9 days, and the remaining characteristics of the composition are those described in this specification (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 8 days, and the remaining characteristics of the composition are those described in this specification (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 7 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 7 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 7 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 6 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 6 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 6 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 5 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 5 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 5 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 4 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 4 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 4 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 3 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 3 days (for example, those described for the first to tenth embodiments). In another option, as part of the eleventh embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 3 days (for example, those described for the first to tenth embodiments). In another option In the case of a part of the 11th embodiment, the anesthetic of the disclosed composition is delivered to the eye in a sustained manner over about 12 hours to about 2 days and the remaining features of the composition are those described herein (e.g., those described for the 1st to 10th embodiments). In another option, as part of the 11th embodiment, the anesthetic of the disclosed composition is for about 18 hours to about 10 days, 18 hours to about 9 days, 18 hours to about 8 days, 18 hours to about 7 days, 18 hours to about 6 days, 18 hours to about 5.5 days, 18 hours to about 5 days, about 18 hours to about 4.5 days, 18 hours to about 4 days, about 18 hours to about 3.5 days, 18 hours to about 3 days, about 18 hours to about 2.5 days, 18 hours to about 2 days, about 24 hours to about 10 days, 24 hours to about 9 days, 24 hours to about 8 days, 24 hours to about 7 days, 24 hours to about 6 days, 24 hours to about 5.5 days, 24 hours to about 5 days, about 24 hours to about 4.5 days, 24 hours to about 4 days, about 24 hours to about 3.5 days, 24 hours to about 3 days, about 24 hours to about 2.5 days, 24 hours to about 2 days, or about 24 hours, about 3 6 hours, about 2 days, about 2.5 days, about 3 days, about 3.5 days, about 4 days, about 4.5 days, about 5 days, about 5.5 days, about 6 days, about 6.5 days, about 7 days, about 7.5 days, about 8 days , about 8.5 days, about 9 days, about 9.5 days, or about 10 days and is delivered to the eye in a sustained manner and the remaining features of the composition are those described herein (e.g., those described for the 1st to 10th embodiments).

[0034] As part of the 12th embodiment, the anesthetic in the disclosed composition is microencapsulated and the remaining features of the composition are those described herein (e.g., those described for the 1st to 11th embodiments). ​​

[0035] As part of the thirteenth embodiment, the anesthetic in the disclosed composition is a lactic acid-glycolic acid copolymer. Polylactide (PLGA) or polylactic acid (PLA), or a combination of both, is used to The remaining characteristics of the composition are as described herein (e.g., 1 to 12 of the embodiment. Alternatively, a part of the 13th embodiment. As such, the anesthetic in the disclosed composition is microencapsulated with PLGA, The remaining characteristics of the composition are as described herein (e.g., for the first to twelfth embodiments). (as described above).

[0036] Anesthetic agents that may be used in the compositions described herein include those suitable for ophthalmic use. As part of the fourteenth embodiment, the anesthetic in the disclosed composition is bupivacaine, ribavirin, Docaine, proparacaine, tetracaine, dibucaine, benoxinate, ropivacaine , articaine, carbocaine, marcaine, mepivacaine, poloc Choose from aine, prilocaine, sensorcaine, and septocaine and the remaining characteristics of the composition are as described herein (e.g., the first to thirteenth embodiments). Alternatively, as part of a fourteenth embodiment, the disclosed composition The anesthetic agent used was chosen from bupivacaine, lidocaine, proparacaine, and tetracaine. and the remaining characteristics of the composition are as described herein (e.g., the first to thirteenth embodiments). In another alternative, as part of the fourteenth embodiment, The anesthetic agent of the composition described herein is bupivacaine, and the remaining characteristics of the composition are as described herein. These are the ones described in the first to thirteenth embodiments (for example, those described in the first to thirteenth embodiments).

[0037] As part of a fifteenth embodiment, the hydrogel compositions described herein may be used to enhance the release of anesthetic agents. a clearance zone where no anesthetic (e.g., undissolved anesthetic) is present prior to the composition The remaining features are as described herein (e.g., as described for the first to fourteenth embodiments). By way of example, in one aspect of this embodiment, the particulate anesthetic is a hydrogel polymer. It is included in the radar network but not in the clearance zone. Based on the design and properties of the polymer network, only the dissolved anesthetic is cleared. The fluid passes through the sensory zone, exits the hydrogel and enters the eye.

[0038] As part of the sixteenth embodiment, the anesthetic in the compositions described herein is at its saturation level. The remaining characteristics of the composition are as described herein. The above-mentioned embodiments are described in the document (for example, the first to fifteenth embodiments).

[0039] As part of the seventeenth embodiment, the hydrogel compositions described herein are used in the clearance zone. The size of the clearance zone increases with the amount of anesthetic released, and the remaining The features of the present invention are as described in the present specification (for example, the first to sixteenth embodiments). ) is.

[0040] As part of an eighteenth embodiment, the hydrogel compositions described herein are used in an intracanalicular insert. and the remaining characteristics of the composition are as described herein (e.g., as described in the first to fourth paragraphs). 17 embodiment).

[0041] As part of the 19th embodiment, the hydrogel composition described herein is in the form of an insert for delivery to the palpebral part of the eye, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 18th embodiments). The remaining features of the composition are as described herein (e.g., those described for the 1st to 18th embodiments). (e.g., those described for the 1st to 18th embodiments).

[0042] As part of the 20th embodiment, the hydrogel composition completely decomposes after the anesthetic has been completely released, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). Alternatively, as part of the 20th embodiment, the hydrogel implant completely decomposes about 12 months, about 11 months, about 10 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, about 1 month (i.e., about 30 days) after the anesthetic has been completely released, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). Alternatively, as part of the 20th embodiment, the hydrogel implant completely decomposes after at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the anesthetic has been released, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). the hydrogel implant completely decomposes after at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the anesthetic has been released, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). the hydrogel implant completely decomposes about 12 months, about 11 months, about 10 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, about 1 month (i.e., about 30 days) after the anesthetic has been completely released, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). months, about 2 months, about 1 month (i.e., about 30 days) after the anesthetic has been completely released, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). The remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). (e.g., those described for the 1st to 19th embodiments). the hydrogel implant completely decomposes after at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the anesthetic has been released, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). 3%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the anesthetic has been released, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). The remaining features of the composition are as described herein (e.g., those described for the 1st to 19th embodiments). (e.g., those described for the 1st to 19th embodiments). (e.g., those described for the 1st to 19th embodiments).

[0043] As part of the 21st embodiment, the hydrogel composition further comprises fluorescein, and the remaining features of the composition are as described herein (e.g., those described for the 1st to 20th embodiments). The remaining features of the composition are as described herein (e.g., those described for the 1st to 20th embodiments). (e.g., those described for the 1st to 20th embodiments).

[0044] Methods, Processes, and Uses The disclosed hydrogel compositions are useful for the treatment and prevention of ocular discomfort. Accordingly, the present specification provides a method for treating or preventing ocular discomfort in a subject, the method comprising administering to the subject an effective amount of the composition described herein. The use of the disclosed composition for the treatment or prevention of ocular discomfort in a subject is also disclosed. The use of the disclosed composition in the manufacture of a medicament for treating or preventing ocular discomfort is further provided .

[0045] Ocular discomfort includes the absence of comfort in or around one or both eyes. This includes, for example, foreign body sensations (a gritty feeling, a sandy feeling, a scratchy feeling, etc.) (upon blinking), a feeling that something is in the eye, a feeling that there are sand grains or eyelashes in the eye, a burning sensation, an ocular sting, irritation, pain, dryness, itching or a scratching desire (e.g., caused by an allergic reaction), pain (throbbing, eye strain, deep pain / dull pain (orbital pain / brow pain), heaviness, headache around the eyes, sharp pain, a stabbing feeling, a feeling of being pricked with a sharp pin, a throbbing pain, a recurrent pain, a pulsating feeling, pain during movement, and tenderness (upon contact), etc.), fatigue associated with conditions (such as tiredness), a need to close the eyes / a desire to close the eyes, difficulty opening and closing the eyes, and a feeling that it is more comfortable to keep the eyes closed, allergic reactions (e.g., photosensitivity, sensitivity to wind), discharge (secretion, tearing, watering, discharge (malodorous substances), mucus, crusts etc.), autonomic symptoms (a feeling of heat, a feeling of warmth, a feeling of cold, etc.), pain associated with eye movement, and general congestion, a prickling sensation, and blinking. Ocular discomfort can also be caused by trauma, infection, inflammation, or surgery. ​​​​​​​​

[0046] In one aspect, the ocular discomfort to be treated or prevented described herein is pain. In another aspect, the ocular discomfort to be treated or prevented described herein is pain caused by surgery. In another aspect, the ocular discomfort to be treated or prevented described herein is pain after intraocular injection. In another aspect, the ocular discomfort to be treated or prevented described herein is corneal detachment or corneal trauma. In another aspect, the ocular discomfort to be treated or prevented described herein is caused by an infectious condition of the eye.

Examples

[0047] 1. Materials and Methods Bupivacaine microspheres were produced using bupivacaine free base (BFB) (Spectrum Chemical, product number: B2353) and PLGA (Sigma-Aldrich , PN: 719897, Resomer RG 502H). BFB (814 mg) and PLGA (804 mg) were mixed and dissolved in dichloromethane (3.155 g ) (Sigma Aldrich, SHBH9222) to create a dispersion phase (DP). Polyvinyl alcohol (Spectrum Chemical, 2GK0231) was included at 0.5% and sodium chloride (Spectrum Chemical, 1FI0675) was included at 2.5%, saturated with BFB, and the pH was adjusted to 10.5 using 1 M tripotassium phosphate (Sigma Aldrich, MKCF3247) to obtain a continuous phase (CP) (500 mL). This CP (500 mL) was added to a jacketed reactor (500 mL , Wilmad Lab Glass, LG-8079B-100) and brought to approximately 5°C ... Balanced and stirred at 900 rpm. Using a syringe pump, DP was injected into CP via a 23G needle at a rate of 350 μL / min. The final volume ratio of DP to CP was set to 1:100 . After the injection, the temperature increase profile was set such that the time at 5 °C was 20 minutes, then the time at 20 °C was 1 hour, and thereafter the time at 30 °C was 2 hours. Thereafter, the hardened microspheres were collected and washed with a sufficient amount of water (7 L of RODI water at 20 - 25 o °C) to remove CP while fractionated with a sieve (20 - 53 μm). Next, the microspheres were transferred to a glass vial (10 mL ) and freeze-dried to dryness. Based on calculations by the weight of the starting material, the final yield was estimated to be 10%, and the drug encapsulation efficiency was estimated to be 96%.

[0048] By mixing BFB-PLGA microspheres with a pH modifier (sodium dihydrogen phosphate and disodium hydrogen phosphate) and a hydrogel precursor (PEG ester (4a20k SG, JenKem, C53-100801) and trilysin acetate (Bachem, 08-0 25)), the PEG concentration (wet weight) in the formulation was set to 14%, and the micro sphere concentration (wet weight) in the formulation was set to 20%. This mixed formulation was pushed into a silicone tube (inner diameter 1 .3 mm, Cole Parmer) before gelation occurred and cured at ambient temperature for 1 hour. Thereafter, the formulated hydrogel in the tube (length 16 cm) was stretched 2.5 times in a stretcher and dried in a glove bag under a nitrogen atmosphere for 72 hours . Thereafter, the dried bupivacaine / PLGA / hydrogel filament was taken out and cut into lengths of approximately 3 mm. These cut inserts were placed in a glass scintillation under a dry nitrogen atmosphere . After placing them in a vial (10 mL), they were put into a foil pouch and sealed. Next, these were sterilized by gamma-ray irradiation at 28.5 to 34.8 kGy. Table 1 shows the normalized bupivacaine-containing biodegradable ophthalmic hydrogel composition for pharmaceutical use (the "composition of the invention"). is shown.

Table 1

[0049] 2. Test design in male beagle dogs with corneal wounds Before treatment, all beagle dogs were given a clinical ophthalmic examination to conduct baseline observations. Seventeen beagle dogs were divided into three groups as shown in Table 2.

Table 2

[0050] On day 0, epithelial debridement was performed to create corneal wounds in both eyes (OU) of 10 female beagle dogs. The animals were monitored postoperatively and treated with eye drops. The composition of the invention (IC) containing approximately 160 μg of bupivacaine was inserted into the lower or upper eyelid punctum of one eye of all 10 dogs on day 0 after corneal wound creation and removed on day 7 after corneal wound creation. Clinical ophthalmic examinations (slit-lamp biomicroscopy) were performed once a day until day 7. Fluorescein staining was performed on day 0, day 3, day 5, and day 7 (Group 1) or day 0, day 2, day 4, and day 7 (Group 2), and slit-lamp photographs were taken. Corneal sensation measurements were taken at the baseline point, and on days 0, 3 - 7, 10 - 14, 31 - 35, and 38 - 42 (Group 1) or days 0 - 4, 7 - 11, 14, 28 - 32, and 35 - 39 (Group 2). were performed. The overall health status was assessed on days 1-11 (group 1) or days 1-8 (group 2). Observations and gross ocular examinations were performed once daily. Body weights were recorded before dosing and on day 7. Days 1, 4, and 5 (Group 1) or Days 1, 2, 3, and 4 (Group 2) Tear samples were collected using Schirmer test strips on the first, second, third, fourth, and fifth days. The two groups were sampled on staggered days to collect tear film samples on the day 1. The tear film test strips were collected in the morning before administration of eye drops to avoid dilution of the samples. Weights were recorded before and after collection, and pH was analyzed for bioanalysis by LC / MS. Samples were shipped to armOptima, LLC (Portage, MI).

[0051] Seven additional untreated (no corneal wound created + no inventive composition insert) female beagle dogs ( In group 3), corneal sensitivity measurements were performed for 7 days (2 days during acclimation, days 1-3, and days 6-7). did.

[0052] 3. Results and Discussion A. Pharmacokinetics and In Vitro Release The PK portion of this study evaluated the efficacy and safety of the compositions of the invention over a 5-day period following intravenous administration to beagle dogs. The concentration of bupivacaine released from the eye drops into the tears was measured, and the results are shown in Table 3. Tear samples were collected prior to administration of the eye drops to ensure that the bupivacaine concentration was not diluted. The PK profile observed showed that bupivacaine concentrations in tears increased by the fourth day and then increased by the fifth day. This indicates that the bupivacaine concentration decreased on the fifth day. refers to in vitro assays carried out in physiologically relevant media (PBS (pH 7.4) at 37°C). In a release test at 100° C., the release of bupivacaine from the composition of the invention was 100% as shown in FIG. This is consistent with the fact that it was demonstrated to be almost completed by the 5th day. Table 4 shows the release rate of bupivacaine calculated on a time basis from in vitro test analysis. After placement in the elution medium, bupivacaine is released at a maximum rate of 14.6 pg / h during the explosion period (0 - 1 hour), and thereafter, the release of bupivacaine gradually decreases over the first 5 days from sample collection, and the results show that the drug release is minimized from the 5th day to the 8th day. [Table 3] [Table 4]

[0053] B. Pharmacodynamic ability Corneal sensitivity was used as a measure of pharmacodynamic ability. Corneal sensitivity was recorded using a Cochet - Bo nnet corneal esthesiometer. This corneal esthesiometer is a nylon filament designed to apply a force that induces a reflex response in the dog's cornea, and this reflex response appears in the form of a blink or physical withdrawal. The length of the filament at the time this response occurs is recorded as the score. The smaller this score, the greater the force required to induce the response (shorter filament length). This force increases exponentially as the filament shortens.

[0054] Corneal sensitivity was compared among animals treated with the test substance (OS in groups 1 and 2: treatment with the composition of the invention + standard treatment after PRK), control animals (OD in groups 1 and 2: standard treatment after PRK), and naive control group 3 (OU: untreated). Figure 3 shows the mean results as the standard of the mean value Plotted with error (error bars), Figure 4 shows the integrated average results for the eyes treated with the test article, untreated eyes, and naive eyes.

[0055] At the time point of day 0 immediately after creating a corneal wound and administering the test article, corneal sensation decreased rapidly in both the eyes not treated with the inserted test article (the "untreated eyes") and the eyes treated with the inserted test article. In the eyes treated with the test article, there was a tendency for the decrease to progress further. One day after creating the corneal wound and administering the test article (day 1), corneal sensation was near baseline in the untreated eyes, and slightly decreased from baseline in the eyes treated with the test article. From day 2 to day 7, corneal sensation decreased moderately in the untreated eyes compared to the baseline level and the average corneal sensation level in the naive control (group 3), while a substantial and significant decrease occurred in the eyes treated with the test article. After day 7 (the day the test article was removed), the corneal sensation in the eyes treated with the test article increased and became equivalent to that of the untreated eyes at all subsequent time points. For the two weeks (up to 14 days) after creating the corneal wound, corneal sensation decreased moderately from baseline in both the treated and untreated wounded eyes. By four weeks after creating the corneal wound (after day 28), corneal sensation returned to the baseline level in both the treated and untreated wounded eyes and became equivalent to the average corneal sensation level in the naive control. The corneal sensation in the naive control (group 3) remained stable at all evaluation time points. In the perception measurement, in the wounded eyes not treated with the inventive inserted composition, if at baseline ... ... both the treated and untreated wounded eyes, corneal sensation returned to the baseline level and became equivalent to the average corneal sensation level in the naive control. The corneal sensation in the naive control (group 3) remained stable at all evaluation time points. points.

[0056] In the perception measurement, in the wounded eyes not treated with the inventive inserted composition, if at baseline Compared with the mean corneal sensation of naive control eyes (no corneal wound creation + no inventive insertion composition), a moderate decrease in corneal sensation was observed. This decrease was recognized from the second day after corneal wound creation and continued until two weeks had passed since corneal wound creation. A decrease in corneal sensation after corneal epithelial debridement has been reported in both rabbits and humans, and it has been clarified that a decrease in corneal sensation after corneal epithelial debridement is associated with corneal anesthesia. For example, see B abst, C.R. and Gilling, B.N. Bupivacaine: A R eview. Anesth. Prog. 25(3), 87 - 91(1978).

[0057] In the wounded eyes treated with the inventive composition, a substantially significant decrease in corneal sensation was observed compared to untreated eyes during the first week after corneal wound creation (Figs. 3 and 4). This difference was only observed while the inventive insertion composition was present, and after removing the inventive composition on the 7th day, the corneal sensation of the eyes treated with the inventive composition returned to a level equivalent to that of untreated wounded eyes. In eyes treated with the inventive composition and then the insert was removed, a moderate decrease in corneal sensation continued until two weeks had passed since corneal wound creation, similar to wounded eyes not treated with the inventive insertion composition. This is considered to reflect (as described above) the corneal anesthesia that occurs after corneal epithelial debridement.

[0058] By four weeks after corneal wound creation, the decrease in corneal sensation had resolved in all eyes. This is considered to reflect that epithelial nerve regeneration occurred after corneal epithelial regeneration after wound healing. Regarding such corneal epithelial nerve regeneration and its relationship with corneal sensation recovery In rabbits (dcLccuw A, Chan K. Corneal nerve r egeneration: correlation between morpholo gy and restoration of sensitivity. Invest Ophthalmol Vis Sci. 1989;30:1980 - 1990) and humans (Campos M et al. Corneal sensitivity af ter photorefractive keratectomy. Am J Oph thalmol. 1992 Jul 15;114(1):51 - 4), it has been reported to be seen during the recovery from

[0059] C. Safety and corneal wound healing No effects of the administration of the inventive composition on general health were observed. Slit - lamp ophthalmic examinations were per formed on groups 1 and 2, and not on group 3 (naive control). After corneal epithelial debridement, ocular irritation characterized by ocular hyperemia / conjunctival hyperemia, swelling, and / or discharge occurred in all wounded eyes. These symptoms resolved in all eyes within the first week after wound creation.

[0060] There was no difference in how the eyes were affected by any of these eye conditions between eyes treated with the inventive insertion composition and eyes not treated with an insert. All animals that had corneal wounds exhibited mild to substantial weight loss, which was presumed to be due to the neck collars placed on these animals interfering with feeding. Fluorescein staining was performed to measure wound size and healing. Damaged tissue was quantified by staining with fluorescein and imaging the cornea over time under blue light, as seen in Figure 5. The damaged tissue will fluoresce due to absorption of fluorescein staining, and this fluorescence can be quantified using imaging software.

[0061] The corneal wound area rapidly decreased in most eyes, and in some eyes, there was no measurable wound area as early as 2 - 3 days after wound creation. In 19 out of 20 wounded eyes, there was no measurable wound area within 7 days after wound creation. There was no substantial difference in the wound healing rate between eyes treated with the inventive insertion composition and eyes not treated with the inventive insertion composition (Figure 6).

[0062] While many embodiments have been described in this regard, it will be apparent that other embodiments utilizing the compounds and methods of the present disclosure can be obtained by modifying the basic examples of the inventors. Accordingly, it will be understood that the scope of the present disclosure is defined by the appended claims, rather than by the specific embodiments shown as examples. ​

Claims

**Claim 1** A biodegradable ophthalmic hydrogel composition comprising an anesthetic and a polymer network, wherein the anesthetic is delivered to the eye in a sustained manner over about 12 hours or more, said biodegradable ophthalmic hydrogel composition. **Claim 2** The hydrogel composition according to claim 1, wherein the polymer network comprises a plurality of polyethylene glycol (PEG) units. **Claim 3** The hydrogel composition according to claim 1 or claim 2, wherein the polymer network comprises a plurality of multi-arm PEG units having 2 to 10 arms. **Claim 4** The hydrogel composition according to any one of claims 1 to 3, wherein the polymer network comprises a plurality of multi-arm PEG units having 4 to 10 arms. **Claim 5** The hydrogel composition according to any one of claims 1 to 4, wherein the polymer network comprises a plurality of multi-arm PEG units having 4 to 8 arms. **Claim 6** The hydrogel composition according to any one of claims 1 to 5, wherein the polymer network comprises a plurality of multi-arm PEG units having 8 arms. **Claim 7** The hydrogel composition according to any one of claims 1 to 6, wherein the polymer network comprises a plurality of multi-arm PEG units having 4 arms. **Claim 8** The hydrogel composition according to any one of claims 1 to 5, wherein the polymer network comprises a plurality of PEG units having the formula: wherein n represents ethylene oxide repeating units and the dashed line represents the junction of the repeating units of the polymer network. **Claim 9** The hydrogel composition according to any one of claims 1 to 8, wherein the polymer network is formed by reacting a plurality of polyethylene glycol (PEG) units selected from 4a20K PEG SAZ, 4a20K PEG SAP, 4a20K PEG SG, 4a20K PEG SS, 8a20K PEG SAZ, 8a20K PEG SAP, 8a20K PEG SG, 8a20K PEG SS with one or more PEG-based or lysine-based amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2, and trilysin or a salt thereof. **Claim 10** The hydrogel composition according to any one of claims 1 to 9, wherein the polymer network is formed by reacting 4a20k PEG SG with trilysin or a salt thereof. ​ ​ ​ ​ 【Chemical 1】 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Product.

11. The hydrogel composition according to any one of claims 1 to 10, wherein the polymer network is amorphous under aqueous conditions.

12. The hydrogel composition according to any one of claims 1 to 11, wherein the polymer network is semicrystalline in the absence of water.

13. The hydrogel composition according to any one of claims 1 to 12, wherein the particulate anesthetic inhibitor is uniformly dispersed within the polymer network.

14. The hydrogel composition according to any one of claims 1 to 13, wherein the anesthetic is delivered to the eye in a sustained manner over about 12 hours to about 10 days.

15. The hydrogel composition according to any one of claims 1 to 14, wherein the anesthetic is delivered to the eye in a sustained manner over about 12 hours to about 7 days.

16. The hydrogel composition according to any one of claims 1 to 15, wherein the anesthetic is delivered to the eye in a sustained manner over about 12 hours to about 4 days.

17. The hydrogel composition according to any one of claims 1 to 16, wherein the anesthetic is delivered to the eye in a sustained manner over about 18 hours to about 4 days, about 24 hours to about 4 days, 12 hours to about 3.5 days, 18 hours to about 3.5 days, 24 hours to about 3.5 days, 12 hours to about 3 days, 18 hours to about 3 days, 24 hours to about 3 days, 12 hours to about 2.5 days, 18 hours to about 2.5 days, 24 hours to about 2.5 days, 12 hours to about 2 days, 18 hours to about 2 days, 24 hours to about 2 days, or about 24 hours, about 36 hours, about 2 days, about 2.5 days, about 3 days, about 3.5 days, or about 4 days.

18. The hydrogel composition according to any one of claims 1 to 17, wherein the anesthetic is microencapsulated.

19. The hydrogel composition according to any one of claims 1 to 18, wherein the anesthetic is microencapsulated using a lactic acid / glycolic acid copolymer (PLGA) or polylactic acid (PLA), or a combination thereof.

20. The hydrogel composition according to any one of claims 1 to 19, wherein the anesthetic is microencapsulated using PLGA.

21. The anesthetic is bupivacaine, lidocaine, proparacaine, tetracaine, dibucaine, benoxinate, ropivacaine, articaine, carbocaine, marcaine ​ ine, mepivacaine, polocaine, prilocaine, sensorcaine, and septocaine, the hydrogel composition according to any one of claims 1 to 20, selected from.

22. The hydrogel composition according to any one of claims 1 to 21, wherein the anesthetic is selected from bupivacaine, lidocaine, propanocaine, and tetracaine. selected.

23. The hydrogel composition according to any one of claims 1 to 22, wherein the anesthetic is bupivacaine. composition.

24. The hydrogel composition according to any one of claims 1 to 23, wherein the hydrogel composition contains a clearance zone in which undissolved anesthetic does not exist before the release of the anesthetic. zone.

25. The hydrogel composition according to any one of claims 1 to 24, wherein the anesthetic is present in the hydrogel composition at or near its saturation level. present.

26. The hydrogel composition according to any one of claims 1 to 25, wherein the size of the clearance zone increases in response to the anesthetic release amount. composition.

27. The hydrogel composition according to any one of claims 1 to 26, wherein the hydrogel composition is an intratubular insert. composition.

28. The hydrogel composition according to any one of claims 1 to 27, wherein the hydrogel composition is for delivery to the eyelid portion of the eye. composition.

29. The ophthalmic insert or insert according to any one of claims 1 to 28, wherein the hydrogel composition completely decomposes after the release of the anesthetic. insert.

30. A method for treating or preventing ocular discomfort in a subject, the method comprising administering the hydrogel composition according to any one of claims 1 to 29 in a therapeutically effective amount to the eye of the subject. including that.

31. The method according to claim 30, wherein the ocular discomfort is caused by trauma, dryness, infection, inflammation, surgery, irritation, or itching. caused.

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